新穎的hcv非結構多肽的製作方法

2023-05-12 00:44:41

專利名稱：新穎的hcv非結構多肽的製作方法
技術領域：
本發明涉及在抗HCV的免疫原性化合物中使用的突變型非結構C型肝炎病毒(「HCV」)多肽、製備和使用這些多肽的方法、以及含有這些多肽的免疫原性組合物。本發明還涉及含有(a)突變型非結構HCV多肽和(b)不是非結構HCV多肽的病毒多肽的組合物和使用這些組合物的方法。
背景技術：
現已認識到，HCV是遍及全世界的慢性肝炎和肝疾病的主要病因。據估計，世界上大約有4億人感染了HCV，佔世界人口的3％以上。
C型肝炎病毒是一種小型有包膜的RNA黃病毒，它含有約10kb的正鏈RNA基因組。該基因組具有編碼3010-3011個胺基酸的蛋白質的單一的未被中斷的ORF。HCV的結構蛋白質包括一個高度免疫原性的核心蛋白質(C)和兩個有可能在活體內形成雜二聚體的包膜蛋白質(E1和E2)，以及非結構蛋白質NS2-NS5。已知該病毒的NS3區域對多蛋白在轉譯後被加工成單獨的蛋白質是重要的，NS5區域則可編碼一種RNA依賴性的RNA聚合酶。
病毒特異性T淋巴細胞與中和抗體都是已建立的病毒感染中的抗病毒免疫防禦的主要支柱。而CD8+細胞毒性T細胞則是消除病毒感染的細胞，CD4+T輔助細胞更是有效調節抗病毒免疫應答所必需的。CD4+T輔助細胞將特異性抗原識別為與自身HLA II類分子相結合的肽(病毒抗原或顆粒被專職的抗原呈遞細胞所攝取，被加工成肽，並結合於溶酶體區室中的HLA II類分子上，然後被轉移回到細胞的表面上)。幾個觀察結果支持了CD4+T細胞在消除HCV感染方面的重要作用。Tsai等人，1997 Hepatology，25449-458；Diepolder等人，1995 Lancet，3461-6-1009；Missale等人，1996 JCI，98706-714；Botarelli等人，1993；Gastro，104580-587；Diepolder等人，1997，J.Virol，716011。免疫原性肽的最小長度通常為8-11個胺基酸。但是，由於HLA II類分子的肽結合溝似乎在兩端都是開放的，所以更長的肽也可承受。因而，從HLA II類分子上洗脫下來的肽一般長15-25個胺基酸。HLA II類分子具有高度多態性，各等位基因似乎有它自己單獨的肽結合要求。因而，特定個體的HLA II類分子的所有組成部分都可確定哪些病毒肽可被呈遞給T細胞。T細胞受體對該特異性HLA-肽複合物的識別伴隨著適當的共刺激信號可引起T細胞激活、細胞因子分泌和T細胞增殖。
大量的研究證明，HLA II類分子限制性CD4+的一系列應答，可通過使用重組病毒抗原或肽刺激外周血單核細胞而被測定。Botarelli等人，(1993)Gastroenterology，104580-587；Farrari等人，(1994)Hepatology，19286-295；Minutello等人，(1993)C.J.Exp.Med.，17817-25；Hoffmann等人，(1995)Hepatology，21632-638；Iwata等人，(1995)Hepatology，221057-1064；和Tsai等人，(1995)Hepatology，21908-912。
已在慢性C型肝炎患者中檢測到多克隆多特異性CD8+T細胞的應答。此外，CD8+CTL已顯示出在解決黑猩猩急性HCV感染方面的重要作用(Cooper等人，Immunity 1999)。約50％的慢性C型肝炎患者表現出可檢測的病毒特異性CD4+T細胞應答，這種應答最常見於針對HCV核心和/或NS4的情況中，並且它在進行α-幹擾素治療期間獲得的持久性病毒清除力的患者中較為常見。
根據淋巴因子的模式，CD4+T輔助細胞已被分成TH1、TH0或TH2。TH1型的細胞因子一般是IFN-γ、淋巴毒素和白介素-2(IL-2)，據認為這些細胞因子可支持病毒特異性CD8+T細胞和自然殺傷細胞的激活過程。TH2型細胞因子IL-4、IL-5、IL-10和IL-13對B細胞的激活和分化具有重要性，從而誘導了體液免疫應答。
在急性C型肝炎感染的過程中，對NS3以及可能對其它非結構蛋白質的強烈而持續的TH1/Th0應答與該疾病的自限進程相關。Diapolder等人，(1995)Lancet，3461006-1007的研究顯示，所有的CD4+T細胞克隆都具有TH1或TH0細胞因子的特徵，這表明這些克隆支持體內的細胞毒性免疫機制。大多數的CD4+T細胞克隆都對NS3的一條相對短的片段(即第1207-1278個胺基酸)應答，這表明NS3的這個區域對CD4+T細胞是免疫顯性。超過70％的感染了HCV的患者發展了慢性感染和肝炎，它們當中有大部分發展成肝硬化，並最終發展成肝細胞癌。目前唯一認可的治療是6到12個月的α-幹擾素治療，這種治療僅可使20％的患者達到持續性改善。迄今為止還沒有商業供應共疫苗。
因而，仍需要能促進抗HCV應答的組合物和方法。
發明概要本發明一方面涉及含有突變型C型肝炎(HCV)多肽的分離的多肽，該C型肝炎多肽至少含有NS3、NS4和NS5的一些部分。較佳的是，NS3由刪除了N末端以除去催化結構域的核酸序列編碼。該NS突變型多肽可包括NS3、NS4s、NS4b、NS5a、NS5b或它們的一些部分。例如，在各種實施例中，該突變型NS多肽含有NS3、NS4(NS4a和NS4b)和NS5(NS5a和NS5b)。在另外一些實施例中，該NS多肽由NS3和NS4(例如，NS4a和/或NS4b)或NS3和NS5(例如，NS5a和/或NS5b)組成。還可考慮使用非結構組分的全長或其片段的其它組合。
在另一較佳方面，該類多肽還含有不屬於非結構HCV多肽的病毒多肽。這種多肽較佳是C，或者是C中的抗原片段，更佳是HCV的截短的C。其它多肽較佳是E，或其抗原片段，更佳是HCV的E1或E2。這些多肽不需被天然的HCV基因組編碼，它們包括如截短的或突變型HCV多肽或從其它基因組得到的多肽，如HBV的一些多肽。因而，本發明包括含有在NS3的催化結構域中發生突變的多肽的分離的突變型非結構(「NS」)HCV多肽，該突變從功能上破壞了該催化結構域。該突變可以是如刪除或取代突變。在某些實施例中，該突變型NS多肽含有NS3、NS4和NS5。在另外一些實施例中，在此所述的各種突變型NS多肽還含有不屬於HCV的NS3、NS4或NS5的次級病毒多肽，例如，HCV核心多肽(「C」)或其片段，或者HCV包膜蛋白質(「E」)，例如E1和/或E2。在某些實施例中，C還被截短(如在第121個胺基酸)。
本發明另一方面涉及含有本文所述的任何突變型肝炎C(「HCV」)多肽的組合物，該多肽如至少含有NS3、NS4和NS5的一部分的多肽。較佳的是，NS3由N末端被刪除以破壞該催化結構域的功能(例如，將此結構域除去)的核酸序列編碼。在另一較佳實施例中，該類多肽還含有不是非結構HCV多肽的病毒多肽。這些多肽較佳是C或其抗原片段，更佳是HCV的截短的C。其它多肽較佳是E或其抗原片段，更佳是HCV的E1或E2。這些多肽不需被天然的HCV基因組編碼，它們包括如截短的或突變型HCV多肽或從其它基因組得到的多肽，如HBV的多肽。另一方面，本發明包括含有(a)本文所述的任何一種多肽和(b)藥學可接受的賦形劑(如載體和/佐劑)的組合物。
另一方面，本發明包括編碼本文所述的任何一種突變型HCV多肽的的分離純化的多肽。在某些實施例中，本發明包括含有(a)編碼任何一種突變型HCV多肽的經分離純化的多肽和(b)藥學上可接受的賦形劑的組合物。該多肽可以是如質粒中的DNA，或者它存在於質粒中。此外，本文所述的多肽可被包含在附圖和序列表所示的表達載體中。
另一方面，本發明涉及被含有編碼至少含有NS3、NS4和NS5的一部分的突變型HCV多肽的核酸序列的表達載體轉化的宿主細胞。較佳的是，這些宿主細胞的表達載體還含有至少一種編碼不屬於非結構HCV多肽的病毒多肽的核酸序列。這些多肽較佳是C或其抗原片段，更佳是HCV的截短的C。其它多肽較佳是E或其抗原片段，更佳是HCV的E1或E2。這些多肽不需被天然的HCV基因組編碼，它們包括如截短的或突變型HCV多肽或從其它基因組得到的多肽，如HBV的多肽。在另一較佳的方面，這些表達載體的核酸序列被共表達。在又一較佳方面，這些宿主細胞是酵母細胞或哺乳動物的細胞。
另一方面，本發明涉及含有編碼含有NS3、NS4和NS5的突變型HCV多肽的核酸序列的表達載體。較佳的是，這些宿主細胞的表達載體還含有至少一種編碼不屬於非結構HCV多肽的病毒多肽的核酸序列。這些多肽較佳是C或其抗原片段，更佳是HCV的截短的C。其它多肽較佳是E或其抗原片段，更佳是HCV的E1或E2。重要的是，這些多肽不需被天然的HCV基因組編碼，它們包括如截短的或突變型HCV多肽或從其它基因組得到的多肽，如HBV的多肽。較佳的是，本發明涉及製備突變型HCV多肽的方法。較佳的是，該方法包括使用含有編碼至少含有NS3、NS4和NS5的一部分的突變型HCV多肽的核酸序列的表達載體轉化宿主細胞和分離所述多肽的步驟。在另一較佳方面，該HCV多肽還含有不屬於非結構HCV多肽的病毒多肽。這些多肽較佳是C或其抗原片段，更佳是HCV的截短的C。其它多肽較佳是E或其抗原片段，更佳是HCV的E1或E2。這些多肽不需被天然的HCV基因組編碼，它們包括如截短的或突變型HCV多肽或從其它基因組得到的多肽，如HBV的多肽。在另一較佳方面，這些宿主細胞是酵母細胞或哺乳動物細胞。
另一方面，本發明涉及與含有NS3、NS4和NS5的突變型HCV多肽特異性結合的抗體和製備及使用這些抗體的方法。在一個較佳方面，該HCV多肽還含有不屬於非結構HCV多肽的病毒多肽。這些多肽較佳是C或其抗原片段，更佳是HCV的截短的C。其它多肽較佳是E或其抗原片段，更佳是HCV的E1或E2。這些多肽不需被天然的HCV基因組編碼，它們包括如截短的或突變型HCV多肽或從其它基因組得到的多肽，如HBV的多肽。在另一較佳方面，該抗體是單克隆抗體或多克隆抗體。
又一方面，本發明涉及一種製備突變型NS HCV多肽的方法，其中，該方法包括(a)使用本文所述的任何一種表達載體在該多肽被表達的條件下轉化宿主細胞；(b)分離出該多肽。該宿主細胞可以是如酵母細胞、哺乳動物細胞、植物細胞或昆蟲細胞。該多肽可以在胞內表達和分離，或者可被分泌到周圍環境中並從中分離。
又一方面，本發明提供了一種引起受檢對象免疫應答的方法。通過以單劑或多劑給予本文所述的任何一種多核苷酸和/或多肽來引起該免疫應答。
本領域熟練的技術人員可根據本文公開的內容而容易地理解本發明的這些和其它實施例。
附圖的簡短描述


圖1顯示產生pCMV-NS35的克隆技術方案。
圖2顯示9621bp的載體pCMV-NS35。
圖3顯示包括NS35 ORF的核酸序列在內的pCMV-NS35(SEQ ID NO1)的核酸序列以及NS35(SEQ ID NO2)的翻譯。
圖4顯示9621bp的pCMV-delNS35。
圖5顯示包括delNS35 ORF的核酸序列在內的pCMV-NS35(SEQ ID NO3)的核酸序列以及delNS35多肽(SEQ ID NO4)的翻譯。
圖6顯示4276bp的pCMV-II。
圖7顯示pCMV-II(SEQ ID NO5)的核酸序列。
圖8顯示6300bp的pCMV-NS34A。
圖9顯示包括NS34A ORF的核酸序列在內的pCMV-NS34A(SEQ ID NO6)的核酸序列以及NS34A(SEQ ID NO7)的翻譯。
圖10顯示產生pd.ΔNS3NS5的克隆技術方案。
圖11顯示pd.ΔNS3NS5(SEQ ID NO8)的核酸序列和胺基酸序列。
圖12顯示經pd.ΔNS3NS5轉化的釀酒酵母AD3株表達的蛋白質的Westem印跡圖。
圖13顯示pd.ΔNS3NS5.pj的克隆方案。
圖14顯示pd.ΔNS3NS5.pj的核酸序列和胺基酸序列(SEQ ID NO10和11)。
圖15顯示經pd.ΔNS3NS5.pj轉化的釀酒酵母AD3株表達的蛋白質的Western印跡圖，突出表示ΔNS3NS5多肽的表達。
圖16顯示產生pd.ΔNS3NS5.pj.core121RT和pd.ΔNS3NS5.pj.core173RT的克隆技術方案。
圖17顯示pd.ΔNS3NS5.pj.core121的核酸序列和胺基酸序列(SEQ ID NO12和13)。
圖18顯示pd.ΔNS3NS5.pj.core173的核酸序列和胺基酸序列(SEQ ID NO14和15)。
圖19顯示經pd.ΔNS3NS5.pj轉化的釀酒酵母AD3株表達的蛋白質的Western印跡圖，特別展現pd.ΔNS3NS5.core121多肽和pd.ΔNS3NS5.core173多肽的表達。泳道1和7表示See Blue標準。泳道2表示對照酵母質粒。泳道3和4表示ΔNS3NS5.core121RT多肽、菌落1和2。泳道5和6顯示ΔNS3NS5.core173RT多肽、菌落3和4。
圖20顯示產生pd.ΔNS3NS5.pj.core140RT和pd.ΔNS3NS5.pj.core150RT的克隆技術方案。
圖21顯示pd.ΔNS3NS5.pj.core140的核酸序列和胺基酸序列(SEQ ID NO16和17)。
圖22顯示pd.ΔNS3NS5.pj.core150的核酸序列和胺基酸序列(SEQ ID NO18和19)。
圖23顯示經pd.ΔNS3NS5.pj轉化的釀酒酵母AD3株表達的蛋白質的Western印跡圖，特別展現pd.ΔNS3NS5.pj.core140多肽和pd.ΔNS3NS5.pj.core150多肽的表達。泳道1表示See Blue標準。泳道2和3表示ΔNS3NS5.core140RT多肽、菌落5和菌落6。泳道4和5表示pd.ΔNS3NS5.core150RT多肽、菌落7和菌落8。泳道6表示對照酵母質粒。泳道7表示ΔNS3NS5.core121RT多肽、菌落1。泳道8表示ΔNS3NS5.core173RT多肽、菌落5。
發明的詳細描述除非另有說明，否則本發明的實施將使用分子生物學、微生物學、重組DNA技術和免疫學的常規技術，這些技術都在本領域熟練技術人所掌握的知識之內。這些技術在文獻中有完整的解釋。例如參見Sambrook等人，MOLECULARCLONING；A LABORATORY MANUAL(1989)；DNA CLONING，第I和II卷(D.N.Glover等人，1985)；OLIGONUCLEOTIDE SYNTHESIS(M.J.Gait編輯，1984)；NUCLEIC ACID HYBRIDIZATION(B.D.HamesS.J.Higgins編輯，1984)；TRANSCRIPTION AND TRANSLATION(B.D.HamesS.J.Higgins編輯，1984)；ANIMAL CELL CULTURE(R.I.Freshney編輯，1986)；IMMOBILIZED CELLS ANDENZYMES(IRL出版社，1986)；B.Perbal，A PRACTICAL GUIDE TO MOLECULARCLONING(1984)；METHODS OF ENZYMOLOGY叢刊(Academic Press，Inc.)；GENE TRANSFER VECTORS FOR MAMMALLAN CELLS(J.H.Miller和M.P.Calos編輯，1987，Cold Springs Harbor Laboratory)，Enzymology第154卷和第155卷中的方法(分別由Wu與Grossman和Wu編輯)；Mayer和Walker編輯(1987)，IMMUNOHISTOCHEMICAL METHODS IN CELL AND MOLECULARBIOLOGY(Academic Press，London)；Scopes(1987)，PROTEIN PURIFICATIONPRINCIPALS AND PRACTICE，第二版(Springer-Verlag，New York)；和HANDBOOK OF EXPERIMENTAL IMMUNOLOGY，第I-IV卷(D.M.Weir和C.C.Blackwell編輯，1986)。
應注意的是，除非在文中另有說明，否則在本說明書和所附的權利要求書中所使用的「一個(種)」和「這個(種)」包括它們的複數形式。因而，如「一種抗原」包括兩種或多種抗原的混合物，等等。
I.定義本發明的描述將使用到下列術語，它們的定義如下所述。
術語「C型肝炎病毒」(HCV)指引起非A非B型肝炎(NANBH)的病原體。美國專利第5856437號和5350671號描述了HCV的核酸序列和推定的胺基酸序列。由HCV引起的疾病稱為C型肝炎，通常稱為NANAH。術語HCV在文中指病毒種類中引起NANBH的致病菌株、減毒株或從中獲得的缺損的幹擾粒子。
HCV是黃病毒家族中的一員。黃病毒粒子的形態學和組成是已知的，並且在Reed等人的文章〔Curr.Stud.Hematol.Blood Transfus.(1998)，621-37 〕、HEPATITISC VIRUSES IN FIELDS VIROLOGY(B.N.Fields、D.M.Kinpe、P.M.Howley編輯，第3版，1996)中有所論述。最近發現，HCV基因組的一些部分也與瘟病毒群同源。通常，從形態上看，黃病毒群含有被脂質雙分子層包圍的中心核衣殼。病毒子是球形的，直徑約為40-50nm。它們的核的直徑約為25-30nm。沿著該病毒子包膜的外表面的是具有直徑約為2nm的球突的長約5-10nm的突出物。
該HCV基因組由RNA組成。已知含有病毒的該RNA自發突變的比例相對較高。因此，該HCV類或種群中可能存在多種病毒株，這些毒株可能是有毒性或無毒性的。HCV的ORF，包括它的核心、非結構蛋白質和包膜蛋白質的翻譯廣度，可從美國專利第5856437號和第5350671號中檢索到。
術語「多肽」和「蛋白質」指胺基酸殘基的聚合物，這兩個術語並不限於所得產物的最小長度。因而，肽、寡肽、二聚體、多聚體等都包括在這個定義內。全長的蛋白質及其片段都包括在這個定義內。該術語還包括多肽在表達後的修飾，例如，糖基化、乙醯化、磷酸化等。此外，為了實現本發明的目的，「多肽」指包含對天然序列進行修飾如刪除、添加和取代(一般仍保留其性質)，只要仍維持其所需活性的蛋白質。這些修飾可以是人為的，如位點定向誘變，或者是偶發的，如產生該蛋白質的宿主的突變作用或PCR擴增過程產生的錯誤。
如上定義，HCV多肽是一種得自HCV多蛋白的多肽。該多肽一定要從HCV形成，也可通過合成或重組而產生。而且，該多肽可從任何一種HCV毒株中獲得，如從HCV的1、2、3或4各毒株獲得。已知在這些毒株中具有大量的保守的和可變的區域，通常，從這些區域得到的表位的胺基酸序列的序列同源性程度高，如當將兩條序列排列，然後使用本文所述的任何一個程序或算法測定它們的同源性時，其胺基酸序列同源性可超過30％，較佳的是超過40％。因而，例如術語「NS4」多肽指從任何一種HCV毒株得到的天然NS4、NS4類似物、突變蛋白和免疫原性片段，下文將進一步描述。
此外，術語「ΔNS35」、「delNS35」、「ΔNS3NS5」和「ΔNS3-5」在本文中指突變型多肽，它們含有NS3、NS4或NS5的至少一部分，含有NS3蛋白酶活性位點區域中的刪除或突變，以使該蛋白酶失去功能。在一個實施例中，如圖5所示，ΔNS3-5含有1242-3011個胺基酸或基本上與這些胺基酸相同的多肽。本領域普通技術人員和容易掌握如何測定該NS3蛋白酶已經失去功能。如果該蛋白酶能起作用，就可在其表達後獲得具有預期分子量的蛋白質。如實施例2和
圖15所示，進行SDS-page(4-20％)，當使用pd.ΔNS3NS5.PJ克隆#5轉化AD3株時，獲得分子量大約為194kD的蛋白質。本領域熟練的技術人員將容易地確定在發生任何給定的刪除或突變時，是否還會有具有所需分子量的蛋白質表達。
術語「類似物」和「突變蛋白」指所涉及的分子的生物學活性衍生物或它們的仍維持所需活性(如下定義的刺激細胞介導的免疫應答的能力)的片段。通常，術語「類似物」指含有相對於天然的分子，在對其進行的修飾不破壞其免疫原性活性的條件下，添加、取代(一般仍保留其性質)和/或刪除了一個或多個胺基酸的天然多肽序列和結構的化合物。術語「突變蛋白」指具有一個或多個肽模擬物的肽(「類肽」)，如國際出版物第WO 91/04282號中所述。較佳的是，該類似物或突變蛋白與天然的分子至少具有相同的免疫活性。製備多肽類似物和突變蛋白的方法在本領域中是已知的，下文將對其進行描述。
特別優選的類似物包括性狀上保守的取代，即這些取代發生在與它們的側鏈有關的一類胺基酸中。具體而言，胺基酸一般被分成四類(1)酸性——天冬氨酸和穀氨酸；(2)鹼性——賴氨酸、精氨酸、組氨酸；(3)非極性——丙氨酸、纈氨酸、亮氨酸、異亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸；(4)無電荷的極性胺基酸——甘氨酸、天冬醯胺、穀氨醯胺、半胱氨酸、絲氨酸、蘇氨酸、酪氨酸。有時將苯丙氨酸、色氨酸和酪氨酸歸為芳族胺基酸。例如，有理由預測，單獨用異亮氨酸或纈氨酸取代亮氨酸、用穀氨酸取代天冬氨酸、用絲氨酸取代蘇氨酸，或者使用結構上相關的胺基酸取代類似的保守的胺基酸，這樣的取代將不會過於影響生物學活性。例如，感興趣的多肽可包括達到5-10個保守的或不保守的胺基酸取代，甚或達到15-25個保守的或不保守的胺基酸取代，或者為2-25之間的整數，只要該分子的所需功能仍維持完整。本領域的熟練技術人員可結合本領域熟知的Hopp/Woods和Kyte-Doolittle曲線圖，容易地測定感興趣的分子中可耐受改變的區域。
術語「片段」指僅由完整的全長多肽序列和結構的一部分組成的多肽。該片段可包括該天然多肽的C末端刪除和/或N末端刪除。具體的HCV蛋白質的「免疫原性片段」一般至少包括該全長分子的約5-10個連續的胺基酸殘基，較佳至少約含有該全長分子的15-25個連續的胺基酸殘基，最佳至少約含有該全長分子的20-50個或以上的連續的胺基酸殘基，這些胺基酸殘基限定了一個表位；或者含有5個到該全長序列胺基酸數目之間的任何整數的胺基酸殘基，只要所述的片段保留了免疫原性活性，其活性的測量可採用本文所述的方法進行。Chien等人，Preoc.Natl.Acad.Sci.USA(1992)，8910011-10015；Chien等人，J.Gastroent.Hepatol.，(1993)，8S33-39；Chien等人，國際出版物第WO 93/00365；Chien，D.Y.，國際出版物第WO 94/01778；共同擁有並被批准的美國專利系列號為08/403590和08/444818的文獻中描述了各種HCV表位。
術語「表位」在文中指至少約有3-5個、較佳約有5到10或15個、但不超過約1000個胺基酸(或其中的任何整數)的序列；它定義了一條自身或作為更大序列的一部分而與在對其應答中產生的抗體結合的序列。該片段的長度沒有嚴格的上限，它幾乎可含有蛋白質序列的全長，或者它甚至可包括含有HCV多蛋白的兩個或多個表位的融合蛋白。用於本發明的表位並不限於具有其母體蛋白質一部分的該確切序列的多肽。實際上，病毒基因組處於不斷變動的狀態，它們含有幾種在隔離種群間具有高度的變動性的可變的結構域。因而，術語「表位」包括與天然序列相同的序列，以及該天然序列的修飾物，如刪除、添加和取代(一般仍保留其性質)。
可使用本領域周知的各種表位繪圖技術中的任何一種來鑑別包括表位在內的給定多肽的區域。例如參見Methods in Molecular Biology中的Epitope MappingProtocols，第66卷(Glenn E.Morris編輯，1996)，Humana Press，Totowa，New Jersey。例如，通過如同時在固相支持物上合成大量的對應於蛋白質分子的一些部分的肽，然後在這些肽仍連接在該支持物上的情況下使它們與抗體反應，就可測定各條形表位。這些技術在本領域中是已知的，並在美國專利第4708871；Geysen等人(1984)，Proc.Natl.Acad.Sci.USA，813998-4002；Geysen等人(1986)，Molec.Immunol.，23709-715中有所描述。類似地，通過使用如X-射線結晶學和二維核磁共振法測定胺基酸的空間構象，從而可容易地鑑定構象表位。例如參見EpitopeMapping Protocols(同上)。使用如供計算使用的標準的抗原性曲線圖和水療法曲線圖，如從Oxford Molecular Group獲得的Omiga 1.0版軟體，也可鑑別出蛋白質的抗原區域。這個電腦程式採用Hopp/Woods方法〔Hopp等人，Proc.Natl.Acad.SciUSA(1981)，783824-3828〕繪製抗原性曲線圖，使用Kyte-Doolittle技術〔Kyte等人，J.Mol.Biol.(1982)，157105-132〕繪製水療法曲線圖。
術語「構象表位」在文中指全長蛋白質的一部分，或該部分的類似物或突變蛋白，它具有編碼該全長天然蛋白質內的表位的胺基酸序列的結構特徵。天然的結構特徵包括但不限於糖基化和三維結構。較佳的是，重組產生構象表位，並使它在一種在保留其所需結構特徵的條件下(如表位沒有變性)能被抽提出來的細胞中表達。這樣的細胞包括細菌、酵母、昆蟲細胞和哺乳動物細胞。重組構象表位在HCV多蛋白中的表達和從中分離的技術在如國際出版物第WO 96/04301、WO94/01778、WO 95/33053、WO 92/08734中有所描述。
對HCV抗原(包括多肽和編碼活體內表達的多肽的多核苷酸)或組合物的「免疫學應答」是受檢對象中發展的對感興趣的組合物中存在的分子產生的體液和/或細胞免疫應答。在本發明中，「體液免疫應答」指由抗體分子介導的免疫應答，而「細胞免疫應答」是由T-淋巴細胞和/或其它白細胞介導的應答。細胞免疫的一個重要方面涉及細胞溶解T細胞(「CTL」)的抗原特異性應答。CTL對與由主要組織相容性複合體(MHC)編碼的蛋白質結合併被表達在細胞表面上的肽抗原具有特異性。CTL幫助誘導和促進細胞內微生物的破壞，或者感染了這些微生物的細胞的溶胞作用。細胞免疫的另一方面涉及輔助T細胞的抗原特異性應答。輔助T細胞起到幫助激發非特異性效應細胞抵抗在其表面上顯示與MHC分子結合的肽抗原的細胞的功能、並將這些效應細胞的活性集中於此項功能上的作用。「細胞免疫應答」還指細胞因子、趨化因子和其它由激活的T細胞和/或其它白細胞產生的分子(包括那些從CD4+和CD8+T細胞得到的因子)的產生。
引起細胞免疫應答的組合物或疫苗可通過將與MHC分子結合的抗原呈遞在細胞表面而使脊椎動物受檢對象致敏。該細胞介導的免疫應答可指導抗原在細胞表面上或附近呈遞。此外，可產生抗原特異性T淋巴細胞，以備在以後保護已經免疫的宿主。
可進行各種實驗測定特定的抗原刺激細胞介導的免疫應答的能力，如淋巴細胞增殖(淋巴細胞激活)實驗、CTL細胞毒性細胞實驗，或者通過檢測對已致敏受檢對象中的抗原特異的T-淋巴細胞來測定上述能力。這些實驗在本領域中是周知的。例如參見Erickson等人，J.Immunol.(1993)，1514189-4199；Doe等人，Eur.J.Immunol.(1994)，242369-2376以及下面的實施例。
因而，文中使用的免疫學應答可以是刺激CTL產生的應答，和/或刺激輔助T細胞的產生或激活的應答。感興趣的抗原還可引起抗體介導的免疫應答。因此，免疫學應答可包括一種或多種下述效果使B細胞產生抗體；和/或激活對存在於感興趣的組合物或疫苗中的抗原特異的抑制T細胞和/或γδT細胞。這些應答可中和傳染力、和/或介導抗體-補體、或抗原依賴性細胞毒性(ADCC)，以保護或減輕已經免疫的宿主的症狀。進行本領域中周知的標準的免疫實驗和中和實驗可測定這些應答。
「編碼序列」或「編碼」選定多肽的序列，是指當它處於適當的調節序列的控制下時，它在活體外或活體內被轉錄(對於DNA)和翻譯(對於mRNA)成多肽的一種核酸分子。該編碼序列的界限可由5＇(氨基)末端的起始密碼子和3＇(羧基)末端的翻譯終止密碼子來限定。轉錄終止序列可以位於該編碼序列的3＇端。
「核酸」分子或「多核苷酸」可包括雙鏈和單鏈序列，它包括但不限於從病毒得到的cDNA、原核細胞或真核細胞的mRNA、從病毒得到的基因組DNA序列(如病毒和逆轉錄病毒的DNA)或原核細胞DNA，特別是合成的DNA序列。該術語還包括含有DNA和RNA的任何已知鹼基類似物的序列。
「操作性連接」指各元件的排列，其中，所述成分被排成一定的形狀，以便執行它們的預定功能。因而，操作性連接於編碼序列的給定的啟動子，在存在正確的轉錄因子等時，能使該編碼序列有效表達。該啟動子不需要與該編碼序列鄰接，只要它起到指導該序列表達的功能即可。因而，例如，不參與翻譯但轉錄的序列可存在於啟動子序列和編碼序列之間，與可轉錄的內含子一樣；並且仍可認為該啟動子序列「操作性連接」於該編碼序列。
「重組子」在文中描述一種核酸分子，指其起源和處理與與其在性質上有關的多核苷酸的全部或部分無關的基因組、cDNA、病毒、半合成或合成的多核苷酸。用來描述蛋白質或多肽的「重組子」指由重組子多核苷酸的表達產生的多肽。通常，如下文的進一步描述，感興趣的基因被克隆，然後被表達在轉化的生物體中。宿主生物體在表達條件下表達該外來基因，產生蛋白質。
「控制元件」指幫助與其連接的編碼序列表達的多核苷酸。該術語包括啟動子、轉錄終止序列、上遊調節結構域、多腺苷酸化信號、不翻譯區域(包括5＇-UTR和3＇UTR)、適當時還有前導序列和增強子，這些序列共同使宿主細胞中的編碼序列轉錄和翻譯。
「啟動子」在本文中指能結合宿主細胞中的RNA聚合酶並啟動與之操作性連接的下遊(3＇方向)編碼序列的轉錄的DNA調節區域。用於本發明的啟動子包括以高於背景值的可檢測的水平啟動感興趣的基因的轉錄所需的最小數量的鹼基或元件。在該啟動子序列中有轉錄啟動位點以及負責RNA聚合酶結合的蛋白質結合結構域(共有序列)。真核細胞啟動子常常(但不總是)含有「TATA」框和「CAT」框。
控制序列在RNA聚合酶結合到啟動子序列時「指導轉錄」了細胞中的編碼序列，並將該編碼序列轉錄成mRNA，之後，該mRNA被翻譯成由該編碼序列編碼的多肽。
「表達盒」或「表達構建物」指能指導感興趣的序列或基因的表達的裝配物。該表達盒包括上述控制元件，如操作性連接於感興趣的序列或基因(以指導其轉錄)的啟動子，該表達盒還常常包括多腺苷酸化序列。在本發明的某些實施例中，在此所述的表達盒可被包含在質粒構建物中。除了該表達盒的組分外，該質粒構建物還含有一種或多種選擇性標記物、使該質粒構建物以單鏈DNA(如M13複製源)存在的信號、至少一個多克隆位點和「哺乳動物」複製源(如SV40或腺病毒複製源性)。
「轉化」在本文中指將外源多核苷酸插入宿主細胞中，而不考慮插入的方法例如，通過直接攝取、轉染、感染等的轉化。下文進一步描述具體的轉染方法。該外源多核苷酸可維持為未整合的載體，例如，游離型載體，或者可以被整合到宿主基因組中。
「宿主細胞」是已被轉化的細胞，或者能被外源DNA序列轉化的細胞。
「分離的」概念用於多肽時，指與它天然存在於其中的整個生物體是分離且分散的，或者基本上不存在相同類型的其它生物大分子的分子。「分離的」多核苷酸指全部或部分沒有通常在天然條件下與其結合的序列的核酸分子；或者指一種以其天然形式存在但與異源序列結合的序列；或者指與染色體脫離的分子。
術語「純化」在本文中指較佳存在至少75重量％、更佳至少85重量％、尤其佳至少95重量％、最佳至少98重量％的相同類型的生物大分子。
「同源性」指兩條多核苷酸或兩條多肽分子部分之間的同一性百分數。當兩條DNA或多肽在定義的長度內有至少約50％的序列同一性時稱它們「基本同源」，該序列同一性較佳至少約為75％、更佳至少約為80-85％、尤其佳至少約為90％、最佳至少約為95-98％。在本文中，基本同源也指與特定的DNA或多肽序列完全相同的序列。結合ΔNS35，術語「基本同源」在本文中一般指至少有60％與ΔNS35(見圖5)編碼的多肽的整個序列相同的HCV核酸序列或胺基酸序列，其中，該同一性較佳至少為75％，更佳至少為80％，尤其佳為90％，最佳為95％以上，特別優選98％以上。這些同源的多肽包括片段，包括這些片段的突變體和等位基因變種。較佳使用MPSRCH程序(Oxford Molecular)中執行的Smith-Waterman同源性檢索算法，使用以gap open penalty(等距開放補償)＝12和gap extensionpenalty(等距延伸補償)＝1這兩個參數檢索的親緣差距(affine gap)測定兩條序列間的同一生。因而，例如，本發明包括有80％與ΔNS35編碼的多肽相同的分離物。在本發明的一些方面，本發明的多肽與ΔNS35基本同源。
通常，「同一性」指兩條多核苷酸或多肽序列上準確的核苷酸對核苷酸或者胺基酸對胺基酸對應。通過排列兩個分子的序列直接比較它們的序列信息，計算兩條排列的序列間匹配的準確數量，將其除以最短序列的長度，然後乘以100，從而可得到同一性百分數。在此分析中可輔助使用易於獲得的電腦程式，如ALIGH、Dayhoff、M.O.〔Atlas of Protein Sequence and Structure、M.O.Dayhoff編輯，5 Suppl.，3353-358，National Biomedical Research Foundation，Washington，DC〕，它適用於Smith和Waterman分析肽用的局部同源性算法(Advances in Appl.Math.，2482-489，1981)。可從Wisconsin Sequence Analysis Package(第8版，從Genetics Computer Group，Madison，WI獲得)獲得測定核苷酸序列同一性的程序，例如，BESTFIT、FASTA和GAP程序，這些程序也依賴於Smith和Waterman算法。使用製造者建議的和上述Wisconsin Sequence Analysis Package所述的默認參數可容易地使用這些程序。例如，可使用Smith和Warerman的同源性算法的默認計分表和6個核苷酸位置的間隔懲罰(gap penalty)測定具體的核苷酸序列與參比序列的同一性百分數。
本發明建立同一性百分數的另一方法是使用版權屬於University ofEdinburgh、由John F.Collins和Shane S.Sturrok開發、由IntelliGenetics，Inc.(Mountain View，CA)發行的MPSRCH程序包。Smith-Waterman算法可在這套程序包中使用，其中，在計分表中使用默認參數(例如，gap open penalty＝12，gap extension penalty＝1，gap＝6)。從這批數據產生的「匹配」值反映出「序列同一性」。計算序列間的同一性百分數或相似性百分數的其它合適的程序在本領域中一般都是已知的，例如，另一種排列校正程序是BLAST，可使用默認參數。例如，可使用下述默認參數的BLASTN和BLASTPgenetic code＝standard；filter＝none；strand＝both；cutoff＝60；expect＝10；Matrix＝BLOSUM62；Descriptions＝50 sequences；sort by＝HIGH SCORE；Databases＝non-redundant，GenBank+EMBL+DDBJ+PDB+GenBank CDS translations+Swiss Protein+Spupdate+PIR。在http//www.ncbi.nim.gov/cgi-bin/BLAST網址上可查到這些程序的詳細描述。
或者，在各同源區域之間形成穩定的複式結構的條件下進行多核苷酸雜交，接著用單鏈特異性核酸酶消化，然後測定消化後片段的大小，從而測出同源性。在如(對具體的體系所定義的)嚴格條件下進行的Southern雜交試驗中，可鑑別基本同源的DNA序列。確定適當的雜交條件在本領域熟練技術人員所掌握的知識之內。例如，參見Sambrook等人，同上；DNA Cloning，同上；Nucleic AcidHybridization，同上。
「嚴格」指有助於非常相似的序列的結合超過不同序列之間的結合的雜交反應條件。例如，應選擇溫度和鹽濃度的配組條件，使其低於所研究的雜交的計算的Tm溫度，大約為120-200℃。該溫度和鹽配組條件常常在初步實驗中憑經驗確定，在該初步實驗中，固定在過濾器上的基因組DNA雜交到感興趣的序列上，然後被在不同的嚴格條件下洗滌。參見Sambrook等人，第9.50頁。
當進行實驗時，如在Southern印跡中，要考慮的變量是(1)被印跡的DNA的複雜性和(2)探針和被檢測的序列間的同源性。所研究的片段的總量可變化10的數量級，為質粒或噬菌體消化的0.1-1μg到非常複雜的真核細胞基因組中的單拷貝基因的10-9-10-8g。對於複雜性較低的多核苷酸，可大大縮短印跡、雜交和曝露時間、較少量的起始多核苷酸和比活性較低的探針。例如，可使用僅1小時的曝露時間，用1μg的酵母DNA進行2小時的印跡，然後使所得產物與108cpm/μg的探針雜交4-8小時，從而可檢測出單拷貝的酵母基因。對於單拷貝的哺乳動物基因，保守的做法是使用10μg的DNA啟動，印跡過夜，然後在10％葡聚糖硫酸酯中用108cpm/μg以上的探針過夜雜交，之後暴露～24小時，可得出結果。
幾個因素可影響探針和感興趣的片段之間的DNA-DNA雜交物的解鏈溫度(Tm)，從而影響到適當的雜交和洗滌條件。在許多情況下，探針與片段不是100％地同源。其它常常遇到的變數包括雜交序列的長度和總的G+C含量以及離子強度和雜交緩衝液中甲醯胺含量。所有這些因素的影響可用下面的方程近似表示Tm＝81+16.6(log10Ci)+0.4[％(G+C)]-0.6(％甲醯胺)-600/n-1.5(％錯配率)式中，Ci是鹽濃度(單價離子)，n是以鹼基對計的雜交物的長度〔據Meinkoth和Wahl(1984)，Anal.Biochem.，138267-284，對其稍微作了修改〕。通常，在50％的甲醯胺存在的條件下，對於有95-100％與靶片段同源的探針，方便的雜交溫度是42℃，對於有90-95％同源性的探針，該溫度是37℃，對於有85-90％同源性的探針，該溫度是32℃。對於同源性較低的情況，在使用上述方程時須減少甲醯胺的含量，並相應地調整溫度。如果在探針和靶片段之間的同源性是未知的，那麼最簡單的方法是以不嚴格的雜交和洗滌條件開始。如果在放射自顯影后觀察到非特異性條帶或強背景，那麼可在高度嚴格的條件下洗滌該過濾器，然後再將其暴露。如果暴露所需的時間使得此方法不可行，那麼應平行測試幾組雜交和/或洗滌嚴格條件。
「核酸免疫」指將編碼一種或多種經選擇的抗原的核酸分子導入宿主細胞中，用於在活體內表達抗原。該核酸分子可被直接導入能接受的受檢對象中，如通過注射、吸入、口服、鼻內和黏膜給藥等，或者可離體導入已從宿主中取出的細胞中。在後一種情況中，將所得的轉化細胞再導入該受檢對象中，該受檢對象將產生抵抗由該核酸分子編碼的抗原的免疫應答。
「開放讀框」或ORF是編碼多肽的多核苷酸序列的一個區域，該區域可以是編碼序列的一部分，或者是整個編碼序列。
術語「抗體」在本文中指含有至少一個抗原結合位點的一條多肽或一組多肽。「抗原結合位點」是由抗體分子的可變區摺疊成而形成，形成具有內表面形狀並且電荷的分布與抗原的表位特徵互補的三維結合位點，在這個位點可發生特異性結合，形成抗體-抗原複合體。抗原結合位點可由重鏈區和/或輕鏈區(分別表示為VH和VL)形成，這些區域形成高度可變的環提供給抗原結合。術語「抗體」(無限制地)包括多克隆抗體、單克隆抗體、嵌合型抗體、改變的抗體、單價抗體、Fab蛋白質和單結構域抗體。在許多例子中，抗體與抗原結合的現象相當於其它的配體/抗配體的結合。
如果需要多克隆抗體，可使用具有HCV表位的免疫原性多肽對經選擇的哺乳動物(如小鼠、家兔、山羊、馬等)進行免疫，然後按已知的方法收集該經免疫的動物的血清。如果該含有抗HCV表位的多克隆抗體的血清含有其它抗原的抗體，那麼通過免疫親和力層析法純化該多克隆抗體。產生和加工多克隆抗血清的技術在本領域中是已知的，例如，可參見Mayer和Walker(1987)編輯的IMMUNOCHEMICAL METHODS IN CELL AND MOLECULAR BIOLOGY(Academic Press，London)。
本領域中的熟練技術人員也可容易地製備抗HCV表位的單克隆抗體。通過雜交瘤製備單克隆抗體的普通方法是我們所熟知的。可通過細胞融合產生生產抗體的無限增殖細胞系，也可使用其它技術如用癌基因DNA直接轉化B淋巴細胞、或者用EB病毒轉染B淋巴細胞。例如，可參見M.Schreier等人(1980)HYBRIDOMATECHNIQUES；Hammerling等人(1981)，MONOCLONAL ANTIBODIES AND T-CELL HYBRIDOMAS；Kennett等人(1980)，MONOCLONAL ANTIBODIES；也可參見美國專利第4341761號、第4399121號、第4427783號、第4444887號、第4466917號、第4472500號、第4491632號和第4493890號。可篩選具有各種特性的產生抗HCV表位的單克隆抗體系列，即具有同型、表位親和力等特性。在本文中「單結構域抗體」(dAb)是由HL結構域組成的抗體，它特異性地與指定的抗原結合。dAb不含有VL結構域，但可含有其它已知為抗體而存在的抗原結合結構域，如κ和λ結構域。製備dAb的方法在本領域中是已知的。例如可參見Ward等人，Nature，341544(1989)。
抗體也可由VH和VL結構域以及其它已知的抗原結合結構域組成。這些類型的抗體的例子和它們的製備方法在本領域中是已知的(例如可參見美國專利第4816467號)，它們包括以下內容。例如，「脊椎動物抗體」指成四聚體或其集合體的抗體，含有通常集結成「Y」形的輕鏈和重鏈，並且這些鏈之間可具有或不具有共價鍵連接。在脊椎動物抗體中，這些鏈的胺基酸序列與在脊椎動物中原位或體外(如雜交瘤)產生的抗體中發現的那些序列是同源的。脊椎動物抗體包括如純化的多克隆抗體和單克隆抗體，下文將描述它們的製備方法。
「雜交抗體」是其鏈分別與參比的哺乳動物的抗體鏈同源、並且代表它們的新裝配集合的抗體，從而這種四聚體或聚集體可使兩種不同的抗原沉澱。在雜交抗體中，一對重鏈和輕鏈與抗第一種抗原的抗體中的鏈是同源的，而第二對鏈則與抗第二種抗原的抗體中的鏈同源。這就產生了「二價」特性，即同時結合兩種抗原的能力。這些雜交物也可使用嵌合型鏈來形成，具體見下文所述。
「嵌合型抗體」指其重鏈和/或輕鏈是融合蛋白質的抗體。一般而言，該鏈的一部分胺基酸序列與從特定物種或特定類別中得到的抗體中的相應序列是同源的，而該鏈剩下的片段則是與從另一物種和/或類別得到的序列同源。通常，輕鏈和重鏈的可變區都可模仿從脊椎動物的一個種類中得到的可變區或抗體，而恆定區則與從脊椎動物的另一種類得到的抗體中的序列同源。但是，這個定義並不限於該特定的例子。還可包括其重鏈或輕鏈或這兩者是由模擬不同來源的抗體中的序列的序列組合物組成的任何抗體，而不論這些來源是否來自相同的種類，也不論該融合點是否在可變區/恆定區交界。因而，有可能製得恆定區與可變區都不模擬已知抗體序列的抗體。之後，也就有可能如構建其可變區對特定抗原具有較高親和力的抗體，或者其恆定區可引起增強的補體結合作用的抗體，或者對特定恆定區具有的特性進行其它一些改進的抗體。
另一例子是「改變的抗體」，它指脊椎動物抗體中天然的胺基酸序列已被改變的抗體。利用重組DNA技術，可重新設計抗體，以獲得所需的特徵。可能的改變方式很多，從改變一個或多個胺基酸到重新完全設計一個區域如恆定區。恆定區中的變化通常是為了獲得所需的細胞加工特性，如補體結合中的變化、與細胞膜相互作用和其它效應器功能。可改變可變區，以改變抗原結合特徵。也可將該抗體設計成輔助將分子或物質指定發送到特定細胞和組織位點中的抗體。可使用分子生物學中已知的技術如重組技術、位點定向突變技術等，獲得所需的改變。
另一例子是「單價抗體」，它是由連接到另一條重鏈的Fc(即莖)區域的重鏈/輕鏈二聚體組成的聚集體。這類抗體可逃避抗原的調節作用。例如可參見Glennie等人，Nature，295712(1982)。該抗體的定義還包括抗體的「Fab」片段。該「Fab」區指與含有這些重鏈和輕鏈的支鏈部分的序列大體相等或相似的重鏈和輕鏈的那些部分，這些區域已顯示出具有與特定的抗原的免疫學結合的能力，但它們缺少效應器Fc部分。「Fab」包括一條重鏈和一條輕鏈的聚集體(通常稱為Fab＇)，和含有2H和2L鏈的四聚體〔常稱為F(ab)2)，它們能選擇性地與指定的抗原或抗原家族發生反應。Fab抗體可被分成與上述那些抗體類似的亞類，即「脊椎動物Fab」、「雜交Fab」、「嵌合型Fab」和「改變的Fab」。抗體的Fab片段的製備方法在本領域中是已知的，包括如蛋白水解和使用重組技術合成。
「抗原-抗體複合體」指由對抗原上的表位特異的抗體形成的複合體。
「免疫原性多肽」指在存在或缺乏佐劑的條件下，單獨地或者連接在載體上的引起哺乳動物的細胞和/或體液免疫應答的多肽。
「抗原決定簇」指抗原或半抗原上特定抗體分子或特定細胞表面受體與其結合的位點。
「治療」在本文中指下述任一種情況(i)預防感染或再感染，如用傳統的疫苗治療；(ii)使症狀減少或消除；(iii)使相關病原體基本上消除或完全消除。治療可以是預防性的(感染之前)或治療性的(感染之後)。
「脊椎動物受檢對象」指cordata亞門的所有成員，包括但不限於人和其它靈長類動物，包括非人靈長類動物如黑猩猩和其它類人猿和猴子種類；農畜，如牛、綿羊、豬、山羊和馬；家養動物如狗和貓；實驗動物，包括齧齒動物如小鼠、大鼠和豚鼠；鳥類，包括家養的、野生的和獵鳥，如雞、火雞和其它雞類鳥、鴨、鵝等。該術語並不指出特定的年齡。因而，它包括成年的和新生的個體。由於可對這些脊椎動物的免疫系統進行類似的操作，所以本發明包括上述任何一種脊椎動物種類。
II.本發明的實施方式在詳細描述本發明之前，應理解本發明並不受到特殊製劑或處理參數的限制，當然這些都是可以改變的。還應理解文中使用的術語其目的僅是描述本發明的特殊實施例，而並無限制意圖。
雖然在實施本發明時可使用大量的與本文所述類似或相同的組合物和方法，但是本文所描述的是優選的材料和方法。
總述因為HCV是如此的趨異，並且需要體液免疫應答以及細胞免疫應答一起來抵抗這種人類的病原體，所以HCV疫苗的目標是對範圍廣泛的各種抗原產生寬幅的免疫力。雖然針對包衣糖蛋白而產生的抗體可能有助於中和病毒，但從含有其它區域的疫苗中仍得到額外的優點。針對多肽而產生的T輔助細胞應答也可能有助於設計產生細胞毒性T細胞的疫苗。非結構區域代表了這樣一種候選抗原，但由蛋白酶加工產生的幾種多肽，卻使得純化變得複雜。因此，獲得不被NS3蛋白酶加工的非結構盒將是有利的。
本發明使用涉及NS3的N末端刪除以除去該催化結構域的組合物和方法解決這些和其它問題。這樣，該非結構區域的餘下的一些或全部部分(通過NS5B)被表達成完整的多肽。已在哺乳動物細胞和酵母細胞中證明了這些種類的表達。此外，在某些方面，編碼HCV核心多肽(或其片段)的多核苷酸被加到(如操作性連接)該非結構盒的羧基末端。由於該核心編碼區域在HCV分離物中相對高度保守，所以這個區域的存在可增強免疫應答。因為核心部分在其C末端具有疏水性強的結構域(第174-191個胺基酸)，所以較短形式的核心部分也被設計在該多肽上。如文中的詳細描述，當將截短到第121個胺基酸的核心和截短到第173個胺基酸的核心經遺傳工程處理設計到突變型NS多肽的C末端上時，前者的表達要高於後者。大多數融合到C末端被截短的核心中的非結構區域合併到多肽中所形成的產物是新穎的，並具有疫苗免疫的優點。此外，因為我們的目標並不需要產生對這種多肽應答的抗體，所以不需要維持一種天然的構象，從而使得純化更容易進行。
突變型HCV非結構多肽HCV株的基因組含有大約9000-12000個核苷酸的單一的開放讀框，這個開放讀框被轉錄成多蛋白。解離該HCV多蛋白，得到至少10種不同的產物，順序是NH2-核心-E1-E2-p7-NS2-NS3-NS4a-NS4b-NS5a-NS5b-COOH。本發明的突變型HCV多肽中的NS3的N末端被刪除，這種刪除除去了它的催化結構域或使該結構域失活。較佳的是，這些多肽還含有該非結構區域的餘下部分，雖然在某些實施例中，這些多肽可含有短於餘下的NS多肽的全部的序列，例如突變型NS多肽可含有NS2-NS3-NS4a-NS4b-NS5a-NS5b的任一種組合(如NS3NS3-NS5a-NS5b、NS3-NS4a-NS4b、NS3-NS4a-NS4b-NS5a、NS3-NS4b-NS5a-NS5b、NS3-NS4a-NS5a、NS3-NS4b-NS5a、NS3-NS4b-NS5b等)。
該HCV NS3蛋白質起到蛋白酶和解旋酶的作用，它大約出現在該多蛋白的第1027個胺基酸到第2657個胺基酸(相對於HCV-1編號)。參見Choo等人(1991)，Proc.Natl.Acad.Sci.USA，882451-2455。HCV NS4大約出現在該多蛋白的第1658-1972個胺基酸，NS5a大約出現在第1973-2420個胺基酸，HCV NS5b大約出現在第2421-3011個胺基酸(相對於HCV-1編號)(Choo等人，1991)。
本文所述的突變型多肽可以是全長的多肽，或者是NS3、NS4(NS4a和NS4b)、NS5a和NS5b多肽。可採用幾種方法鑑別NS3、NS4(NS4a和NS4b)、NS5a、NS5b、NS3NS4NS5a和NS3NS4NS5aNS5b的表位。例如，通過如使用針對該多肽或蛋白質的單克隆抗體進行免疫親和力純化處理，可分離出NS3、NS4、NS5a、NS5b多肽或含有上述多肽的任何組合的融合蛋白質。然後，通過蛋白水解解離該純化的蛋白質，製得包括該蛋白質整個序列的短肽系列，從而篩選出分離的蛋白質序列。從如100聚體的多肽開始，使用每一條多肽測試HCV激活的T細胞上的T細胞受體識別的表位的存在，然後從已鑑別的100聚體多肽中檢測逐漸變小和重疊的片段，用於繪製感興趣的表位的圖譜。
通過進行如51Cr釋放試驗(見實施例2)或淋巴細胞增殖試驗(見實施例4)，可鑑別出HCV激活的T細胞上的T細胞受體識別的表位。在51Cr釋放試驗中，通過將編碼感興趣表位的多核苷酸克隆到一個表達載體中，然後將此表達載體轉化到靶細胞中，從而構建具有感興趣的表位的靶細胞。非結構多肽可在該融合蛋白質中以任何順序出現。如果需要，在該融合蛋白質中可出現至少2、3、4、5、6、7、8、9或10個以上的一種或多種這些多肽。HCV存在多種病毒株，並且這些病毒株中的任何一株的NS3、NS4、NS5a和NS5b多肽都可用在融合蛋白質中。
已測定了一批HCV病毒株和分離物的核酸序列和胺基酸序列，包括NS3、NS4、NS5a、NS5b基因和多肽的核酸序列和胺基酸序列。例如，Kubo等人(1989)，Japan.Nucl.Acids.Res，1710367-10372；Takeuchi等人(1990)，Gene，91287-291；Takeuchi等人(1990)，J.Gen.Virol.，713027-3033以及Takeuchi等人(1990)，Nucl.Acids Res.，184626中描述了分離物HCV J1.1。兩個獨立的分離物HCV-J和BK的完整的編碼序列分別由Kato等人〔(1990)，Proc.Natl.Acad.Sci.USA，879524-9528〕和Takamizawa等人〔(1991)，J.Virol.，651105-1113〕描述。
描述HCV-1分離物的出版物包括Choo等人(1990)，Brit.Med.Bull.，46423-441；Choo等人(1991)，Proc.Natl.Acad.Sci.USA，882451-2455和Han等人(1991)，Proc.Natl.Acad.Sci.USA，88171 1-1715。在Okamoto等人(1991)，JapanJ.Exp.Med.，60167-177中描述了HCV分離物HC-J1和HC-J4。Weiner等人(1991)，Virol.，180842-848中描述了HCV分離物HCT 18-、HCT 23、Th、HCT27、EC1和EC10。在Enomoto等人(1990)，Biochem.Biophys.Res.Commun.，1701021-1025中描述了HCV分離物Pt-1、HCV-K1和HCV-K2。在Tsukiyama-Kohara等人(1991)，Virus Genes，5243-254中描述了HCV分離物A、C、D和E。
每一條含有NS3、NS4和NS5的至少一部分的突變型HCV多肽都可從相同或不同的HCV株或分離物獲得。因而，多肽的每一個非結構區域可從相同的HCV株或分離物或從各不相同的HCV株或分離物獲得。除了本文所描述的突變型HCV非結構多肽外，這些蛋白質還可含有從該HCV多蛋白得到的其它多肽。例如，包括從該HCV多蛋白的核心區得到的多肽在內是合乎需要的。這個區域出現在該HCV多蛋白的第1-191個胺基酸(相對於HCV-1編號)。在這些融合蛋白質中可以使用該全長蛋白質或其表位，如在第10-53個胺基酸、第10-45個胺基酸、第67-88個胺基酸、第120-130個胺基酸之間發現的那些表位，或者在以下文獻中鑑別出來的任何核心表位Houghton等人，美國專利第5350671；Chien等人，Proc.Natl.Acad.Sci.USA(1992)，8910011-10015；Chien等人，J.Gastroent.Hepatol.(1993)，8S33-39；Chien等人，國際出版物第WO 93/00365號；Chien，D.Y.，國際出版物第WO 94/01778；和共同擁有的美國專利第6150087號。當存在時，額外的非結構HCV多肽如核心部分可從相同的HCV株或分離物或從不同的HCV株或分離物獲得。
較佳的是上述突變型蛋白質以及這些蛋白質的單獨成分通過重組獲得。可將編碼這些蛋白質的多核苷酸導入可在合適的表達系統中表達的表達載體中。各種細菌、酵母、哺乳動物、昆蟲和植物的表達系統在本領域中都可以獲得，並且其中的任一種都可以被使用。可任意地在無細胞的翻譯系統中翻譯編碼這些蛋白質的多核苷酸。這些方法在本領域中是周知的。也可通過固相蛋白質合成來構建這些蛋白質。
如果需要，這些突變型多肽或者它們的單獨的成分也可含有其它胺基酸序列(如胺基酸連接物或信號序列)和用於蛋白質純化的配體(如穀胱甘肽-S-轉移酶和葡萄球菌A蛋白)。
多核苷酸本發明的多核苷酸在實際上並不一定要從已查明的核苷酸序列中衍生得到，而可以任何方式產生，包括如化學合成或DNA複製或反轉錄或轉錄。此外，可採用本領域已知的方法將對應於指定序列的區域的組合修改成與計劃用途一致的形式。
編碼所需多肽的DNA，不論它是否是融合的或成熟的形式，也不論它是否含有允許分泌的信號序列，都可將它連接到適合於任何常規宿主的表達載體中。目前使用真核和原核宿主系統形成重組多肽，下文給出了一些較常用的控制系統和宿主細胞。然後從溶解的細胞中或從培養基中分離出這些宿主細胞中產生的多肽，然後將它們純化至計劃用途所需的程度。
可使用本領域已知的技術進行純化，例如，示差提取(differential extraction)、鹽分級分離、離子交換樹脂層析、親和層析、離心、不溶蛋白質的鹼性再增溶等。例如，可參見描述純化蛋白質的各種方法的Methods in Enzymology。
多核苷酸含有的序列少於整個HCV基因組，它們可以是RNA或單鏈或雙鏈DNA。較佳的是，可分離出不含有其它成分(如蛋白質和脂質)的這些多核苷酸。本發明的多核苷酸也可含有其它核苷酸序列，如編碼連接物的序列、信號序列或用於蛋白質純化的配體如穀胱甘肽-S-轉移酶和葡萄球菌A蛋白。
可從得自存在於如HCV感染的個體的血漿、血清或肝勻漿中的核酸序列的基因組庫中分離編碼突變型HCV非結構多肽的多核苷酸，或者可在實驗室中合成，例如使用自動合成儀。也可使用擴增方法如PCR從HCV基因組DNA或cDNA擴增多核苷酸。
此外，雖然不是本發明的HCV的NS3、NS4或NS5的多肽也可含有基本上完整的病毒結構域，但是，在許多應用中所需要的是，該多肽應含有該病毒的抗原區域或免疫原性區域。多肽的抗原區域一般都相當小，一般為8-10個胺基酸或更少。小到5個胺基酸的片段也可表現出抗原區域的特徵。這些片段可對應於如C、E1或E2表位的區域。因此，以C、E1或E2的cDNA作為基礎，可將編碼C、E1或E2多肽的短片段的DNA重組地表達為融合蛋白質或分離的多肽。此外，使用化學合成可方便地獲得短的胺基酸序列。
本文所述的編碼多肽的多核苷酸都可含有這些多肽的編碼序列，這些編碼序列可以是天然的或非天然的人工產生的序列。使用標準的分子生物學技術可將這些多核苷酸連接，形成上述融合蛋白的編碼序列。如果需要，可將多核苷酸克隆到表達載體中，然後轉化到如細菌、酵母、昆蟲、植物或哺乳動物細胞中，這樣本發明的融合蛋白質可在這些細胞培養物中表達，並從中分離出來。
在各種重組宿主細胞包括如細菌、酵母、昆蟲、植物和脊椎動物細胞中含有這些結構域的多肽的表達，產生了可用於診斷、檢測的重要的免疫學試劑和疫苗。
用於從病毒中提取基因組、製備和探測cDNA庫、給克隆產物測序、構建表達載體、轉化細胞、進行免疫學試驗如放射免疫測定和ELISA、在培養基中培育細胞等各種常用的技術在本領域中是已知的，並且可獲得描述這些技術的實驗手冊。但是，作為一般的指南材料，下文將提供目前可得到的這些方法和用於實施它們的材料的一些來源。
當使用與指定的宿主相適配的適當的控制序列時，原核宿主細胞和真核宿主細胞來都可用來表達所需的編碼序列。在原核宿主中，最常使用的是大腸桿菌。原核生物的表達控制序列包括啟動子(可任選含有操縱基因部分)和核糖體結合位點。與原核宿主適配的轉移載體通常可從如pBR322(含有賦予氨苄青黴素和四環素抗性的操縱子)和各種pUC載體(也含有賦予抗生素抗性標記物的序列)中獲得。這些標記物可用於通過選擇而獲得的成功的轉化子。常用的原核細胞控制序列包括β-內醯胺酶(青黴素酶)和乳糖啟動子系統〔Chang等人(1977)，Nature，1981056〕、色氨酸(trp)啟動子系統〔Goeddel等人(1980)，Nucleic Acid Res.，84057〕、從trp和lac的UV5啟動子序列得到的λ衍生的P[L]啟動子和N基因核糖體結合位點〔Shikatake等人(1981)，Nature，292128〕和雜交體tac啟動子〔De Boer等人(1983)，Proc.Natl.Acad.Sci.USA，292128〕。前述各系統與大腸桿菌特別適配；如果需要，也可使用其它具有相應的控制系統的原核宿主如芽胞桿菌屬(Bacillus)和假單胞桿菌屬(Pseudomonas)。
真核宿主包括培育系統中的哺乳動物和酵母細胞。可作為表達宿主的哺乳動物細胞系在本領域中是已知的，包括從American Type Culture Collection(ATCC)得到的多種無限增殖的細胞系，包括Hela細胞系、中國倉鼠卵巢(CHO)細胞系、幼齡倉鼠腎(BHK)細胞系和其它一批細胞系。用於哺乳動物細胞的合適的啟動子在本領域中也是已知的，包括病毒啟動子，如從猿猴病毒40(SV40)〔Fiers(1978)，Nature，273113〕、Rous肉瘤病毒(RSV)、腺病毒(ADV)和牛乳頭瘤病毒(BPV)得到的啟動子。哺乳動物細胞可能還需要終止序列和poly A附加序列；提高表達的增強子序列也可包括在內，以及引起該基因的擴增的序列。這些序列在本領域中是已知的。適合用於哺乳動物細胞中的複製的載體可包括病毒複製子，或確保編碼NANBV表位的適當序列整合到宿主基因組中的序列。
也可使用痘苗病毒系統在哺乳動物細胞中表達外源DNA。為了表達異源基因，該外來DNA通常被插入該痘苗表達的胸苷激酶基因，然後挑選出感染的細胞。這個方法在本領域中是已知的，更進一步的信息可在這些文獻中獲得Mackett等人，J.Virol.，49857-864(1984)和DNA Cloning中的第2卷第7章，IRL出版社。
酵母表達系統對於本領域的普通技術人員來說也是已知的。酵母啟動子是任何能結合酵母RNA聚合酶並啟動編碼序列(如結構基因)的下遊(3＇)轉錄成mRNA的DNA序列。啟動子具有一個轉錄起始區域，該區域通常位於接近該編碼序列的5＇端的位置上。這個轉錄起始區域一般包括一個RNA聚合酶結合位點(「TATA」框)和一個轉錄起始位點。酵母啟動子還可含有另一稱為上遊激活序列(UAS)的結構域，這個結構域在存在時通常在該結構基因的遠端。這個USA可對表達進行調節(可誘導)。在缺乏USA的情況下產生組成型表達。調節性表達可以是正的或負的，從而增強或減弱轉錄。
酵母是具有活潑的代謝途徑的發酵生物，因此，編碼該代謝途徑中的酶的序列提供了特別有效的啟動子序列。例子包括醇脫氫酶(ADH)(EP-A-0284044)、烯醇化酶、葡糖激酶、葡萄糖-6-磷酸異構酶、甘油醛-3-磷酸脫氫酶(GAP或GAPDH)、己糖激酶、果糖磷酸激酶、3-磷酸甘油酯變位酶和丙酮酸酯激酶(PyK)(EPO-A-0329203)。編碼酸性磷酸酶的酵母PHO5基因也提供了有效的啟動子序列〔Myanohara等人(1983)，Proc.Natl.Acad.Sci.USA，801〕。
此外，不是天然產生的合成的啟動子也可具有酵母啟動子的功能。例如，一個酵母啟動子的USA序列可與另一酵母啟動子的轉錄激活區域連接，得到合成的雜交啟動子。這些雜交啟動子的例子包括連接於GAP轉錄激活區域的ADH調節序列(美國專利第4876197號和第4880734號)。雜交啟動子的其它例子還包括由ADH2、GAL4、GAL10或PHO5基因中的任一調節序列與糖酵解酶基因如GAP或PyK的轉錄激活區相結合而組成的啟動子(EP-A-0164556)。此外，酵母啟動子可包括如非酵母來源的具有結合酵母RNA聚合酶並啟動轉錄的能力的天然啟動子。這種啟動子的例子包括尤其是〔Cohen等人(1980)，Proc.Natl.Acad.Sci.USA，771078；Henikoff等人(1981)，Nature，283835；Hollenberg等人(1981)，Curr.Topics Microbiol.Immunol.，96119；Hollenberg等人(1979)，「細菌的抗生素抗性基因在釀酒酵母中的表達」，Plasmids of Medical，Environmental and commercialImportance(K.N.Timmis和A.Puhler編輯)；Mercerau-Puigalon等人(1980)，Gene，11163；Panthier等人(1980)，Curr.Genet.，2109〕。
DNA分子可在酵母細胞內表達。可直接使啟動子序列與該DNA分子連接，在這種情況下，該重組蛋白質的N末端的第一個胺基酸將始終由ATG起始密碼子編碼的甲硫氨酸。如果需要，可通過在活體外與溴化氰一起培育，從該蛋白質上將該N末端上的甲硫氨酸解離下來。
融合蛋白質給酵母表達系統以及哺乳動物、杆狀病毒和細菌病毒系統提供了另一種選擇。通常，編碼內源酵母蛋白質或其它穩定的蛋白質的N-末端部分的DNA序列被融合到異源編碼序列的5＇端上。在表達後，這個構建物將提供一種兩條胺基酸序列的融合蛋白。例如，酵母或人的超氧化物歧化酶(SOD)基因可連在外源基因的5＇端上，並在酵母中表達。兩條胺基酸序列的連接處的DNA序列可以編碼或不編碼一個可解離的位點。例如，可參見EP-A-0196056。另一例子是泛在蛋白融合蛋白質。這種融合蛋白質由較佳保留了加工酶(如泛在蛋白質特異性加工蛋白酶)從該外源蛋白質解離該泛在蛋白的位點的泛在蛋白區域製得。因此，通過此方法可分離出天然的外源蛋白質(如WO88/024066)。
或者，也可通過產生編碼由使外源蛋白質在酵母中分泌的前導序列片段組成的融合蛋白質的嵌合型DNA分子，從而使該外源蛋白質從細胞中分泌到生長培養基中。較佳的是，在該前導片段和該外源基因之間存在可編碼的能在體內或體外解離的加工位點。該前導序列片段通常編碼一個由疏水胺基酸組成的指導該蛋白質從細胞中分泌的信號肽。
可從分泌酵母蛋白質的基因〔如酵母轉化酶基因(EP-A-0012873；JPO第62096086號)和A因子基因(美國專利4588684號)〕得到編碼合適的信號序列的DNA。或者，存在非酵母來源的前導序列，如幹擾素前導序列，它們也可使酵母產生分泌功能(EP-A-0060057)。
較佳的分泌功能前導序列是那些可利用用酵母α-因子基因的片段的前導序列，該片段同時含有「pre」信號序列和「pro」區域。可使用的α-因子片段包括該pre-pro α-因子前導序列的全長(大約83個胺基酸殘基)以及截短的α-因子前導序列(通常約長25-50個胺基酸殘基)(美國專利4546083和4870008；EP-A-0324274)。使用可產生分泌作用的α-因子前導片段的另外的前導序列包括使用第一酵母的pre序列與來自第二酵母α-因子的pro區域製得的雜交α-因子前導序列。(如，可參見WO 89/02463)。
通常，被酵母識別的轉錄終止序列是位於翻譯終止密碼子的3＇端的調節區域，它與啟動子一起側接在編碼系列上。這些序列指導了mRNA的轉錄，而該mRNA則可被翻譯成由該DNA編碼的多肽。轉錄終止序列和酵母識別的其它終止序列的例子如那些編碼糖酵解酶的序列。
通常，上述成分，包括啟動子、前導序列(如果需要)、感興趣的編碼序列和轉錄終止序列都一起被歸入表達構建物中。表達構建物常常被維持在一個複製子中，如能穩定維持在宿主(如酵母或細菌)中的染色體外元件(如質粒)。該複製子可能具有兩套複製系統，從而使得它可以維持在如酵母中進行表達，以及在原核宿主中進行克隆和擴增。這類酵母-細菌穿梭載體的例子，包括Yep24(Botstein等人(1979)，Gene，817-24)〕、pC1/1(Brake等人(1984)，Proc.Natl.Acad.Sci.USA，814642-4646〕和YRp17〔Stinchcomb等人(1982)，J.Mol.Biol.，158157〕。此外，複製子可以是高拷貝數或低拷貝數的質粒。高拷貝數質粒的拷貝數範圍一般約為5-200，通常約為10-150。宿主含有的高拷貝數質粒較佳至少約10個、更佳至少約20個。可選擇進入高拷貝數或低拷貝數的載體，這依賴於所選擇的載體和宿主中的外源蛋白質的性能。如可參見Brake等人，同上。
或者，表達構建物可與一個整合載體一起整合到酵母基因組中。整合載體一般含有至少一條與酵母染色體同源、並使它能被整合的序列，較佳含有兩條同源序列側接該表達構建物。整合過程似乎可由該載體中的同源DNA和該酵母染色體之間的重組而形成〔Orr-Weaver等人(1983)，Methods in Enzymol.，101228-245〕。通過選擇適當的同源序列作為整合載體中的內含物，使得它被引入酵母中的特定位置上。參見Orr-Weaver等人，同上。可整合一種或多種表達構建物，以可能影響所產生的重組蛋白質的水平〔Rine等人(1983)，Proc.Natl.Acad.Sci.USA，806750〕。該載體中含有的染色體序列可以單一片段的形式存在於該載體中，或者以兩條與該染色體中鄰近片段同源並側接於該載體中的表達構建物的片段的形式出現，前一種情況導致了整個載體的整合，後一種情況則僅使該表達構建物形成穩定整合。
通常，染色體外的表達構建物和整合表達構建物都可含有可選擇的標記物，這樣可選擇出已被轉化的酵母株。可選擇的標記物可包括可在該酵母宿主中表達的生物合成性基因，如ADE2、HIS4、LEU2、TRPl和ALG7，以及G418抗性基因，這兩類基因分別賦予酵母細胞以衣黴素抗性和G418抗性。此外，合適的可選擇的標記物還可使酵母具有在毒性化合物(如金屬)的存在下維持生長的能力。例如，CUPl的存在使得酵母可在銅離子的存在下繼續生長〔Butt等人(1987)，Microbiol，Rev.，51351〕。
或者，可將上述一些成分一起加到轉化載體中。轉化載體一般由可選擇的標記物組成，如上述該標記物要麼維持在複製子中，要麼進入整合的載體中。
表達載體和轉化載體，不論是染色體外的複製子還是整合的載體，都已被開發而用來轉化到許多種酵母中。例如，尤其是各種表達載體已經被開發用於下述酵母中白假絲酵母(Candida albicans)〔Kurtz等人(1986)，Mol.Cell.Biol.，6142〕、麥芽糖假絲酵母(Candida maltosa)〔Kunze等人(1985)，J.Basic Microbiol.，25141〕、多形漢遜酵母(Hansenula polymorpha)〔Gleeson等人(1986)，J.Gen.Microbiol.，1323459；Roggenkamp等人(1986)，Mol.Gen.Genet.，202302〕、脆壁克魯維酵母(Kluyveromyces fragilis)〔Das等人(1984)，J.Bacteriol.，1581165〕、乳酸克魯維酵母(Kluyveromyces lactis)〔De Louvencourt等人(1983)，J.Bacteriol.，154737；Van den Berg等人(1990)，Bio/Technology，8135〕、季也蒙畢赤酵母(Pichiaguillerimondii)〔Kunze等人(1985)，J.Basic Microbiol.，25141〕、巴斯德畢赤酵母(Pichia pastons)〔Cregg等人(1985)，Mol.Cell.Biol.，53376；美國專利第4837148號和第4929555號〕、釀酒酵母(Saccharomyces cerevisiae)〔Hinnen等人(1978)，Proc.Natl.Acad.Sci.USA，751929；Ito等人(1983)，J.Bacteriol.，153163〕、粟酒裂殖酵母(Schizosaccharomyces pombe)〔Beach和Nurse(1981)，Nature，300706〕和Yarrowia lipolytica〔Davidow等人(1985)，Curr.Genet.，10380471；Gaillardin等人(1985)，Curr.Genet.，1049〕。
將外源DNA導入酵母宿主中的方法在本領域中是已知的，一般包括原生質球或經鹼性陽離子處理的完整的酵母細胞的轉化。轉化方法一般隨所要轉化的酵母種類而變。例如，可參見假絲酵母屬Kurtz等人(1986)，Mol.Cell.Biol.，6142；Kunze等人(1985)，J.Basic Microbiol.，25141；漢遜酵母屬Gleeson等人(1986)，J.Gen.Microbiol.，1323459；Roggenkamp等人(1986)，Mol.Gen.Genet.，202302；克魯維酵母屬Das等人(1984)，J.Bacteriol.，1581165；De Louvencourt等人(1983)，J.Bacteriol.，154737；Van den Berg等人(1990)，Bio/Technology，8135；畢赤酵母屬Cregg等人(1985)，Mol.Cell.Biol，53376；Kunze等人(1985)，J.Basic Microbiol.，25141；美國專利第4837148號和第4929555號；釀酒酵母屬Hinnen等人(1978)，Proc.Natl.Acad.Sci.USA，751929；Ito等人(1983)，J.Bacteriol.，153163；Ito等人(1983)，J.Bacteriol.，153163；裂殖酵母屬Beach和Nurse(1981)，Nature，300706；YarrowiaDavidow等人(1985)，Curr.Genet.，10380471；Gaillardin等人(1985)，Curr.Genet.，1049。
細菌的表達技術在本領域中是已知的。細菌啟動子是能結合細菌RNA聚合酶並啟動編碼序列(如結構基因)的下遊(3＇)轉錄(成mRNA)的任何DNA序列。啟動子具有一個轉錄起始區，該區一般接近該編碼序列的5＇端。這個轉錄起始區一般含有RNA聚合酶結合位點和轉錄起始位點。細菌啟動子還具有另一稱為操縱子的結構域，該結構域可疊加在開始RNA合成的鄰近RNA聚合酶結合位點上。因為基因阻遏蛋白可結合該操縱子從而抑制特定基因的轉錄，所以該操縱子允許對轉錄進行負調節(可誘導的)。結構型表達可在負調節元件如操縱子缺乏的條件下發生。此外，基因激活蛋白質結合的序列可產生正調節，該序列如果存在，則一般存在於該RNA聚合酶結合序列的近端(5＇)。基因激活蛋白質的一個例子是代謝物激活蛋白質(CAP)，這種蛋白質可幫助啟動大腸桿菌(E.coli)中lac操縱子的轉錄〔Raibaud等人(1984)，Annu.Rev.Genet.，18173〕。因此，調節性表達可以是正的或負的，從而增強或減弱轉錄過程。
表達載體和轉化載體，不論是染色體外複製子還是整合的載體，都已被開發而用來轉化到許多種細菌中。例如，尤其是各種表達載體已經被開發用於下述細菌中枯草芽孢桿菌(Bacillus subtilis)〔Palva等人(1982)，Proc.Natl.Acad.Sci.USA，795582；EP-A-0036259和EP-A-0063953；WO 84/04541〕；大腸桿菌(Shimatake等人(1981)，Nature，292128；Amann等人(1985)，Gene，40183；Studier等人(1986)，J.Mol.Biol.，189113；EP-A-0036776、EP-A-0136829和EP-A-0136907〕；乳脂鏈球菌(Streptococcus cremoris)〔Powell等人(1988)，Appl.Environ.Microbiol.，54655〕；變鉛青鏈球菌(Streptococcus lividans)〔Powell等人(1988)，Appl.Environ.Microbiol.，54655〕；變鉛青鏈黴菌(Streptomyces lividans)(美國專利第4745056號)。
將外源DNA導入細菌宿主中的方法在本領域中是已知的，通常包括經CaCl2或其它試劑如二價陽離子和DMSO處理的細菌的轉化。也可採用電穿孔法將DNA導入細菌細胞中。通常，轉化方法可根據要轉化的不同的細菌種類而改變。例如，可參見Masson等人(1989)，FEMS Microbiol.Lett.，60273；Palva等人(1982)，Proc.Natl.Acad.Sci.USA，795582；EP-A-0036259和EP-A-0063953；WO84/04541，芽胞桿菌屬(Bacillus)，Miller等人(1988)，Proc.Natl.Acad.Sci.USA，85856；Wang等人(1990)，J.Bacteriol.，172949；彎曲菌屬(Campylobacter)，Cohen等人(1973)，Proc.Natl.Acad.Sci.，692110；Dower等人(1988)，Nucleic Acids Res.，166127；Kushner(1978)，「用Co1E1衍生的質粒轉化大腸埃希桿菌的改進方法「，Genetic EngineeringProceedings of the International Symposium on GeneticEngineering(H.W.Boyer和S.Nicosia編輯)；Mandel等人(1970)，J.Mol.Biol.，53159；Taketo(1988)，Biochim.Biophys.Acta，949318；埃希桿菌屬(Escherichia)；Chassy等人(1987)，FEMS Microbiol.Lett.，44173；乳桿菌屬(Lactobacillus)；Fiedler等人(1988)，Anal.Biochem，17038，假單孢菌屬(Pseudomonas)；Augustin等人(1990)，FEMS Microbiol.Lett.，66203，葡萄球菌屬(Staphylococcus)，Barany等人(1980)，J.Bacteriol.，144698；Harlander(1987)，「電穿孔法轉化乳鏈球菌」，Streptococcal Genetics(J.Ferretti和R.Curtiss III編輯)；Perry等人(1981)，Infect.Immun.，321295；Powell等人(1988)，Appl.Environ.Microbiol.，54655；Somkuti等人(1987)，Proc.4th Evr.Cong.Biotechnology，1412，鏈球菌屬(Streptococcus)。
此外，可通過杆狀病毒系統使病毒抗原在昆蟲細胞中表達。Summer和Smith編寫的杆狀病毒實用指南是「A Manual of Methods for Baculovirus Vectors andInsect Cell Culture Procedures」(Texas Agricultural Experiment Station Bulletin No.1555)。為了將異源基因結合到杆狀病毒基因組中，首先要將該基因克隆到含有一些杆狀病毒序列的轉移載體中。這種轉移載體在與野生型病毒被共轉染到昆蟲細胞中時，將與該野生型病毒重組。通常，該轉移載體將被遺傳加工，使該異源基因破壞該野生型杆狀病毒的多面體基因。這種破壞使得重組病毒的選擇易於進行，因為感染了該重組病毒的細胞在表型上與感染了野生型病毒的細胞不同。可使用經純化的重組病毒感染細胞，以使其表達該異源基因。如果信號肽連接在該異源基因框架上，就會有外源蛋白質分泌到培養基中，否則，該蛋白質將結合在該細胞的溶胞產物中。更進一步的信息可參見Smith等人，Mol.Cell.Biol.，32156-2165(1983)或Luckow和Summers，Virology，1731-39(1989)。
也可在植物細胞中進行杆狀病毒表達。許多植物細胞培養物和全植物遺傳表達系統在本領域中是已知的。植物細胞遺傳表達系統的例子包括在專利如美國專利第5693506號、第5659122號和第5608143號中所述的那些系統。Zenk〔Phytochemistry，303861-3863(1991)〕已描述了植物細胞培養物中遺傳表達的另外一些例子。除了上述文獻外，在下述文獻中還可檢索到植物蛋白信號肽的描述Vaulcombe等人，Mol.Gen.Genet.，20933-40(1987)；Chandler等人，PlantMolecular Biology，3407-418(1984)；Rogers，J.Biol.Chem.，2603731-3738(1985)；Rothstein等人，Gene，55353-356(1987)；Whittier等人，Nucleic Acids Research，152515-2535(1987)；Wirsel等人，Molecular Microbiology，33-14(1989)；Yu等人，Gene，122247-253(1992)。在R.L.Jones和J.MacMillin，「赤黴素」，Advanced Plant Physiology，Malcolm B.Wilkins編輯，1984，Pitman PublishingLimited，London，第21-52頁中描述了由植物激素、赤黴酸和由赤黴酸誘導的分泌酶調節植物基因表達的描述。描述其它代謝性調節基因的文獻有Sheen，PlantCell，21027-1038(1990)；Maas等人，EMBO J.，93447-3452(1990)；Benkel和Hickey，Proc.Natl.Acad.Sci.，841337-1339(1987)。
可從中分離出原生質體並將其培養，以得到完整的再生植物的所有植物都可使用本發明進行轉化，以便可回收含有轉基因的全植物。已知在實踐上，所有的植物後可從培養細胞或組織中再生，包括但不限於甘蔗、甜菜、棉花、水果和其它樹木、豆類和蔬菜類的所有主要物種。合適的植物包括如從草莓屬(Fragaria)、蓮屬(Lotus)、苜蓿屬(Medicago)、驢喜豆屬(Onobrychis)、三葉草屬(Trifolium)、胡蘆巴屬(Trigonella)、豇豆屬(Vigna)、柑橘屬(Citrus)、亞麻屬(Linum)、牻牛兒屬(Geranium)、木薯屬(Manihot)、胡蘿蔔屬(Daucus)、擬南芥屬(Arabidopsis)、芸苔屬(Brassica)、蘿蔔屬(Raphanus)、芥屬(Sinapis)、顛茄屬(Atropa)、辣椒屬(Capsicum)、曼陀羅屬(Datura)、莨菪屬(Hyoscyamus)、番茄屬(Lycopersicon)、菸草屬(Nicotiana)、茄屬(Solanum)、矮牽牛屬(Petunia)、毛地黃屬(Digitalis)、馬約喇納屬(Majorana)、菊苣屬(Cichoriurn)、向日葵屬(Helianthus)、萵苣屬(Lactuca)、雀麥屬(Bromus)、天門冬屬(Asparagus)、金魚草屬(Antirrhinum)、Hererocallis、龍面花屬(Nemesia)、天竺葵屬(Pelargonium)、黍屬(Panicum)、狼尾屬(Pennisetum)、毛莨屬(Ranunculus)、千裡光屬(Senecio)、蛾蝶屬(Salpiglossis)、黃瓜屬(Cucumis)、Browaalia、大豆屬(Glycine)、毒麥屬(Lolium)、玉米屬(Zea)、小麥屬(Triticum)、高粱屬(Sorghum)和曼陀羅屬(Datura)。
可採用任何方法將多核苷酸導入宿主細胞中，從而實現轉化，這些方法包括如將該多核苷酸包裝在病毒中，然後用該病毒轉導宿主細胞，使該細胞直接攝取該多核苷酸。所選用的轉化方法取決於要轉化的宿主。通過直接攝取的細菌轉化一般採用氯化鈣或氯化銣處理〔Cohen(1972)，Proc.Natl.Acad.Sci.USA，692110；Maniatis等人(1982)，MOLECULAR CLONING；A LABORATORY MANUAL(ColdSpring Harbor Press，Cold Spring Harbor，N.Y.)。通過直接攝取的酵母轉化可採用Hinnen等人的方法進行(1978，Proc.Natl.Acad.Sci.USA，751929)。通過直接攝取的哺乳動物轉化可採用Graham和Van der Eb的磷酸鈣沉澱法(1978，Virology，52546)或該方法的各種已知的改良法進行。
使用本領域已知的技術構建載體。使用合適的限制酶，在它們的製造商通常所指定的條件下進行位點特異性的DNA解離。根據Methods in Enzymology(1980，65499-560)中所得的常規方法，可使用聚丙烯醯胺凝膠電泳或瓊脂糖凝膠電泳技術分離解離得到的片段。可在混合物中存在適當的脫氧核苷酸三磷酸酯(dNTP)的條件下，使用大腸桿菌聚合酶I(Klenow)使粘性末端的解離片段的末端便鈍。也可使用S1核酸酶進行處理，得到任何單鏈DNA部分的水解產物。
在標準的緩衝液和溫度條件下，使用T4 DNA連接酶和ATP進行連接；粘性末端連接需要的ATP和連接酶的量比平整末端需要的少。當將載體片段用作連接混合物的一部分時，常使用細菌鹼性磷酸酶(BAP)或牛小腸鹼性磷酸酶處理該載體片段，以除去它的5＇-磷酸酯，從而防止該載體的再連接；或者，可讓限制酶消化不需要的片段，從而防止連接。將連接混合物轉化到合適的克隆宿主中(如大腸桿菌)，然後根據如抗生素抗性選擇來成功的轉化子，然後將其篩選出來，進行正確的構建。
可如Warner(1984，DNA，3401)所述，使用寡核苷酸自動合成儀製備合成的寡核苷酸。如果需要，可在32p-ATP的存在下，採用標準的反應條件，用多核苷酸激酶處理該合成的鏈，使它們標記上32P。如Zoller(1982，Nucleic Acids Res.，106487)所述，可使用已知的技術包括如位點定向誘變修改DNA序列，包括那些從cDNA庫中分離得到的序列。
使用標準的基因傳送方法，可將本發明的表達構建物，包括所需的融合蛋白或含有這些融合蛋白的單個成分的單獨病毒構建物，用於核酸免疫處理，以激活HCV特異性T細胞。基因傳送方法在本領域中是已知的。例如可參見美國專利第5399346號、第5580859號和第5589466號。可直接將基因傳送給脊椎動物受檢對象，或者以離體方式將該基因傳送給從該受檢對象得到的細胞中，然後再將這些細胞種到該受檢對象體內。例如，這些構建物可以質粒DNA的形式傳送，如它們被包含在質粒如pBR322、pUC或Co1E1中。
此外，在將表達構建物傳送到細胞中之前，可先將這些表達構建物包裝在脂質體中。通常使用能穩定結合或捕獲並保留核酸的脂質體製得脂質包囊。濃縮的DNA和脂質製品的比例可變化，但是，一般約為1∶1(毫克DNA微摩爾脂質)，或者脂質的量多一些。關於將脂質體用作傳送核酸的載體的總述，可參見Hug和Sleight，Biochim.Biophys.Acta.(1991)，10971-17；Straubinger等人，Methods ofEnzymology(1983)，第101卷，第512-527頁。
本發明使用的脂質體製品含有陽離子(正電荷)、陰離子(負電荷)和中性製品，特別優選陽離子脂質體。陽離子脂質體易於獲得。例如，從GIBCO BRL，GrandIsland，NY〔還可參見Felgner等人，Proc.Natl.Acad.Sci.USA(1987)，847413-7416〕獲得商標為Lipofectin的N[1-2，3-二油醯氧基)丙基]-N，N，N-三乙基銨(DOTMA)脂質體。可從商業上得到的其它脂質體包括transfectace(DDAB/DOPE)和DOTAP/DOPE(Boerhinger)。可使用本領域周知的技術，由易於獲得的材料製備其它陽離子脂質體。例如，可參見Szoka等人，Proc.Natl.Acad.Sci.USA(1978)，754194-4198；描述DOTAP脂質體〔1，2-二(油醯氧基)-3-(三甲基銨基)丙烷〕的合成的PCT出版物第WO 90/11092號。可採用本領域已知的方法製備各種脂質體-核酸複合體。例如，可參見Straubinger等人，METHODS OF IMMUNOLOGY(1983)，第101卷，第512-527頁；Szoka等人，Proc.Natl.Acad.Sci.USA(1978)，754194-4198；Papahadjopoulos等人，Biochim.Biophys.Acta(1975)，394483；Wilson等人，Cell(1979)，1717；Deamer和Bangham，Biochim.Biophys.Acta(1976)，443629；Ostro等人，Biochem.Biophys.Res.Commun.(1977)，76836；Fraley等人，Proc.Natl.Acad.Sci.USA(1979)，763348；Enoch和Strittmatter，Proc.Natl.Acad.Sci.USA(1979)，76145；Fraley等人，J.Biol.Chem.(1980)，22510431；Szoka和Papahadjopoulos，Proc.Natl.Acad.Sci.USA(1978)，75145；和Schaefer-Ridder等人，Science(1982)，215166。
也可將DNA傳送到與Papahadjopoulos等人〔Biochim.Biophys.Acta(1975)，394483-491〕以及美國專利第4663161號和第4871488號中所述的類似的螺旋狀脂質組合物中。
已開發了大量的基於病毒的系統，用它們將基因轉移到哺乳動物細胞中。例如，逆轉錄病毒可給基因傳送系統提供一個適宜的平臺，如鼠肉瘤病毒、小鼠乳腺瘤病毒、莫洛尼鼠類白血病毒和Rous肉瘤病毒。可使用本領域已知的技術將經選擇的基因插入載體中，然後將所得載體包裝到逆轉錄病毒粒子中。然後分離出該重組的病毒，將其在活體內或離體條件下傳送到受檢對象的細胞中。已描述了大量的逆轉錄病毒系統〔美國專利第5219740號，Miller和Rosman，Biotechniques(1989)，7980-990；Miller，A.D.，Human Gene Therapy(1990)，15-14；Scarpa等人，Virology(1991)，180849-852；Burns等人，Proc.Natl.Acad.Sci.USA(1993)，908033-8037；和Boris-Lawrie和Temin，Cur.Opin.Genet.Develop.(1993)，3102-109。簡言之，可容易地從多種多樣的逆轉錄病毒中構建本發明的逆轉錄病毒基因傳送載體，包括如B、C和D型逆轉錄病毒以及泡沫病毒和慢病毒如FIV、HIV、HIV-1、HIV-2和SIV(見RNA Tumor Viruses，第二版，Cold Spring Harbor Laboratory，1985)。可從保管單位或收藏單位如American TypeCulture Collection(「ATCC」，10801 University Blvd，Manassa，VA 20110-2209)容易地獲得這些逆轉錄病毒，或者可採用可獲得的普通技術，由已知的來源分離得到。
也已經描述了大量的腺病毒載體，如腺病毒2型和5型載體。與整合到宿主基因組中的逆轉錄病毒不同，腺病毒始終存在於染色體外，這樣使得它產生插入性突變的風險最小化〔Haj-Ahmad和Graham，J.Virol.(1986)，57267-274；Bett等人，J.Virol.(1993)，675911-5921；Mittereder等人，Human Gene Therapy(1994)，5717-729；Seth等人，J.Virol.(1994)，68933-940；Barr等人，Gene Therapy(1994)，151-58；Berkner，K.L.，BioTechniques(1988)，6616-629；和Rich等人，HumanGene Therapy(1993)，4461-476〕。
也可用分子共軛載體傳送基因，這類載體如Michael等人，J.Biol.Chem.(1993)，2686866-6869和Wagner等人，Proc.Natl.Acad.Sci.USA(1992)，896099-6103中所述的腺病毒嵌合型載體。
甲病毒屬的成員，如但不限於從新培斯病毒和澤姆利基森林病毒、VEE，也已被發現可用作傳送感興趣的基因的病毒載體。關於用於實施本發明的新培斯病毒源性載體的描述，可參見Dubensky等人，J.Virol.(1996)，70508-519；和國際出版物第WO 95/07995號和WO 96/17072號。
可使用的其它載體包括但不限於猿猴病毒40、巨細胞病毒。也可使用細菌載體，如沙門氏菌、小腸結腸炎耶爾森菌(Yersinia enterocolitica)、志賀菌、霍亂弧菌(Vibrio cholerae)、分支桿菌BCG株和產單核細胞李斯特菌(Listeriamonocytogenes)。也可使用微型染色體如MC和MC1、噬菌體、粘粒(插入了噬菌體λcos位點的質粒)和複製子(細胞中能在它們的控制下進行複製的遺產元件)。
也可將病毒構建物包裹、吸附到顆粒狀載體中，或者使它們與這類載體結合。這類載體將經選擇的分子的大量拷貝呈遞給免疫系統，並可促使這些分子在局部淋巴結被捕獲和滯留。這些粒子可被巨噬細胞吞噬，並可通過細胞因子的釋放而增強抗原呈遞作用。粒子狀載體的例子包括那些從聚甲基丙烯酸甲酯聚合物得到的載體，以及從聚(丙交酯)和聚(丙交酯-共-乙交酯)(通稱為PLG)得到的微粒。例如，可參見Jeffery等人，Pharm.Res.(1993)，10362-368；和McGee等人，J.Microencap.(1996)。
可採用多種其它方法將表達載體傳送到細胞中。這些方法包括DEAE葡聚糖介導的轉染法、磷酸鈣沉澱法、聚賴氨酸或聚鳥氨酸介導的轉染法，或使用其它不溶性無機鹽如磷酸鍶、矽酸鋁類包括皂土和高嶺土、氧化鉻、矽酸鎂、滑石粉等進行的沉澱作用。其它有效的轉染方法包括電穿孔法；超聲波穿孔法；原生質體融合法；脂質體、類肽的傳送法或微注射法。例如，可參見Sambrook等人，同上，關於轉化感興趣的細胞技術的討論；Felgner，P.L.，AdvancedDrugDeliveryReviews(1990)，5163-187，關於用於基因轉移的傳送系統的綜述。一個使用電穿孔法傳送DNA的特別有效的方法在國際出版物第WO 00/45823中有所述及。
此外，使用粒子狀載體如金和鎢的biolistic傳送系統特別有用於傳送本發明的表達構建物。這些粒子被要傳送的構建物所包裹，然後高速度加速傳送，這樣的處理一般在減壓下使用從「基因槍」釋放的發射功率進行。關於這些技術及使用這些技術的設備的描述，可參見如美國專利第4945050號、第5036006號、第5100792號、第5179022號、第5371015號和第5478744號。
組合物本發明還提供含有上述HCV多肽或多核苷酸的組合物。這些組合物可用於診斷，例如，在診斷試劑中使用突變型多肽(或編碼這些多肽的多核苷酸)。使用多肽或多核苷酸的診斷學對於本領域的熟練技術人員來說是已知的。
此外，可由一種或多種從本文所述的多肽如ΔNS35多肽得到的免疫原性多肽製備免疫原性化合物。含有作為活性成分的免疫原性多肽的免疫原性化合物的製備，對於本領域的熟練技術人員來說是已知的。通常將這些免疫原性化合物製成可注射的液體溶液形式或懸浮液形式；也可將其製成在注射前可配製成溶液、或懸浮液的固體形式。也可將該製品乳化，或者將該蛋白質包被在脂質體中。
本發明的免疫原性組合物和診斷組合物較佳含有藥學上可接受的載體。該載體本身不可使宿主產生有害的抗體。藥學上可接受的載體對於本領域的熟練技術人員來說是已知的。這些載體包括但不限於大型代謝緩慢的大分子，如蛋白質、多糖(如乳膠功能化的瓊脂糖凝膠(sepharose)、瓊脂糖、纖維素、纖維素珠等)；聚乳酸；聚乙醇酸；胺基酸聚合物如聚穀氨酸、聚賴氨酸等；胺基酸共聚物；和滅活的病毒粒子。
本發明的組合物中還可含有藥學上可接受的鹽，如無機鹽類，包括鹽酸鹽、氫溴酸鹽、磷酸鹽或硫酸鹽；以及有機酸鹽類，如醋酸鹽、丙酸鹽、丙二酸鹽或苯甲酸鹽。特別有用的蛋白質基質是血清白蛋白、匙孔血藍蛋白、免疫球蛋白分子、甲狀腺球蛋白、卵白蛋白、破傷風類毒素和其它本領域熟練技術人員所周知的蛋白質。本發明的組合物還可含有液體或賦形劑，如水、鹽水、甘油、葡萄糖、乙醇等的一種或任意組合，以及潤溼劑、乳化劑或pH緩衝劑之類的物質。脂質體也可用作本發明組合物的載體，這些脂質體如上所述。
如果需要，可將促進免疫原呈遞給淋巴細胞的共刺激分子(如B7-1或B7-2)或細胞因子(如GM-CSF、IL-2和IL-12)加到本發明的組合物中。視需要，還可在本發明的組合物中加入佐劑。可使用的佐劑包括但不限於(1)鋁鹽(alum)，如氫氧化鋁、磷酸鋁、硫酸鋁等；(2)水包油乳化製劑(有或沒有其它特異的免疫刺激製劑，如胞壁醯肽(見下文)或其它細菌細胞壁成分〕，如(a)MF59(PCT出版物第WO 90/14837)，含有5％角鯊烯(Squalene)、0.5％Tween 80和0.5％Span 85(可任意含有不同量的MTP-PE)，使用微流化床如110Y型微流化床(Microfluidics，Newton，MA)製成亞微型顆粒；(b)SAF，含有10％角鯊烯、0.4％Tween 80、5％pluronic嵌段聚合物L121和thr-MDP(見下文)，將它們微流化，製成亞微粒乳化液，或者使它們經渦流處理而形成顆粒較大的乳化液；(c)RibiTM佐劑體系(BAS)(Ribi Immunochem，Hamilton，MY)，含有2％Squalene、0.2％Tween 80和選自單磷醯基脂A(MPL)、海藻糖二黴菌酸酯(TDM)和細胞壁骨架(CWS)中的一種或多種細菌細胞壁成分，較佳是MPL+CWS(DetoxTM)；(3)皂苷佐劑，如可使用StimulonTM(Cambridge Bioscience，Worcester，MA)，或者由它獲得的顆粒如ISCOM(免疫刺激複合體)；(4)完全福氏佐劑(Complete Freund＇s Adjuvant，CFA)和不完全福氏佐劑(Incomplete Freund＇s Adjuvant，IFA)；(5)細胞因子，如白介素(如IL-1、IL-2、IL-4、IL-5、IL-6、IL-7、IL-12等)、幹擾素(如γ-幹擾素)、巨噬細胞集落刺激因子(M-CSF)、腫瘤壞死因子(TNF)等；(6)細菌ADP核糖基化毒素的解毒突變體，如霍亂毒素(CT)、百日咳毒素(PT)或大腸桿菌熱不穩定性毒素(LT)，尤其是LT-K63、LT-R72、CT-S109、PT-K9/G129等，例如，可參見WO 93/13302和WO 92/19265；(7)其它起到增強該組合物的有效性的免疫刺激製劑作用的物質；(8)吸附大分子的微粒體，如待授權美國專利申請系列號第09/285855號(1999年4月2日申請)和國際專利申請系列號PCT/US99/17308(1999年7月29日申請)中所述的。較佳是alum和MF59。可通過測量針對含有HCV抗原序列的免疫原性多肽的抗體的量來確定佐劑的有效性，該抗體是由於免疫原性化合物中使用了所述多肽而產生，該化合物中也含有各種佐劑。
如上述，胞壁醯肽包括但不限於N-乙醯基-胞壁醯基-L-蘇氨醯基-D-異穀氨醯胺(thr-MDP)、-乙醯基-正胞壁醯基-L-丙氨醯基-D-異穀氨醯胺(CGP 11637，稱為nor-MDP)、N-乙醯基胞壁醯基-L-丙氨醯基-D-異穀氨醯胺基-L-丙氨酸-2-(1＇，2＇-二棕櫚醯基-sa-丙三基-3-羥基磷醯基氧基)-乙胺(CGP 19835A，稱為MTP-PE)等。
因此，可在疫苗中使用這些重組的或合成的HCV多肽，並將它們用於診斷。而且，針對這些多肽產生的抗體也可用作診斷劑，或者用於被動免疫治療。此外，可使用針對這些多肽的抗體分離和鑑別HCV粒子。
也可從HCV病毒粒子中分離出天然的HCV抗原。這些病毒粒子可在組織培養物中的HCV感染的細胞中或者感染的宿主體內生長。
給藥和輸送可採用任何合適的傳送方法向受檢對象給予本文所述的多核苷酸和多肽組合物(如免疫原性化合物)。上面已經討論了將核酸傳送到宿主細胞中的方法。此外，可通過注射，一般是皮下注射、肌肉內注射、經皮注射或皮下注射(transdermally andtranscutaneously)等經腸道外方法給予HCV多核苷酸和/或多肽。可經鼻給予或口服某些佐劑，如LTK63、LTR72或PLG製劑。其它製劑適於採用另一種給藥方法，包括栓劑。對於栓劑，傳統的粘合劑和載體可包括如聚(亞烷基)二醇或甘油三酯；可用含有0.5-10％、較佳1-2％活性成分的混合物製成這些栓劑。其它口服製劑包括通常使用的賦形劑，如藥用級的甘露糖醇、乳糖、澱粉、硬脂酸鎂、糖精鈉、纖維素、碳酸鎂等。這些組合物可以是溶液、懸浮液、藥片、丸狀、膠囊、持續釋放的製劑或粉末的形式，含有10-95％、較佳25-70％的活性成分。
可將本發明的多肽製成中性或鹽形式的免疫原性化合物。藥用鹽包括酸加成鹽(與該肽的游離氨基形成)，包括與無機酸(如鹽酸或磷酸)或有機酸(如乙酸、草酸、酒石酸、馬來酸等)形成的酸加成鹽。還可由無機鹼如鈉、鉀、銨、鈣或三價鐵的氫氧化物以及有機鹼如異丙胺、三甲胺、2-乙氨基乙醇、組氨酸、普魯卡因鹼等得到與游離的羧基形成的鹽。
以與其劑型相應的方式給予這些免疫原性化合物，給藥量應是預防有效量和/或治療有效量。給藥量視要治療的受檢對象、該受檢對象的免疫系統合成抗體的能力以及所需的保護程度而定，一般是每劑5-250微克多肽。所給予的活性成分的準確量由醫師判斷，並且對不同患者該量不同。
可以單劑療程給予該免疫有效化合物，或者較佳以多劑療程給予。多劑療程是指將初級免疫接種過程的給藥分為1-10個分離的劑份，在隨後的需要維持和/或增強免疫反應的時間間隔中給予其它劑份，例如在1-4個月時給予第二劑份，之後，如果需要，在幾個月後可接著給予劑。給藥過程可包括一起或順次給予多核苷酸和多肽(例如，先用多核苷酸組合物引起免疫應答，然後再用多肽組合物加強)。這套給藥方式至少還要部分地根據個體的需要以及醫師的判斷而確定。
在某些實施例中，本文所述的這些多核苷酸和多肽是用來激活T細胞。除了簡化構建和修改這些實際優點外，編碼突變型NS多肽的多核苷酸的給予還導致突變型NS多肽在宿主中的合成。因而，這些免疫原以天然的翻譯後修飾、結構和構象被呈遞給宿主免疫系統。這些多核苷酸較佳經肌肉內注射到大型哺乳動物(如人)中，劑量為0.5、0.75、1.0、1.5、2.0、2.5、5或10mg/kg。
可將這些蛋白質和/或多核苷酸給予未受HCV感染或已受HCV感染的哺乳動物。組合物中多核苷酸或融合蛋白質的具體劑量或可受到許多因素的影響，包括但不限於給予該組合物的哺乳動物的物種、年齡和一般症狀以及給予該組合物的方式。進行常規實驗方法可容易地就可測定本發明組合物的有效量。可使用體外和體內模型測定適當的劑量。通常，給予大型哺乳動物如狒狒、黑猩猩或人的劑量為0.5、0.75、1.0、1.5、2.0、2.5、5或10mg/kg。如果需要，在給予這些組合物之前、之後或者一起給予共刺激分子或佐劑。
抗體和診斷針對HCV表位的抗體，包括單克隆和多克隆抗體在內，對診斷都特別有用，那些中和性抗體則可用在被動免疫治療中。尤其是，可使用單克隆抗體來產生抗獨特型抗體。
抗獨特型抗體屬於免疫球蛋白類，它們攜帶有針對需要保護的感染性因子的抗原的「內部影像」。產生抗獨特型抗體的技術在本領域中是已知的。例如，可參見Grzych(1985)，Nature，31674；MacNamara等人(1984)，Science，2261325，Uytdehaag等人(1985)，J.Immunol.，1341225。還可使用這些抗獨特型抗體治療和/或診斷NANBH，以及用它們解釋HCV抗原的免疫原性區域。
可使用例如針對病毒表位的單克隆抗體、針對一條病毒多肽的表位的單克隆抗體的組合、針對不同病毒多肽的表位的單克隆抗體、針對同一病毒抗原的多克隆抗體、針對不同病毒抗原的多克隆抗體或單克隆抗體與多克隆抗體的混合物，進行病毒抗原的免疫檢測。
免疫檢測方案可以以如競爭作用、或直接反應或夾心式試驗為基礎。這些方案還可使用如固相支持物，或者可採用免疫沉澱法進行。大多數的檢測方法涉及標記抗體或多肽的使用。這類標記物包括如螢光素、化學發光物、放射性分子或染料分子。使用探針放大信號的試驗也是已知的。這些檢測方法的例子包括使用生物素和抗生物素蛋白的檢測法和酶標記和介導的免疫檢測法，如ELISA。
可進行酶聯免疫吸附檢測法(ELISA)測量抗原或抗體的濃度。這種方法依賴於酶與抗原或抗體的結合，它使用結合的酶活性作為定量標記。為了測量抗體，將已知的抗原固定到固相材料(如微平板或塑料杯)上，使其與測試血清稀釋系列培育，之後洗滌，與經酶標記的抗免疫球蛋白培育，再次洗滌。適合用於標記的酶在本領域中是已知的，例如，辣根過氧化物酶。通過加入特異性底物，然後通過比色分析測定產物的形成或底物的利用，從而可測得酶結合到該固相材料上的活性。這個酶結合活性與抗體結合的量形成直接函數關係。
為了測量抗原，將已知的具體抗體固定到固相材料上，加入含有抗原的測試材料，培育後洗滌該固相材料，然後加入第二種標記了酶的抗體。洗滌後，加入底物，通過比色分析估計酶活性，這個活性與抗原濃度有關。
HCV融合蛋白質如NS3突變體和核心融合蛋白質也可用於生產HCV特異性多克隆抗體和單克隆抗體。HCV特異性多克隆抗體和單克隆抗體與HCV抗原形成特異結合。
給予哺乳動物如小鼠、家兔、山羊或馬以該融合蛋白質可產生多克隆抗體。從經免疫的動物得到血清，通過如用硫酸銨進行沉澱處理，從該血漿中純化出抗體，接著進行層析，較佳是親和層析。生產和加工多克隆抗血清的技術在本領域中是已知的。
也可容易地生產針對存在於這些融合蛋白質中的HCV特異性表位的單克隆抗體。從接種了突變型NS3多肽或NS-核心融合蛋白質的哺乳動物如小鼠得到的正常的B細胞可與如HAT敏感的小鼠骨髓瘤細胞融合，產生雜交瘤。進行RIA或ELISA，然後通過克隆到半固體瓊脂中或通過有限稀釋進行分離，可鑑別出生產HCV特異性抗體的雜交瘤。進行另一輪的篩選，分離出生產HCV特異性抗體的克隆。
針對HCV表位的抗體，不論是單克隆還是多克隆，在檢測樣品(如從感染了HCV的人得到的血清樣品)中HCV或HCV抗原的存在方面都特別有用。HCV抗原的免疫檢測可能使用到一種或幾種抗體。HCV抗原的免疫檢測可使用如針對HCV表位的單克隆抗體、針對一條HCV多肽的表位的單克隆抗體的組合、針對不同HCV多肽的表位的單克隆抗體、針對同一HCV抗原的多克隆抗體、針對不同HCV抗原的多克隆抗體或單克隆抗體與多克隆抗體的混合物。免疫檢測方案可以如使用標記抗體的競爭作用、直接反應或夾心式檢測為基礎。這類標記物可以是如螢光素、化學發光物或放射性標記物。
可在免疫親和柱層析中進一步將多克隆和單克隆抗體用於分離HCV粒子或抗原。通過使抗原保持它們的免疫選擇活性的方式如吸附或共價連接將抗體連接到固相支持物上。視需要可使用間隔基團，這樣該抗體的抗原結合位點保持為可接近的狀態。然後可使用這些固定的抗體結合從生物樣品(如血液或血清)得到的HCV粒子或抗原。如通過改變pH值就可從層析柱基質中回收結合著的HCV粒子或抗原。
引起免疫應答的方法由上述多肽激活的在體內或體外表達的HCV特異性T細胞較佳識別HCV多肽如突變型NS3多肽的表位，包括突變型HCV多肽的表位。HCV特異性T細胞可以是CD8+或CD4+細胞。
HCV特異性CD8+T細胞較佳是能殺死具有與MHC I類分子形成複合物的NS3、NS4、NS5a、NS5b表位的HCV感染細胞的細胞毒性T淋巴細胞(CTL)。HCV特異性CD8+T細胞也可以表達γ-幹擾素(IFN-γ)。可進行如51Cr釋放試驗檢測HCV特異性CD8+T細胞。51Cr釋放試驗測定HCV特異性CD8+T細胞溶解具有非結構(如突變型NS)表位的靶細胞的能力。也可採用免疫學方法檢測表達IFN-γ的HCV特異性CD8+T細胞，較佳採用經突變型NS多肽體外刺激後的IFN-γ細胞內染色的方法。
由上述多肽和這些蛋白質的單獨組分的混合物激活的在活體內或活體外表達的HCV特異性CD4+細胞，較佳識別與HCV感染細胞上的MHC II類分子結合的突變型非結構多肽的表位，包括突變型蛋白質的表位，並隨該突變型肽的刺激而增殖。
可進行淋巴細胞增殖試驗檢測HCV特異性CD4+T細胞。淋巴細胞增殖試驗測定HCV特異性CD4+T細胞因對表位的應答而增殖的能力。
可使用突變型NS(或其它與核心部分、包膜或其它病毒多肽的融合物)體外或體內激活HCV特異性T細胞。尤其可使用HCV特異性T細胞的激活來提供各種模型系統，以使對HCV的CTL應答最優化，並對HCV感染提供預防性的或治療性的措施。對於體外激活，較佳如上述藉助於質粒或病毒載體(如腺病毒載體)將蛋白質提供給T細胞。
可從感染了HCV的哺乳動物的血液、較佳從其外周淋巴器官如淋巴結、脾或胸腺中得到T細胞的多克隆種群。較佳的動物包括小鼠、黑猩猩、狒狒和人。該HCV起到擴增該哺乳動物體內激活的HCV特異性T細胞的數量的作用。然後通過體外將HCV表位肽加到這些T細胞中再刺激從該哺乳動物得到的HCV特異性T細胞。之後，尤其可使用該HCV特異性T細胞測試增殖作用(如本領域已知的淋巴細胞增殖試驗、IFN-γ的產生和體外溶解具有HCV NS表位的靶細胞的能力。
以闡述而非限制本發明的方式給出下列實施例。本領域普通的技術人員將認識到在本發明的實質和範圍內作出的改動。
實施例實施例1構建物pCMV-II產生含有人CMV啟動子、增強子、內含子A、多接頭和在刪除了pUC的骨架中的牛生長激素終止子(Life Technologies)的pCMV-II(圖7，SEQ IDNO5)。
pT7-HCV在多接頭修飾的pUC載體中產生pT7-HCV，使其在合成的T7啟動子之前含有全長HCV cDNA。pT7-HCV還含有完整的5＇UTR，以及3＇UTR的poly A型式。
pCMV.ΔNS35產生pCMV.ΔNS35(圖5，SEQ ID NO3)需要進行兩個步驟。首先，從pT7-HCV得到PCR產物，它的結構如下連接ACCATGG Kozak序列的5＇EcoRI位點；連接胺基酸#1242直至StuI位點的啟動ATG。其次，從全長基因組克隆中分離出StuI-XbaI片段。該基因組克隆由pUC載體中融合到具有3＇端poly A型式的該全長HCV cDNA的T7啟動子組成。最後，將EcoRI-StuI和StuI-XbaI片段連接到該pCMV-II表達載體中，將所得產物轉化到HB101反應潛能細胞中，然後將這些細胞接種到氨苄青黴素(100μg/ml)上。進行Miniprep分析，得到所需的克隆，然後在製造商的說明書的指導下，使用Quigen Gigaprep試劑盒進行大規模的擴增。將所得的克隆命名為pCMV.ΔNS35(圖5，SEQ ID NO3)。
pd.ΔNS3NS5如
圖10中的示意性顯示，使用從哺乳動物表達質粒pCMV.KM.ΔNS35得到的限制片段構建酵母表達質粒pd.ΔNS3NS5(SEQ ID NO8)。pCMV.KM.ΔNS35除了在病毒骨架上含有卡那黴素抗性基因外，其餘與pCMV.ΔNS35(圖5，SEQ ID NO3)相同。使用EcoRI和NheI消化pCMV.KM.ΔNS35，得到2895bp的EcoRI-NheI片段。使用HindIII與EcoRI之間的寡核苷酸(HE)將此EcoRI-NheI片段連接到pRSET HindIII-NheI亞克隆載體上。驗證序列後，用HindIII和NheI消化pRSETHindIII-NheI#6，得到2908bp的HindIII-NheI片段。
使用XbaI使pCMV.KM.ΔNS35直線化，然後將所得產物連接到從XbaI-SalI合成的寡核苷酸(XS)上。用NheI和SalI消化所得連接物，獲得2481bp NheI-SalI片段。將該片段連接到pET3a NheI-SalI亞克隆載體上。驗證序列後，用NheI和SalI消化pET3a NheI-SalI#2，得到2481bp的NheI-SalI片段。然後將BamHI-HindIIIADH2/GAPDH啟動子片段與HindIII-NheI和NheI-SalI片段連接克隆到pBS24.1BamHI-SalI酵母表達載體中。
pd.ΔNS3NS5.PJ製備pd.ΔNS3NS5.PJ(
圖13和14，SEQ ID NO10)，在該HCV編碼區域的5＇和3＇端產生「較佳的連接點」。在pd.ΔNS3NS5的5＇端，在酵母ADH2/GAPDH啟動子和多肽的ATG之間有6個額外的鹼基。在3＇端，在該多肽的終止密碼子和該酵母表達載體的α-因子終止子之間有52個不翻譯的鹼基序列。用ScaI和SphI消化pd.ΔNS3NS5#17，可產生pd.NS3NS5.PJ，獲得4963bp的ScaI-SphI片段。用SphI和SalI消化pd.NS5b3011，得到321bp的SphI-SalI片段，此片段在該多肽的3＇端有一個「較佳連接點」。使該ScaI-SphI片段和SphI-SalI片段與從HindIII-ScaI(HS)的合成寡核苷酸連接，以獲得該5＇端的「較佳連接點」，然後將所得產物連接到pSP72 HindIII-SalI亞克隆載體中。
驗證pSP72 HindIII-SalI克隆#6中的合成系列的區域。用HindIII和BlnI或者BlnI和SalI消化pSP72 HindIII-SalI克隆#6，分別得到2441bp的HindIII-BlnI片段和2895bp的BlnI-SalI片段。將該BamHI-HindIII ADH2/GAPDH啟動子與片段HindIII-BlnI和BinI-SalI片段一起連接到pBS24.1 BamHI-SalI酵母表達載體中。
pd.ΔNS3NS5.PJ.core.121RT和pd.ΔNS3NS5.PJ.core.173RT產生這兩條片段，使其編碼ΔNS3NS5多肽C末端的HCV核心第1-121個胺基酸(稱為pd.ΔNS3NS5.PJ.core.121RT，SEQ ID NO12)和該C末端的HCV核心第1-173個胺基酸(稱為pd.ΔNS3NS5.PJ.core.173RT，SEQ ID NO14)。該核心序列的第9個胺基酸由Lys突變為Arg，第11個胺基酸由Asn突變為Thr，稱之為core 121RT或core173RT。
pd.ΔNS3NS5.PJ.core.121RT和pd.ΔNS3NS5.PJ.core.173RT為了獲得pd.ΔNS3NS5.PJ.core.121RT(
圖17，SEQ ID NO12)和pd.ΔNS3NS5.PJ.core.173RT(
圖18，SEQ ID NO14)，如
圖16所示，對大腸桿菌表達質粒pSODCF2.HCVcore191RT#2進行PCR，擴增得到NotI-Sal HCVcore121RT和HCVcore173RT。將該core 121RTNot-SalI PCR產物或該core 173RT Not-SalI PCR產物與從PstI-NotI得到的合成寡核苷酸(PN)連接到pT7Blue2 PstI-SalI亞克隆載體上。確證序列後，用PstI和SalI消化pT2Blue2core121RT克隆#9和pTBlue2core173RT克隆#11，分別得到403bp和559bp的PstI-SalI片段，將它們用於進一步的克隆。
如上述，在克隆pd.ΔNS3NS5.PJ的過程中從pSP72 HindIII-SalI克隆#6中分離出一個121bp的NotI-PatI片段。將NotI-PstI和PstI-SalI片段裝配到用NotI和SalI消化pd.NS3NS5.PJ克隆#5(如上述)得到的載體中。
ΔNS3NS5和Core 140和Core 150發現HCV核心表位(第121-135個胺基酸的HCV核心)引起狒狒的CTL。由於pd.ΔNS3NS5.PJ.core.121RT正好在這個潛在重要的表位之前終止，並且它的表達要好於較長的pd.ΔNS3NS5.PJ.core.173RT構建物(實施例2)，所以製成含有這個表位的兩個中間構建物，就有可能獲得折中的表達水平。這兩個新的構建物將HCV核心第1-140個胺基酸或HCV核心第1-150個胺基酸融合到ΔNS3NS5.PJ的C末端中。
pd.ΔNS3NS5.PJ.core.140RT(圖21，SEQ ID NO16)和pd.ΔNS3NS5.PJ.core.150RT(圖22，SEQ ID NO18)如圖20所示，對pd.ΔNS3NS5.PJ.core.173RT克隆#6進行PCR，從中擴增得到PstI-SalI HCVcore140RT片段和PstI-SalIHCVcore150RT片段。將任一HCV核心PstI-SalI PCR產物連接到pT7Blue2 PstI-SalI亞克隆載體中。確證序列後，用PstI-SalI消化pT7Blue2core140RT克隆#22和pT7Blue2core150RT克隆#26，分別得到460bp和490bp的PstI-SalI片段，將所得片段用於進一步的克隆。
如上述，在克隆pd.ΔNS3NS5.PJ的過程中從pSP72 HindIII-SalI克隆#6中分離出一個121bp的NotI-PstI片段。將NotI-PstI和PstI-SalI片段裝配到用NotI和SalI消化pd.NS3NS5.PJ克隆#5(如上述)得到的載體中。實施例2蛋白質表達本文上述各種編碼HCV-1ΔNS3和NS5抗原(第1242-3011個胺基酸)的構建物都可在酵母中表達。用pd.ΔNS3NS5轉化釀酒酵母AD3株，然後檢測其表達。在預期的194kD的分子量位置上沒有觀察到被染色蛋白質的條帶(
圖12)。還用pd.ΔNS3NS5.PJ克隆#5轉化AD3株，然後檢測其表達。檢測到所期望的194kD分子量位置上的蛋白質條帶(
圖15)。
用pd.ΔNS3NS5.PJ.core121RT克隆#6和pd.ΔNS3NS5.PJ.core173RT克隆#15轉化AD3株，然後檢測它們的表達。分別在期望的分子量206kD和210kD處觀察到蛋白質條帶。pd.ΔNS3NS5.PJ.core173RT構建物的表達水平比pd.ΔNS3NS5.PJ.core121RT構建物的低得多(見
圖19)。因此，蛋白質表達水平和HCV核心長度之間有聯繫。
用pd.ΔNS3NS5.PJ.core140RT克隆#29和pd.ΔNS3NS5.PJ.core150RT克隆#35轉化AD3株，然後檢測其表達。通過染色，在期望的分子量為208kD和209kD處觀察到條帶，這個水平與pd.ΔNS3NS5.PJ.core173RT的接近(圖23)。實施例3免疫應答的引起A.免疫接種為了評價這些突變型NS多肽的免疫原性，使用豚鼠、家兔、小鼠、獼猴和/或狒狒進行研究。如下進行該研究單獨用DNA免疫接種(一次或多次)；DNA免疫接種後接著用蛋白質免疫接種(增強)；DNA免疫接種後接著用蛋白質免疫接種；用PLG粒子接種。經肌肉內或經黏膜接種。
B.體液免疫應答在免疫接種後的不同時間進行抗NS抗體ELISA(酶聯免疫吸附檢測)，檢測經免疫的動物的血清樣品中的體液免疫應答。簡言之，在從經免疫的動物的血清中篩選出針對NS或突變型NS蛋白質的抗體。將所選擇的HCV蛋白質塗布在ELISA微滴定板的孔中，使其過夜，然後洗滌4次；接著，使用PBS-0.2％Tween(Sigma)進行阻斷。棄去阻斷溶液後，加入稀釋的小鼠血清。以各種稀釋液測試血清。洗滌該微滴定板後，用第二種偶聯了過氧化物酶的抗小鼠IgG抗體(Pierce，Rockford，IL)進行培育。再洗滌該ELISA板，然後在每個孔中加入3，3＇，5，5＇-四甲基聯苯胺(TMB，Pierce)。測量各孔的光密度。一般以產生半量最大光密度(O.D.)的血清稀釋度的倒數記錄滴度。同樣，可採用本領域已知的方法測量結合(NOB)抗體中和反應的產生。
C.細胞免疫應答通過肽脈衝處理的Balb/c小鼠CD4細胞的標準鉻釋放試驗評價特異性細胞毒性T淋巴細胞(CTL)的頻率。簡言之，從經免疫的BALB/c小鼠得到脾細胞(效應細胞，E)，將其培育，再刺激，然後檢測針對HCV肽-脈衝的靶細胞的CTL活性。在標準的51Cr釋放試驗中測量細胞毒性活性。實施例4用PLG-傳送的DNA免疫接種從Boehringer Ingellheim(U.S.A.)得到聚丙交酯-共-乙交酯(PLG)聚合物。該PLG聚合物是RG505，它的共聚物比例是50/50，分子量是65kDa(製造商數據)。採用改性溶劑蒸發法製備吸附有DNA的陽離子微粒，基本上如Singh等人，Proc.Natl.Acad.Sci.USA(2000)，97811-816中所述。簡言之，使用IKA均質器以高速率用PBS使5％w/v的聚合物溶液在二氯甲烷中乳化。然後將初步的乳化液加到含有溴化十六烷基三甲銨(CTAB)(0.5％w/v)的蒸餾水中。這個操作獲得水包油油包水的乳化液，室溫攪拌該乳化液，使二氯甲烷蒸發。在蒸餾水中離心洗滌所得微粒，然後凍幹。在製備、洗滌和收集之後，將這些陽離子微粒加到DNA溶液中培育，DNA被吸附到這些微粒上。然後離心分離出這些微粒，用TE緩衝液洗滌這些微粒，然後將其凍幹，再懸浮，然後給予動物。進行ELISA測量抗體滴度。
序列表110希龍公司120新穎的HCV非結構多肽130PP01617.00314014116019170PatentIn Ver.2.021012119620212DNA213人工序列220221CDS222(1990)..(7302)220223人工序列的描述C型肝炎pns3454001cgcgcgtttc ggtgatgacg gtgaaaacct ctgacacatg cagctcccgg agacggtcac 60agcttgtctg taagcggatg ccgggagcag acaagcccgt cagggcgcgt cagcgggtgt 120tggcgggtgt cggggctggc ttaactatgc ggcatcagag cagattgtac tgagagtgca 180ccatatgaag ctttttgcaa aagcctaggc ctccaaaaaa gcctcctcac tacttctgga 240atagctcaga ggccgaggcg gcctcggcct ctgcataaat aaaaaaaatt agtcagccat 300ggggcggaga atgggcggaa ctgggcgggg agggaattat tggctattgg ccattgcata 360cgttgtatct atatcataat atgtacattt atattggctc atgtccaata tgaccgccat 420gttgacattg attattgact agttattaat agtaatcaat tacggggtca ttagttcata 480gcccatatat ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc 540ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag 600ggactttcca ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac 660atcaagtgta tcatatgcca agtccgcccc ctattgacgt caatgacggt aaatggcccg 720cctggcatta tgcccagtac atgaccttac gggactttcc tacttggcag tacatctacg 780tattagtcat cgctattacc atggtgatgc ggttttggca gtacaccaat gggcgtggat 840agcggtttga ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt 900tttggcacca aaatcaacgg gactttccaa aatgtcgtaa taaccccgcc ccgttgacgc 960aaatgggcgg taggcgtgta cggtgggagg tctatataag cagagctcgt ttagtgaacc 1020gtcagatcgc ctggagacgc catccacgct gttttgacct ccatagaaga caccgggacc 1080gatccagcct ccgcggccgg gaacggtgca ttggaacgcg gattccccgt gccaagagtg 1140acgtaagtac cgcctataga ctctataggc acaccccttt ggctcttatg catgctatac 1200tgtttttggc ttggggccta tacacccccg ctccttatgc tataggtgat ggtatagctt 1260agcctatagg tgtgggttat tgaccattat tgaccactcc cctattggtg acgatacttt 1320ccattactaa tccataacat ggctctttgc cacaactatc tctattggct atatgccaat 1380actctgtcct tcagagactg acacggactc tgtattttta caggatgggg tccatttatt 1440atttacaaat tcacatatac aacaacgccg tcccccgtgc ccgcagtttt tattaaacat 1500agcgtgggat ctccgacatc tcgggtacgt gttccggaca tgggctcttc tccggtagcg 1560gcggagcttc cacatccgag ccctggtccc atccgtccag cggctcatgg tcgctcggca 1620gctccttgct cctaacagtg gaggccagac ttaggcacag cacaatgccc accaccacca 1680gtgtgccgca caaggccgtg gcggtagggt atgtgtctga aaatgagctc ggagattggg 1740ctcgcacctg gacgcagatg gaagacttaa ggcagcggca gaagaagatg caggcagctg 1800agttgttgta ttctgataag agtcagaggt aactcccgtt gcggtgctgt taacggtgga 1860gggcagtgta gtctgagcag tactcgttgc tgccgcgcgc gccaccagac ataatagctg 1920acagactaac agactgttcc tttccatggg tcttttctgc agtcaccgtc gtcgacctaa 1980gaattcacc atg gct gca tat gca gct cag ggc tat aag gtg cta gta ctc 2031Met Ala Ala Tyr Ala Ala Gln Gly Tyr Lys Val Leu Val Leu1 5 10aac ccc tct gtt gct gca aca ctg ggc ttt ggt gct tac atg tcc aag 2079Asn Pro Ser Val Ala Ala Thr Leu Gly Phe Gly Ala Tyr Met Ser Lys15 20 25 30gct cat ggg atc gat cct aac atc agg acc ggg gtg aga aca att acc 2127Ala His Gly Ile Asp Pro Asn Ile Arg Thr Gly Val Arg Thr Ile Thr35 40 45act ggc agc ccc atc acg tac tcc acc tac ggc aag ttc ctt gcc gac 2175Thr Gly Ser Pro Ile Thr Tyr Ser Thr Tyr Gly Lys Phe Leu Ala Asp50 55 60ggc ggg tgc tcg ggg ggc gct tat gac ata ata att tgt gac gag tgc 2223Gly Gly Cys Ser Gly Gly Ala Tyr Asp Ile Ile Ile Cys Asp Glu Cys65 70 75cac tcc acg gat gcc aca tcc atc ttg ggc att ggc act gtc ctt gac 2271His Ser Thr Asp Ala Thr Ser Ile Leu Gly Ile Gly Thr Val Leu Asp80 85 90caa gca gag act gcg ggg gcg aga ctg gtt gtg ctc gcc acc gcc acc 2319Gln Ala Glu Thr Ala Gly Ala Arg Leu Val Val Leu Ala Thr Ala Thr95 100 105 110cct ccg ggc tcc gtc act gtg ccc cat ccc aac atc gag gag gtt gct 2367Pro Pro Gly Ser Val Thr Val Pro His Pro Asn Ile Glu Glu Val Ala115 120 125ctg tcc acc acc gga gag atc cct ttt tac ggc aag gct atc ccc ctc 2415Leu Ser Thr Thr Gly Glu Ile Pro Phe Tyr Gly Lys Ala Ile Pro Leu130 135 140gaa gta atc aag ggg ggg aga cat ctc atc ttc tgt cat tca aag aag 2463Glu Val Ile Lys Gly Gly Arg His Leu Ile Phe Cys His Ser Lys Lys145 150 155aag tgc gac gaa ctc gcc gca aag ctg gtc gca ttg ggc atc aat gcc 2511Lys Cys Asp Glu Leu Ala Ala Lys Leu Val Ala Leu Gly Ile Asn Ala160 165 170gtg gcc tac tac cgc ggt ctt gac gtg tcc gtc atc ccg acc agc ggc 2559Val Ala Tyr Tyr Arg Gly Leu Asp Val Ser Val Ile Pro Thr Ser Gly175 180 185 190gat gtt gtc gtc gtg gca acc gat gcc ctc atg acc ggc tat acc ggc 2607Asp Val Val Val Val Ala Thr Asp Ala Leu Met Thr Gly Tyr Thr Gly195 200 205gac ttc gac tcg gtg ata gac tgc aat acg tgt gtc acc cag aca gtc 2655Asp Phe Asp Ser Val Ile Asp Cys Asn Thr Cys Val Thr Gln Thr Val210 215 220gat ttc agc ctt gac cct acc ttc acc att gag aca atc acg ctc ccc 2703Asp Phe Ser Leu Asp Pro Thr Phe Thr Ile Glu Thr Ile Thr Leu Pro225 230 235caa gat gct gtc tcc cgc act caa cgt cgg ggc agg act ggc agg ggg 2751Gln Asp Ala Val Ser Arg Thr Gln Arg Arg Gly Arg Thr Gly Arg Gly240 245 250aag cca ggc atc tac aga ttt gtg gca ccg ggg gag cgc ccc tcc ggc 2799Lys Pro Gly Ile Tyr Arg Phe Val Ala Pro Gly Glu Arg Pro Ser Gly255 260 265 270atg ttc gac tcg tcc gtc ctc tgt gag tgc tat gac gca ggc tgt gct 2847Met Phe Asp Ser Ser Val Leu Cys Glu Cys Tyr Asp Ala Gly Cys Ala275 280 285tgg tat gag ctc acg ccc gcc gag act aca gtt agg cta cga gcg tac 2895Trp Tyr Glu Leu Thr Pro Ala Glu Thr Thr Val Arg Leu Arg Ala Tyr290 295 300atg aac acc ccg ggg ctt ccc gtg tgc cag gac cat ctt gaa ttt tgg 2943Met Asn Thr Pro Gly Leu Pro Val Cys Gln Asp His Leu Glu Phe Trp305 310 315gag ggc gtc ttt aca ggc ctc act cat ata gat gcc cac ttt cta tcc 2991Glu Gly Val Phe Thr Gly Leu Thr His Ile Asp Ala His Phe Leu Ser320 325 330cag aca aag cag agt ggg gag aac ctt cct tac ctg gta gcg tac caa 3039Gln Thr Lys Gln Ser Gly Glu Asn Leu Pro Tyr Leu Val Ala Tyr Gln335 340 345 350gcc acc gtg tgc gct agg gct caa gcc cct ccc cca tcg tgg gac cag 3087Ala Thr Val Cys Ala Arg Ala Gln Ala Pro Pro Pro Ser Trp Asp Gln355 360 365atg tgg aag tgt ttg att cgc ctc aag ccc acc ctc cat ggg cca aca 3135Met Trp Lys Cys Leu Ile Arg Leu Lys Pro Thr Leu His Gly Pro Thr370 375 380ccc ctg cta tac aga ctg ggc gct gtt cag aat gaa atc acc ctg acg 3183Pro Leu Leu Tyr Arg Leu Gly Ala Val Gln Asn Glu Ile Thr Leu Thr385 390 395cac cca gtc acc aaa tac atc atg aca tgc atg tcg gcc gac ctg gag 3231His Pro Val Thr Lys Tyr Ile Met Thr Cys Met Ser Ala Asp Leu Glu400 405 410gtc gtc acg agc acc tgg gtg ctc gtt ggc ggc gtc ctg gct gct ttg 3279Val Val Thr Ser Thr Trp Val Leu Val Gly Gly Val Leu Ala Ala Leu415 420 425 430gcc gcg tat tgc ctg tca aca ggc tgc gtg gtc ata gtg ggc agg gtc 3327Ala Ala Tyr Cys Leu Ser Thr Gly Cys Val Val Ile Val Gly Arg Val435 440 445gtc ttg tcc ggg aag ccg gca atc ata cct gac agg gaa gtc ctc tac 3375Val Leu Ser Gly Lys Pro Ala Ile Ile Pro Asp Arg Glu Val Leu Tyr450 455 460cga gag ttc gat gag atg gaa gag tgc tct cag cac tta ccg tac atc 3423Arg Glu Phe Asp Glu Met Glu Glu Cys Ser Gln His Leu Pro Tyr Ile465 470 475gag caa ggg atg atg ctc gcc gag cag ttc aag cag aag gcc ctc ggc 3471Glu Gln Gly Met Met Leu Ala Glu Gln Phe Lys Gln Lys Ala Leu Gly480 485 490ctc ctg cag acc gcg tcc cgt cag gca gag gtt atc gcc cct gct gtc 3519Leu Leu Gln Thr Ala Ser Arg Gln Ala Glu Val Ile Ala Pro Ala Val495 500 505 510cag acc aac tgg caa aaa ctc gag acc ttc tgg gcg aag cat atg tgg 3567Gln Thr Asn Trp Gln Lys Leu Glu Thr Phe Trp Ala Lys His Met Trp515 520 525aac ttc atc agt ggg ata caa tac ttg gcg ggc ttg tca acg ctg cct 3615Asn Phe Ile Ser Gly Ile Gln Tyr Leu Ala Gly Leu Ser Thr Leu Pro530 535 540ggt aac ccc gcc att gct tca ttg atg gct ttt aca gct gct gtc acc 3663Gly Asn Pro Ala Ile Ala Ser Leu Met Ala Phe Thr Ala Ala Val Thr545 550 555agc cca cta acc act agc caa acc ctc ctc ttc aac ata ttg ggg ggg 3711Ser Pro Leu Thr Thr Ser Gln Thr Leu Leu Phe Asn Ile Leu Gly Gly560 565 570tgg gtg gct gcc cag crc gcc gcc ccc ggt gcc gct act gcc ttt gtg 3759Trp Val Ala Ala Gln Leu Ala Ala Pro Gly Ala Ala Thr Ala Phe Val575 580 585 590ggc gct ggc tta gct ggc gcc gcc atc ggc agt gtt gga ctg ggg aag 3807Gly Ala Gly Leu Ala Gly Ala Ala Ile Gly Ser Val Gly Leu Gly Lys595 600 605gtc ctc ata gac atc ctt gca ggg tat ggc gcg ggc gtg gcg gga gct 3855Val Leu Ile Asp Ile Leu Ala Gly Tyr Gly Ala Gly Val Ala Gly Ala610 615 620ctt gtg gca ttc aag atc atg agc ggt gag gtc ccc tcc acg gag gac 3903Leu Val Ala Phe Lys Ile Met Ser Gly Glu Val Pro Ser Thr Glu Asp625 630 635ctg gtc aat cta ctg ccc gcc atc ctc tcg ccc gga gcc ctc gta gtc 3951Leu Val Asn Leu Leu Pro Ala Ile Leu Ser Pro Gly Ala Leu Val Val640 645 650ggc gtg gtc tgt gca gca ata ctg cgc cgg cac gtt ggc ccg ggc gag 3999Gly Val Val Cys Ala Ala Ile Leu Arg Arg His Val Gly Pro Gly Glu655 660 665 670ggg gca gtg cag tgg atg aac cgg ctg ata gcc ttc gcc tcc cgg ggg 4047Gly Ala Val Gln Trp Met Asn Arg Leu Ile Ala Phe Ala Ser Arg Gly675 680 685aac cat gtt tcc ccc acg cac tac gtg ccg gag agc gat gca gct gcc 4095Asn His Val Ser Pro Thr His Tyr Val Pro Glu Ser Asp Ala Ala Ala690 695 700cgc gtc act gcc ata ctc agc agc ctc act gta acc cag ctc ctg agg 4143Arg Val Thr Ala Ile Leu Ser Ser Leu Thr Val Thr Gln Leu Leu Arg705 710 715cga ctg cac cag tgg ata agc tcg gag tgt acc act cca tgc tcc ggt 4191Arg Leu His Gln Trp Ile Ser Ser Glu Cys Thr Thr Pro Cys Ser Gly720 725 730tcc tgg cta agg gac atc tgg gac tgg ata tgc gag gtg ttg agc gac 4239Ser Trp Leu Arg Asp Ile Trp Asp Trp Ile Cys Glu Val Leu Ser Asp735 740 745 750ttt aag acc tgg cta aaa gct aag ctc atg cca cag ctg cct ggg atc 4287Phe Lys Thr Trp Leu Lys Ala Lys Leu Met Pro Gln Leu Pro Gly Ile755 760 765ccc ttt gtg tcc tgc cag cgc ggg tat aag ggg gtc tgg cga ggg gac 4335Pro Phe Val Ser Cys Gln Arg Gly Tyr Lys Gly Val Trp Arg Gly Asp770 775 780ggc atc atg cac act cgc tgc cac tgt gga gct gag atc act gga cat 4383Gly Ile Met His Thr Arg Cys His Cys Gly Ala Glu Ile Thr Gly His785 790 795gtc aaa aac ggg acg atg agg atc gtc ggt cct agg acc tgc agg aac 4431Val Lys Asn Gly Thr Met Arg Ile Val Gly Pro Arg Thr Cys Arg Asn800 805 810atg tgg agt ggg acc ttc ccc att aat gcc tac acc acg ggc ccc tgt 4479Met Trp Ser Gly Thr Phe Pro Ile Asn Ala Tyr Thr Thr Gly Pro Cys815 820 825 830acc ccc ctt cct gcg ccg aac tac acg ttc gcg cta tgg agg gtg tct 4527Thr Pro Leu Pro Ala Pro Asn Tyr Thr Phe Ala Leu Trp Arg Val Ser835 840 845gca gag gaa tac gtg gag ata agg cag gtg ggg gac ttc cac tac gtg 4575Ala Glu Glu Tyr Val Glu Ile Arg Gln Val Gly Asp Phe His Tyr Val850 855 860acg ggt atg act act gac aat ctt aaa tgc ccg tgc cag gtc cca tcg 4623Thr Gly Met Thr Thr Asp Asn Leu Lys Cys Pro Cys Gln Val Pro Ser865 870 875ccc gaa ttt ttc aca gaa ttg gac ggg gtg cgc cta cat agg ttt gcg 4671Pro Glu Phe Phe Thr Glu Leu Asp Gly Val Arg Leu His Arg Phe Ala880 885 890ccc ccc tgc aag ccc ttg ctg cgg gag gag gta tca ttc aga gta gga 4719Pro Pro Cys Lys Pro Leu Leu Arg Glu Glu Val Ser Phe Arg Val Gly895 900 905 910ctc cac gaa tac ccg gta ggg tcg caa tta cct tgc gag ccc gaa ccg 4767Leu His Glu Tyr Pro Val Gly Ser Gln Leu Pro Cys Glu Pro Glu Pro915 920 925gac gtg gcc gtg ttg acg tcc atg ctc act gat ccc tcc cat ata aca 4815Asp Val Ala Val Leu Thr Ser Met Leu Thr Asp Pro Ser His Ile Thr930 935 940gca gag gcg gcc ggg cga agg ttg gcg agg gga tca ccc ccc tct gtg 4863Ala Glu Ala Ala Gly Arg Arg Leu Ala Arg Gly Ser Pro Pro Ser Val945 950 955gcc agc tcc tcg gct agc cag cta tcc gct cca tct ctc aag gca act 4911Ala Ser Ser Ser Ala Ser Gln Leu Ser Ala Pro Ser Leu Lys Ala Thr960 965 970tgc acc gct aac cat gac tcc cct gat gct gag ctc ata gag gcc aac 4959Cys Thr Ala Asn His Asp Ser Pro Asp Ala Glu Leu Ile Glu Ala Asn975 980 985 990ctc cta tgg agg cag gag atg ggc ggc aac atc acc agg gtt gag tca 5007Leu Leu Trp Arg Gln Glu Met Gly Gly Asn Ile Thr Arg Val Glu Ser99510001005gaa aac aaa gtg gtg att ctg gac tcc ttc gat ccg ctt gtg gcg gag 5055Glu Asn Lys Val Val Ile Leu Asp Ser Phe Asp Pro Leu Val Ala Glu101010151020gag gac gag cgg gag atc tcc gta ccc gca gaa atc ctg cgg aag tct 5103Glu Asp Glu Arg Glu Ile Ser Val Pro Ala Glu Ile Leu Arg Lys Ser102510301035cgg aga ttc gcc cag gcc ctg ccc gtt tgg gcg cgg ccg gac tat aac 5151Arg Arg Phe Ala Gln Ala Leu Pro Val Trp Ala Arg Pro Asp Tyr Asn104010451050ccc ccg cta gtg gag acg tgg aaa aag ccc gac tac gaa cca cct gtg 5199Pro Pro Leu Val Glu Thr Trp Lys Lys Pro Asp Tyr Glu Pro Pro Val1055 106010651070gtc cat ggc tgc ccg ctt cca cct cca aag tcc cct cct gtg cct ccg 5247Val His Gly Cys Pro Leu Pro Pro Pro Lys Ser Pro Pro Val Pro Pro107510801085cct cgg aag aag cgg acg gtg gtc ctc act gaa tca acc cta tct act 5295Pro Arg Lys Lys Arg Thr Val Val Leu Thr Glu Ser Thr Leu Ser Thr109010951100gcc ttg gcc gag ctc gcc acc aga agc ttt ggc agc tcc tca act tcc 5343Ala Leu Ala Glu Leu Ala Thr Arg Ser Phe Gly Ser Ser Ser Thr Ser110511101115ggc att acg ggc gac aat acg aca aca tcc tct gag ccc gcc cct tct 5391Gly Ile Thr Gly Asp Asn Thr Thr Thr Ser Ser Glu Pro Ala Pro Ser11201125ll30ggc tgc ccc ccc gac tcc gac gct gag tcc tat tcc tcc atg ccc ccc 5439Gly Cys Pro Pro Asp Ser Asp Ala Glu Ser Tyr Ser Ser Met Pro Pro1135 114011451150ctg gag ggg gag cct ggg gat ccg gat ctt agc gac ggg tca tgg tca 5487Leu Glu Gly Glu Pro Gly Asp Pro Asp Leu Ser Asp Gly Ser Trp Ser115511601165acg gtc agt agt gag gcc aac gcg gag gat gtc gtg tgc tgc tca atg 5535Thr Val Ser Ser Glu Ala Asn Ala Glu Asp Val Val Cys Cys Ser Met117011751180tct tac tct tgg aca ggc gca ctc gtc acc ccg tgc gcc gcg gaa gaa 5583Ser Tyr Ser Trp Thr Gly Ala Leu Val Thr Pro Cys Ala Ala Glu Glu118511901195cag aaa ctg ccc atc aat gca cta agc aac tcg ttg cta cgt cac cac 5631Gln Lys Leu Pro Ile Asn Ala Leu Ser Asn Ser Leu Leu Arg His His120012051210aat ttg gtg tat tcc acc acc tca cgc agt gct tgc caa agg cag aag 5679Asn Leu Val Tyr Ser Thr Thr Ser Arg Ser Ala Cys Gln Arg Gln Lys1215 1220 1225 1230aaa gtc aca ttt gac aga ctg caa gtt ctg gac agc cat tac cag gac 5727Lys Val Thr Phe Asp Arg Leu Gln Val Leu Asp Ser His Tyr Gln Asp123512401245gta ctc aag gag gtt aaa gca gcg gcg tca aaa gtg aag gct aac ttg 5775Val Leu Lys Glu Val Lys Ala Ala Ala Ser Lys Val Lys Ala Asn Leu125012551260cta tcc gta gag gaa gct tgc agc ctg acg ccc cca cac tca gcc aaa 5823Leu Ser Val Glu Glu Ala Cys Ser Leu Thr Pro Pro His Ser Ala Lys126512701275tcc aag ttt ggt tat ggg gca aaa gac gtc cgt tgc cat gcc aga aag 5871Ser Lys Phe Gly Tyr Gly Ala Lys Asp Val Arg Cys His Ala Arg Lys128012851290gcc gta acc cac atc aac tcc gtg tgg aaa gac ctt ctg gaa gac aat 5919Ala Val Thr His Ile Asn Ser Val Trp Lys Asp Leu Leu Glu Asp Asn1295 130013051310gta aca cca ata gac act acc atc atg gct aag aac gag gtt ttc tgc 5967Val Thr Pro Ile Asp Thr Thr Ile Met Ala Lys Asn Glu Val Phe Cys131513201325gtt cag cct gag aag ggg ggt cgt aag cca gct cgt ctc atc gtg ttc 6015Val Gln Pro Glu Lys Gly Gly Arg Lys Pro Ala Arg Leu Ile Val Phe133013351340ccc gat ctg ggc gtg cgc gtg tgc gaa aag atg gct ttg tac gac gtg 6063Pro Asp Leu Gly Val Arg Val Cys Glu Lys Met Ala Leu Tyr Asp Val134513501355gtt aca aag ctc ccc ttg gcc gtg atg gga agc tcc tac gga ttc caa 6111Val Thr Lys Leu Pro Leu Ala Val Met Gly Ser Ser Tyr Gly Phe Gln136013651370tac tca cca gga cag cgg gtt gaa ttc ctc gtg caa gcg tgg aag tcc 6159Tyr Ser Pro Gly Gln Arg Val Glu Phe Leu Val Gln Ala Trp Lys Ser1375 138013851390aag aaa acc cca atg ggg ttc tcg tat gat acc cgc tgc ttt gac tcc 6207Lys Lys Thr Pro Met Gly Phe Ser Tyr Asp Thr Arg Cys Phe Asp Ser139514001405aca gtc act gag agc gac atc cgt acg gag gag gca atc tac caa tgt 6255Thr Val Thr Glu Ser Asp Ile Arg Thr Glu Glu Ala Ile Tyr Gln Cys141014151420tgt gac ctc gac ccc caa gcc cgc gtg gcc atc aag tcc ctc acc gag 6303Cys Asp Leu Asp Pro Gln Ala Arg Val Ala Ile Lys Ser Leu Thr Glu142514301435agg ctt tat gtt ggg ggc cct ctt acc aat tca agg ggg gag aac tgc 6351Arg Leu Tyr Val Gly Gly Pro Leu Thr Asn Ser Arg Gly Glu Asn Cys144014451450ggc tat cgc agg tgc cgc gcg agc ggc gta ctg aca act agc tgt ggt 6399Gly Tyr Arg Arg Cys Arg Ala Ser Gly Val Leu Thr Thr Ser Cys Gly1455 146014651470aac acc ctc act tgc tac atc aag gcc cgg gca gcc tgt cga gcc gca 6447Asn Thr Leu Thr Cys Tyr Ile Lys Ala Arg Ala Ala Cys Arg Ala Ala147514801485ggg ctc cag gac tgc acc atg ctc gtg tgt ggc gac gac tta gtc gtt 6495Gly Leu Gln Asp Cys Thr Met Leu Val Cys Gly Asp Asp Leu Val Val149014951500atc tgt gaa agc gcg ggg gtc cag gag gac gcg gcg agc ctg aga gcc 6543Ile Cys Glu Ser Ala Gly Val Gln Glu Asp Ala Ala Ser Leu Arg Ala150515101515ttc acg gag gct atg acc agg tac tcc gcc ccc cct ggg gac ccc cca 6591Phe Thr Glu Ala Met Thr Arg Tyr Ser Ala Pro Pro Gly Asp Pro Pro152015251530caa cca gaa tac gac ttg gag ctc ata aca tca tgc tcc tcc aac gtg 6639Gln Pro Glu Tyr Asp Leu Glu Leu Ile Thr Ser Cys Ser Ser Asn Val1535 154015451550tca gtc gcc cac gac ggc gct gga aag agg gtc tac tac ctc acc cgt 6687Ser Val Ala His Asp Gly Ala Gly Lys Arg Val Tyr Tyr Leu Thr Arg155515601565gac cct aca acc ccc ctc gcg aga gct gcg tgg gag aca gca aga cac 6735Asp Pro Thr Thr Pro Leu Ala Arg Ala Ala Trp Glu Thr Ala Arg His157015751580act cca gtc aat tcc tgg cta ggc aac ata atc atg ttt gcc ccc aca 6783Thr Pro Val Asn Ser Trp Leu Gly Asn Ile Ile Met Phe Ala Pro Thr158515901595ctg tgg gcg agg atg ata ctg atg acc cat ttc ttt agc gtc ctt ata 6831Leu Trp Ala Arg Met Ile Leu Met Thr His Phe Phe Ser Val Leu Ile160016051610gcc agg gac cag ctt gaa cag gcc ctc gat tgc gag atc tac ggg gcc 6879Ala Arg Asp Gln Leu Glu Gln Ala Leu Asp Cys Glu Ile Tyr Gly Ala1615 162016251630tgc tac tcc ata gaa cca ctg gat cta cct cca atc att caa aga ctc 6927Cys Tyr Ser Ile Glu Pro Leu Asp Leu Pro Pro Ile Ile Gln Arg Leu163516401645cat ggc ctc agc gca ttt tca ctc cac agt tac tct cca ggt gaa atc 6975His Gly Leu Ser Ala Phe Ser Leu His Ser Tyr Ser Pro Gly Glu Ile165016551660aat agg gtg gcc gca tgc ctc aga aaa ctt ggg gta ccg ccc ttg cga 7023Asn Arg Val Ala Ala Cys Leu Arg Lys Leu Gly Val Pro Pro Leu Arg166516701675gct tgg aga cac cgg gcc cgg agc gtc cgc gct agg ctt ctg gcc aga 7071Ala Trp Arg His Arg Ala Arg Ser Val Arg Ala Arg Leu Leu Ala Arg168016851690gga ggc agg gct gcc ata tgt ggc aag tac ctc ttc aac tgg gca gta 7119Gly Gly Arg Ala Ala Ile Cys Gly Lys Tyr Leu Phe Asn Trp Ala Val1695 170017051710aga aca aag ctc aaa ctc act cca ata gcg gcc gct ggc cag ctg gac 7167Arg Thr Lys Leu Lys Leu Thr Pro Ile Ala Ala Ala Gly Gln Leu Asp171517201725ttg tcc ggc tgg ttc acg gct ggc tac agc ggg gga gac att tat cac 7215Leu Set Gly Trp Phe Thr Ala Gly Tyr Set Gly Gly Asp Ile Tyr His173017351740agc gtg tct cat gcc cgg ccc cgc tgg atc tgg ttt tgc cta ctc ctg 7263Set Val Ser His Ala Arg Pro Arg Trp Ile Trp Phe Cys Leu Leu Leu174517501755ctt gct gca ggg gta ggc atc tac ctc ctc ccc aac cga tgaaggttgg7312Leu Ala Ala Gly Val Gly Ile Tyr Leu Leu Pro Asn Arg176017651770ggtaaacact ccggcctaaa aaaaaaaaaa aatctagaaa ggcgcgccaa gatatcaagg 7372atccactacg cgttagagct cgctgatcag cctcgactgt gccttctagt tgccagccat 7432ctgttgtttg cccctccccc gtgccttcct tgaccctgga aggtgccact cccactgtcc 7492tttcctaata aaatgaggaa attgcatcgc attgtctgag taggtgtcat tctattctgg 7552ggggtggggt ggggcaggac agcaaggggg aggattggga agacaatagc aggcatgctg 7612gggagctctt ccgcttcctc gctcactgac tcgctgcgct cggtcgttcg gctgcggcga 7672gcggtatcag ctcactcaaa ggcggtaata cggttatcca cagaatcagg ggataacgca 7732ggaaagaaca tgtgagcaaa aggccagcaa aaggccagga accgtaaaaa ggccgcgttg 7792ctggcgtttt tccataggct ccgcccccct gacgagcatc acaaaaatcg acgctcaagt 7852cagaggtggc gaaacccgac aggactataa agataccagg cgtttccccc tggaagctcc 7912ctcgtgcgct ctcctgttcc gaccctgccg cttaccggat acctgtccgc ctttctccct 7972tcgggaagcg tggcgctttc tcaatgctca cgctgtaggt atctcagttc ggtgtaggtc 8032gttcgctcca agctgggctg tgtgcacgaa ccccccgttc agcccgaccg ctgcgcctta 8092tccggtaact atcgtcttga gtccaacccg gtaagacacg acttatcgcc actggcagca 8152gccactggta acaggattag cagagcgagg tatgtaggcg gtgctacaga gttcttgaag 8212tggtggccta actacggcta cactagaagg acagtatttg gtatctgcgc tctgctgaag 8272ccagttacct tcggaaaaag agttggtagc tcttgatccg gcaaacaaac caccgctggt 8332agcggtggtt tttttgtttg caagcagcag attacgcgca gaaaaaaagg atctcaagaa 8392gatcctttga tcttttctac ggggtctgac gctcagtgga acgaaaactc acgttaaggg 8452attttggtca tgagattatc aaaaaggatc ttcacctaga tccttttaaa ttaaaaatga 8512agttttaaat caatctaaag tatatatgag taaacttggt ctgacagtta ccaatgctta 8572atcagtgagg cacctatctc agcgatctgt ctatttcgtt catccatagt tgcctgactc 8632cccgtcgtgt agataactac gatacgggag ggcttaccat ctggccccag tgctgcaatg 8692ataccgcgag acccacgctc accggctcca gatttatcag caataaacca gccagccgga 8752agggccgagc gcagaagtgg tcctgcaact ttatccgcct ccatccagtc tattaattgt 8812tgccgggaag ctagagtaag tagttcgcca gttaatagtt tgcgcaacgt tgttgccatt 8872gctacaggca tcgtggtgtc acgctcgtcg tttggtatgg cttcattcag ctccggttcc 8932caacgatcaa ggcgagttac atgatccccc atgttgtgca aaaaagcggt tagctccttc 8992ggtcctccga tcgttgtcag aagtaagttg gccgcagtgt tatcactcat ggttatggca 9052gcactgcata attctcttac tgtcatgcca tccgtaagat gcttttctgt gactggtgag 9112tactcaacca agtcattctg agaatagtgt atgcggcgac cgagttgctc ttgcccggcg 9172tcaatacggg ataataccgc gccacatagc agaactttaa aagtgctcat cattggaaaa 9232cgttcttcgg ggcgaaaact ctcaaggatc ttaccgctgt tgagatccag ttcgatgtaa 9292cccactcgtg cacccaactg atcttcagca tcttttactt tcaccagcgt ttctgggtga 9352gcaaaaacag gaaggcaaaa tgccgcaaaa aagggaataa gggcgacacg gaaatgttga 9412atactcatac tcttcctttt tcaatattat tgaagcattt atcagggtta ttgtctcatg 9472agcggataca tatttgaatg tatttagaaa aataaacaaa taggggttcc gcgcacattt 9532ccccgaaaag tgccacctga cgtctaagaa accattatta tcatgacatt aacctataaa 9592aataggcgta tcacgaggcc ctttcgtc962021022111771212PRT213C型肝炎病毒220223人工序列的描述C型肝炎pns3454002Met Ala Ala Tyr Ala Ala Gln Gly Tyr Lys Val Leu Val Leu Asn Pro1 5 10 15Ser Val Ala Ala Thr Leu Gly Phe Gly Ala Tyr Met Ser Lys Ala His20 25 30Gly Ile Asp Pro Asn Ile Arg Thr Gly Val Arg Thr Ile Thr Thr Gly35 40 45Ser Pro Ile Thr Tyr Ser Thr Tyr Gly Lys Phe Leu Ala Asp Gly Gly50 55 60Cys Ser Gly Gly Ala Tyr Asp Ile Ile Ile Cys Asp Glu Cys His Ser65 70 75 80Thr Asp Ala Thr Ser Ile Leu Gly Ile Gly Thr Val Leu Asp Gln Ala85 90 95Glu Thr Ala Gly Ala Arg Leu Val Val Leu Ala Thr Ala Thr Pro Pro100 105 110Gly Ser Val Thr Val Pro His Pro Asn Ile Glu Glu Val Ala Leu Ser115 120 125Thr Thr Gly Glu Ile Pro Phe Tyr Gly Lys Ala Ile Pro Leu Glu Val130 135 140Ile Lys Gly Gly Arg His Leu Ile Phe Cys His Ser Lys Lys Lys Cys145 150 155 160Asp Glu Leu Ala Ala Lys Leu Val Ala Leu Gly Ile Asn Ala Val Ala165 170 175Tyr Tyr Arg Gly Leu Asp Val Ser Val Ile Pro Thr Ser Gly Asp Val180 185 190Val Val Val Ala Thr Asp Ala Leu Met Thr Gly Tyr Thr Gly Asp Phe195 200 205Asp Ser Val Ile Asp Cys Asn Thr Cys Val Thr Gln Thr Val Asp Phe210 215 220Ser Leu Asp Pro Thr Phe Thr Ile Glu Thr Ile Thr Leu Pro Gln Asp225 230 235 240Ala Val Ser Arg Thr Gln Arg Arg Gly Arg Thr Gly Arg Gly Lys Pro245 250 255Gly Ile Tyr Arg Phe Val Ala Pro Gly Glu Arg Pro Ser Gly Met Phe260 265 270Asp Ser Ser Val Leu Cys Glu Cys Tyr Asp Ala Gly Cys Ala Trp Tyr275 280 285Glu Leu Thr Pro Ala Glu Thr Thr Val Arg Leu Arg Ala Tyr Met Asn290 295 300Thr Pro Gly Leu Pro Val Cys Gln Asp His Leu Glu Phe Trp Glu Gly305 310 315 320Val Phe Thr Gly Leu Thr His Ile Asp Ala His Phe Leu Ser Gln Thr325 330 335Lys Gln Ser Gly Glu Asn Leu Pro Tyr Leu Val Ala Tyr Gln Ala Thr340 345 350Val Cys Ala Arg Ala Gln Ala Pro Pro Pro Ser Trp Asp Gln Met Trp355 360 365Lys Cys Leu Ile Arg Leu Lys Pro Thr Leu His Gly Pro Thr Pro Leu370 375 380Leu Tyr Arg Leu Gly Ala Val Gln Asn Glu Ile Thr Leu Thr His Pro385 390395 400Val Thr Lys Tyr Ile Met Thr Cys Met Ser Ala Asp Leu Glu Val Val405 410 415Thr Ser Thr Trp Val Leu Val Gly Gly Val Leu Ala Ala Leu Ala Ala420 425 430Tyr Cys Leu Ser Thr Gly Cys Val Val Ile Val Gly Arg Val Val Leu435 440 445Ser Gly Lys Pro Ala Ile Ile Pro Asp Arg Glu Val Leu Tyr Arg Glu450 455 460Phe Asp Glu Met Glu Glu Cys Ser Gln His Leu Pro Tyr Ile Glu Gln465 470475 480Gly Met Met Leu Ala Glu Gln Phe Lys Gln Lys Ala Leu Gly Leu Leu485 490 495Gln Thr Ala Ser Arg Gln Ala Glu Val Ile Ala Pro Ala Val Gln Thr500 505 510Asn Trp Gln Lys Leu Glu Thr Phe Trp Ala Lys His Met Trp Asn Phe515 520 525Ile Ser Gly Ile Gln Tyr Leu Ala Gly Leu Ser Thr Leu Pro Gly Asn530 535 540Pro Ala Ile Ala Ser Leu Met Ala Phe Thr Ala Ala Val Thr Ser Pro545 550 555 560Leu Thr Thr Ser Gln Thr Leu Leu Phe Asn Ile Leu Gly Gly Trp Val565 570 575Ala Ala Gln Leu Ala Ala Pro Gly Ala Ala Thr Ala Phe Val Gly Ala580 585 590Gly Leu Ala Gly Ala Ala Ile Gly Ser Val Gly Leu Gly Lys Val Leu595 600 605Ile Asp Ile Leu Ala Gly Tyr Gly Ala Gly Val Ala Gly Ala Leu Val610 615 620Ala Phe Lys Ile Met Ser Gly Glu Val Pro Ser Thr Glu Asp Leu Val625 630 635 640Asn Leu Leu Pro Ala Ile Leu Ser Pro Gly Ala Leu Val Val Gly Val645 650 655Val Cys Ala Ala Ile Leu Arg Arg His Val Gly Pro Gly Glu Gly Ala660 665 670Val Gln Trp Met Asn Arg Leu Ile Ala Phe Ala Ser Arg Gly Asn His675 680 685Val Ser Pro Thr His Tyr Val Pro Glu Ser Asp Ala Ala Ala Arg Val690 695 700Thr Ala Ile Leu Ser Ser Leu Thr VaI Thr Gln Leu Leu Arg Arg Leu705 710 715 720His Gln Trp Ile Ser Ser Glu Cys Thr Thr Pro Cys Ser Gly Ser Trp725 730 735Leu Arg Asp Ile Trp Asp Trp Ile Cys Glu Val Leu Ser Asp Phe Lys740 745 750Thr Trp Leu Lys Ala Lys Leu Met Pro Gln Leu Pro Gly Ile Pro Phe755 760 765Val Ser Cys Gln Arg Gly Tyr Lys Gly Val Trp Arg Gly Asp Gly Ile770 775 780Met His Thr Arg Cys His Cys Gly Ala Glu Ile Thr Gly His Val Lys785 790 795 800Asn Gly Thr Met Arg Ile Val Gly Pro Arg Thr Cys Arg Asn Met Trp805 810 815Ser Gly Thr Phe Pro Ile Asn Ala Tyr Thr Thr Gly Pro Cys Thr Pro820 825 830Leu Pro Ala Pro Asn Tyr Thr Phe Ala Leu Trp Arg Val Ser Ala Glu835 840 845Glu Tyr Val Glu Ile Arg Gln Val Gly Asp Phe His Tyr Val Thr Gly850 855 860Met Thr Thr Asp Asn Leu Lys Cys Pro Cys Gln Val Pro Ser Pro Glu865 870 875 880Phe Phe Thr Glu Leu Asp Gly Val Arg Leu His Arg Phe Ala Pro Pro885 890 895Cys Lys Pro Leu Leu Arg Glu Glu Val Ser Phe Arg Val Gly Leu His900 905 910Glu Tyr Pro Val Gly Ser Gln Leu Pro Cys Glu Pro Glu Pro Asp Val915 920 925Ala Val Leu Thr Ser Met Leu Thr Asp Pro Ser His Ile Thr Ala Glu930 935 940Ala Ala Gly Arg Arg Leu Ala Arg Gly Ser Pro Pro Ser Val Ala Ser945 950 955 960Ser Ser Ala Ser Gln Leu Ser Ala Pro Ser Leu Lys Ala Thr Cys Thr965 970 975Ala Asn His Asp Ser Pro Asp Ala Glu Leu Ile Glu Ala Asn Leu Leu980 985 990Trp Arg Gln Glu Met Gly Gly Asn Ile Thr Arg Val Glu Ser Glu Asn99510001005Lys Val Val Ile Leu Asp Ser Phe Asp Pro Leu Val Ala Glu Glu Asp101010151020Glu Arg Glu Ile Ser Val Pro Ala Glu Ile Leu Arg Lys Ser Arg Arg025103010351040Phe Ala Gln Ala Leu Pro Val Trp Ala Arg Pro Asp Tyr Asn Pro Pro104510501055Leu Val Glu Thr Trp Lys Lys Pro Asp Tyr Glu Pro Pro Val Val His106010651070Gly Cys Pro Leu Pro Pro Pro Lys Ser Pro Pro Val Pro Pro Pro Arg107510801085Lys Lys Arg Thr ValVal Leu Thr Glu Ser Thr Leu Ser Thr Ala Leu1090 10951100Ala Glu Leu Ala Thr Arg Ser Phe Gly Ser Ser Ser Thr Ser Gly Ile105111011151120Thr Gly Asp Asn Thr Thr Thr Ser Ser Glu Pro Ala Pro Ser Gly Cys112511301135Pro Pro Asp Ser Asp Ala Glu Ser Tyr Ser Ser Met Pro Pro Leu Glu114011451150Gly Glu Pro Gly Asp Pro Asp Leu Ser Asp Gly Ser Trp Ser Thr Val115511601165Ser Ser Glu Ala Asn Ala Glu Asp Val Val Cys Cys Ser Met Ser Tyr117011751180Ser Trp Thr Gly Ala Leu Val Thr Pro Cys Ala Ala Glu Glu Gln Lys185119011951200Leu Pro Ile Asn Ala Leu Ser Asn Ser Leu Leu Arg His His Asn Leu120512101215Val Tyr Ser Thr Thr Ser Arg Ser Ala Cys Gln Arg Gln Lys Lys Val122012251230Thr Phe Asp Arg Leu Gln Val Leu Asp Ser His Tyr Gln Asp Val Leu123512401245Lys Glu Val Lys Ala Ala Ala Ser Lys Val Lys Ala Asn Leu Leu Ser125012551260Val Glu Glu Ala Cys Ser Leu Thr Pro Pro His Ser Ala Lys Ser Lys265127012751280Phe Gly Tyr Gly Ala Lys Asp Val Arg Cys His Ala Arg Lys Ala Val128512901295Thr His Ile Asn Ser Val Trp Lys Asp Leu Leu Glu Asp Asn Val Thr130013051310Pro Ile Asp Thr Thr Ile Met Ala Lys Asn Glu Val Phe Cys Val Gln131513201325Pro Glu Lys Gly Gly Arg Lys Pro Ala Arg Leu Ile Val Phe Pro Asp133013351340Leu Gly Val Arg Val Cys Glu Lys Met Ala Leu Tyr Asp Val Val Thr345135013551360Lys Leu Pro Leu Ala Val Met Gly Ser Ser Tyr Gly Phe Gln Tyr Ser136513701375Pro Gly Gln Arg Val Glu Phe Leu Val Gln Ala Trp Lys Ser Lys Lys138013851390Thr Pro Met Gly Phe Ser Tyr Asp Thr Arg Cys Phe Asp Ser Thr Val139514001405Thr Glu Ser Asp Ile Arg Thr Glu Glu Ala Ile Tyr Gln Cys Cys Asp141014151420Leu Asp Pro Gln Ala Arg Val Ala Ile Lys Ser Leu Thr Glu Arg Leu425143014351440Tyr Val Gly Gly Pro Leu Thr Asn Ser Arg Gly Glu Asn Cys Gly Tyr144514501455Arg Arg Cys Arg Ala Ser Gly Val Leu Thr Thr Ser Cys Gly Asn Thr146014651470Leu Thr Cys Tyr Ile Lys Ala Arg Ala Ala Cys Arg Ala Ala Gly Leu147514801485Gln Asp Cys Thr Met Leu Val Cys Gly Asp Asp Leu Val Val Ile Cys149014951500Glu Ser Ala Gly Val Gln Glu Asp Ala Ala Ser Leu Arg Ala Phe Thr505151015151520Glu Ala Met Thr Arg Tyr Ser Ala Pro Pro Gly Asp Pro Pro Gln Pro152515301535Glu Tyr Asp Leu Glu Leu Ile Thr Ser Cys Ser Ser Asn Val Ser Val154015451550Ala His Asp Gly Ala Gly Lys Arg Val Tyr Tyr Leu Thr Arg Asp Pro155515601565Thr Thr Pro Leu Ala Arg Ala Ala Trp Glu Thr Ala Arg His Thr Pro157015751580Val Asn Ser Trp Leu Gly Asn Ile Ile Met Phe Ala Pro Thr Leu Trp585159015951600Ala Arg Met Ile Leu Met Thr His Phe Phe Ser Val Leu Ile Ala Arg160516101615Asp Gln Leu Glu Gln Ala Leu Asp Cys Glu Ile Tyr Gly Ala Cys Tyr162016251630Ser Ile Glu Pro Leu Asp Leu Pro Pro Ile Ile Gln Arg Leu His Gly163516401645Leu Ser Ala Phe Ser Leu His Ser Tyr Ser Pro Gly Glu Ile Asn Arg165016551660Val Ala Ala Cys Leu Arg Lys Leu Gly Val Pro Pro Leu Arg Ala Trp665167016751680Arg His Arg Ala Arg Ser Val Arg Ala Arg Leu Leu Ala Arg Gly Gly168516901695Arg Ala Ala Ile Cys Gly Lys Tyr Leu Phe Asn Trp Ala Val Arg Thr170017051710Lys Leu Lys Leu Thr Pro Ile Ala Ala Ala Gly Gln Leu Asp Leu Ser171517201725Gly Trp Phe Thr Ala Gly Tyr Ser Gly Gly Asp Ile Tyr His Ser Val173017351740Ser His Ala Arg Pro Arg Trp Ile Trp Phe Cys Leu Leu Leu Leu Ala745175017551760Ala Gly Val Gly Ile Tyr Leu Leu Pro Asn Arg1765177021032119620212DNA213人工序列22022lCDS222(1990)..(7302)220223人工序列的描述pDeltaNS3NS54003cgcgcgtttc ggtgatgacg gtgaaaacct ctgacacatg cagctcccgg agacggtcac 60agcttgtctg taagcggatg ccgggagcag acaagcccgt cagggcgcgt cagcgggtgt 120tggcgggtgt cggggctggc ttaactatgc ggcatcagag cagattgtac tgagagtgca 180ccatatgaag ctttttgcaa aagcctaggc ctccaaaaaa gcctcctcac tacttctgga 240atagctcaga ggccgaggcg gcctcggcct ctgcataaat aaaaaaaatt agtcagccat 300ggggcggaga atgggcggaa ctgggcgggg agggaattat tggctattgg ccattgcata 360cgttgtatct atatcataat atgtacattt atattggctc atgtccaata tgaccgccat 420gttgacattg attattgact agttattaat agtaatcaat tacggggtca ttagttcata 480gcccatatat ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc 540ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag 600ggactttcca ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac 660atcaagtgta tcatatgcca agtccgcccc ctattgacgt caatgacggt aaatggcccg 720cctggcatta tgcccagtac atgaccttac gggactttcc tacttggcag tacatctacg 780tattagtcat cgctattacc atggtgatgc ggttttggca gtacaccaat gggcgtggat 840agcggtttga ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt 900tttggcacca aaatcaacgg gactttccaa aatgtcgtaa taaccccgcc ccgttgacgc 960aaatgggcgg taggcgtgta cggtgggagg tctatataag cagagctcgt ttagtgaacc 1020gtcagatcgc ctggagacgc catccacgct gttttgacct ccatagaaga caecgggacc 1080gatccagcct ccgcggccgg gaacggtgca ttggaacgcg gattccccgt gccaagagtg 1140acgtaagtac cgcctataga ctctataggc acaccccttt ggctcttatg catgctatac 1200tgtttttggc ttggggccta tacacccccg ctccttatgc tataggtgat ggtatagctt 1260agcctatagg tgtgggttat tgaccattat tgaccactcc cctattggtg acgatacttt 1320ccattactaa tccataacat ggctctttgc cacaactatc tctattggct atatgccaat 1380actctgtcct tcagagactg acacggactc tgtattttta caggatgggg tccatttatt 1440atttacaaat tcacatatac aacaacgccg tcccccgtgc ccgcagtttt tattaaacat 1500agcgtgggat ctccgacatc tcgggtacgt gttccggaca tgggctcttc tccggtagcg 1560gcggagcttc cacatccgag ccctggtccc atccgtccag cggctcatgg tcgctcggca 1620gctccttgct cctaacagtg gaggccagac ttaggcacag cacaatgccc accaccacca 1680gtgtgccgca caaggccgtg gcggtagggt atgtgtctga aaatgagctc ggagattggg 1740ctcgcacctg gacgcagatg gaagacttaa ggcagcggca gaagaagatg caggcagctg 1800agttgttgta ttctgataag agtcagaggt aactcccgtt gcggtgctgt taacggtgga 1860gggcagtgta gtctgagcag tactcgttgc tgccgcgcgc gccaccagac ataatagctg 1920acagactaac agactgttcc tttccatggg tcttttctgc agtcaccgtc gtcgacctaa 1980gaattcacc atg gct gca tat gca gct cag ggc tat aag gtg cta gta ctc 2031Met Ala Ala Tyr Ala Ala Gln Gly Tyr Lys Val Leu Val Leu1 5 10aac ccc tct gtt gct gca aca ctg ggc ttt ggt gct tac atg tcc aag 2079Asn Pro Ser Val Ala Ala Thr Leu Gly Phe Gly Ala Tyr Met Ser Lys15 20 25 30gct cat ggg atc gat cct aac atc agg acc ggg gtg aga aca att acc 2127Ala His Gly Ile Asp Pro Asn Ile Arg Thr Gly Val Arg Thr Ile Thr35 40 45act ggc agc ccc atc acg tac tcc acc tac ggc aag ttc ctt gcc gac 2175Thr Gly Ser Pro Ile Thr Tyr Ser Thr Tyr Gly Lys Phe Leu Ala Asp50 55 60ggc ggg tgc tcg ggg ggc gct tat gac ata ata att tgt gac gag tgc 2223Gly Gly Cys Ser Gly Gly Ala Tyr Asp Ile Ile Ile Cys Asp Glu Cys65 70 75cac tcc acg gat gcc aca tcc atc ttg ggc att ggc act gtc ctt gac 2271His Ser Thr Asp Ala Thr Ser Ile Leu Gly Ile Gly Thr Val Leu Asp80 85 90caa gca gag act gcg ggg gcg aga ctg gtt gtg ctc gcc acc gcc acc 2319Gln Ala Glu Thr Ala Gly Ala Arg Leu Val Val Leu Ala Thr Ala Thr95 100 105 110cct ccg ggc tcc gtc act gtg ccc cat ccc aac atc gag gag gtt gct 2367Pro Pro Gly Ser Val Thr Val Pro His Pro Asn Ile Glu Glu Val Ala115 120 125ctg tcc acc acc gga gag atc cct ttt tac ggc aag gct atc ccc ctc 2415Leu Ser Thr Thr Gly Glu Ile Pro Phe Tyr Gly Lys Ala Ile Pro Leu
130 135 140gaa gta atc aag ggg ggg aga cat ctc atc ttc tgt cat tca aag aag 2463Glu Val Ile Lys Gly Gly Arg His Leu Ile Phe Cys His Ser Lys Lys145 150 155aag tgc gac gaa ctc gcc gca aag ctg gtc gca ttg ggc atc aat gcc 2511Lys Cys Asp Glu Leu Ala Ala Lys Leu Val Ala Leu Gly Ile Asn Ala160 165 170gtg gcc tac tac cgc ggt ctt gac gtg tcc gtc atc ccg acc agc ggc 2559Val Ala Tyr Tyr Arg Gly Leu Asp Val Ser Val Ile Pro Thr Ser Gly175 180 185 190gat gtt gtc gtc gtg gca acc gat gcc ctc atg acc ggc tat acc ggc 2607Asp Val Val Val Val Ala Thr Asp Ala Leu Met Thr Gly Tyr Thr Gly195 200 205gac ttc gac tcg gtg ata gac tgc aat acg tgt gtc acc cag aca gtc 2655Asp Phe Asp Ser Val Ile Asp Cys Asn Thr Cys Val Thr Gln Thr Val210 215 220gat ttc agc ctt gac cct acc ttc acc att gag aca atc acg ctc ccc 2703Asp Phe Ser Leu Asp Pro Thr Phe Thr Ile Glu Thr Ile Thr Leu Pro225 230 235caa gat gct gtc tcc cgc act caa cgt cgg ggc agg act ggc agg ggg 2751Gln Asp Ala Val Ser Arg Thr Gln Arg Arg Gly Arg Thr Gly Arg Gly240 245 250aag cca ggc atc tac aga ttt gtg gca ccg ggg gag cgc ccc tcc ggc 2799Lys Pro Gly Ile Tyr Arg Phe Val Ala Pro Gly Glu Arg Pro Ser Gly255 260 265 270atg ttc gac tcg tcc gtc ctc tgt gag tgc tat gac gca ggc tgt gct 2847Met Phe Asp Ser Ser Val Leu Cys Glu Cys Tyr Asp Ala Gly Cys Ala275 280 285tgg tat gag ctc acg ccc gcc gag act aca gtt agg cta cga gcg tac 2895Trp Tyr Glu Leu Thr Pro Ala Glu Thr Thr Val Arg Leu Arg Ala Tyr290 295 300atg aac acc ccg ggg ctt ccc gtg tgc cag gac cat ctt gaa ttt tgg 2943Met Asn Thr Pro Gly Leu Pro Val Cys Gln Asp His Leu Glu Phe Trp305 310 315gag ggc gtc ttt aca ggc ctc act cat ata gat gcc cac ttt cta tcc 2991Glu Gly Val Phe Thr Gly Leu Thr His Ile Asp Ala His Phe Leu Ser320 325 330cag aca aag cag agt ggg gag aac ctt cct tac ctg gta gcg tac caa 3039Gln Thr Lys Gln Ser Gly Glu Asn Leu Pro Tyr Leu Val Ala Tyr Gln335 340 345 350gcc acc gtg tgc gct agg gct caa gcc cct ccc cca tcg tgg gac cag 3087Ala Thr Val Cys Ala Arg Ala Gln Ala Pro Pro Pro Ser Trp Asp Gln355 360 365atg tgg aag tgt ttg att cgc ctc aag ccc acc ctc cat ggg cca aca 3135Met Trp Lys Cys Leu Ile Arg Leu Lys Pro Thr Leu His Gly Pro Thr
370 375 380ccc ctg cta tac aga ctg ggc gct gtt cag aat gaa atc acc ctg acg 3183Pro Leu Leu Tyr Arg Leu Gly Ala Val Gln Asn Glu Ile Thr Leu Thr385 390 395cac cca gtc acc aaa tac atc atg aca tgc atg tcg gcc gac ctg gag 3231His Pro Val Thr Lys Tyr Ile Met Thr Cys Met Ser Ala Asp Leu Glu400 405 410gtc gtc acg agc acc tgg gtg ctc gtt ggc ggc gtc ctg gct gct ttg 3279Val Val Thr Ser Thr Trp Val Leu Val Gly Gly Val Leu Ala Ala Leu415 420 425 430gcc gcg tat tgc ctg tca aca ggc tgc gtg gtc ata gtg ggc agg gtc 3327Ala Ala Tyr Cys Leu Ser Thr Gly Cys Val Val Ile Val Gly Arg Val435 440 445gtc ttg tcc ggg aag ccg gca atc ata cct gac agg gaa gtc ctc tac 3375Val Leu Ser Gly Lys Pro Ala Ile Ile Pro Asp Arg Glu Val Leu Tyr450 455 460cga gag ttc gat gag atg gaa gag tgc tct cag cac tta ccg tac atc 3423Arg Glu Phe Asp Glu Met Glu Glu Cys Ser Gln His Leu Pro Tyr Ile465 470 475gag caa ggg atg atg ctc gcc gag cag ttc aag cag aag gcc ctc ggc 3471Glu Gln Gly Met Met Leu Ala Glu Gln Phe Lys Gln Lys Ala Leu Gly480 485 490ctc ctg cag acc gcg tcc cgt cag gca gag gtt atc gcc cct gct gtc 3519Leu Leu Gln Thr Ala Ser Arg Gln Ala Glu Val Ile Ala Pro Ala Val495 500 505 510cag acc aac tgg caa aaa ctc gag acc ttc tgg gcg aag cat atg tgg 3567Gln Thr Asn Trp Gln Lys Leu Glu Thr Phe Trp Ala Lys His Met Trp515 520 525aac ttc atc agt ggg ata caa tac ttg gcg ggc ttg tca acg ctg cct 3615Asn Phe Ile Set Gly Ile Gln Tyr Leu Ala Gly Leu Ser Thr Leu Pro530 535 540ggt aac ccc gcc att gct tca ttg atg gct ttt aca gct gct gtc acc 3663Gly Asn Pro Ala Ile Ala Ser Leu Met Ala Phe Thr Ala Ala Val Thr545 550 555agc cca cta acc act agc caa acc ctc ctc ttc aac ara ttg ggg ggg 3711Ser Pro Leu Thr Thr Ser Gln Thr Leu Leu Phe Asn Ile Leu Gly Gly560 565 570tgg gtg gct gcc cag ctc gcc gcc ccc ggt gcc gct act gcc ttt gtg 3759Trp Val Ala Ala Gln Leu Ala Ala Pro Gly Ala Ala Thr Ala Phe Val575 580 585 590ggc gct ggc tta gct ggc gcc gcc atc ggc agt gtt gga ctg ggg aag 3807Gly Ala Gly Leu Ala Gly Ala Ala Ile Gly Ser Val Gly Leu Gly Lys595 600 605gtc ctc ata gac atc ctt gca ggg tat ggc gcg ggc gtg gcg gga gct 3855Val Leu Ile Asp Ile Leu Ala Gly Tyr Gly Ala Gly Val Ala Gly Ala
610 615 620ctt gtg gca ttc aag atc atg agc ggt gag gtc ccc tcc acg gag gac 3903Leu Val Ala Phe Lys Ile Met Ser Gly Glu Val Pro Ser Thr Glu Asp625 630 635ctg gtc aat cta ctg ccc gcc atc ctc tcg ccc gga gcc ctc gta gtc 3951Leu Val Asn Leu Leu Pro Ala Ile Leu Ser Pro Gly Ala Leu Val Val640 645 650ggc gtg gtc tgt gca gca ata ctg cgc cgg cac gtt ggc ccg ggc gag 3999Gly Val Val Cys Ala Ala Ile Leu Arg Arg His Val Gly Pro Gly Glu655 660 665 670ggg gca gtg cag tgg atg aac cgg ctg ata gcc ttc gcc tcc cgg ggg 4047Gly Ala Val Gln Trp Met Asn Arg Leu Ile Ala Phe Ala Ser Arg Gly675 680 685aac cat gtt tcc ccc acg cac tac gtg ccg gag agc gat gca gct gcc 4095Asn His Val Ser Pro Thr His Tyr Val Pro Glu Ser Asp Ala Ala Ala690 695 700cgc gtc act gcc ata ctc agc agc ctc act gta acc cag ctc ctg agg 4143Arg Val Thr Ala Ile Leu Ser Ser Leu Thr Val Thr Gln Leu Leu Arg705 710 715cga ctg cac cag tgg ata agc tcg gag tgt acc act cca tgc tcc ggt 4191Arg Leu His Gln Trp Ile Ser Ser Glu Cys Thr Thr Pro Cys Ser Gly720 725 730tcc tgg cta agg gac atc tgg gac tgg ata tgc gag gtg ttg agc gac 4239Ser Trp Leu Arg Asp Ile Trp Asp Trp Ile Cys Glu Val Leu Ser Asp735 740 745 750ttt aag acc tgg cta aaa gct aag ctc atg cca cag ctg cct ggg atc 4287Phe Lys Thr Trp Leu Lys Ala Lys Leu Met Pro Gln Leu Pro Gly Ile755 760 765ccc ttt gtg tcc tgc cag cgc ggg tat aag ggg gtc tgg cga ggg gac 4335Pro Phe Val Ser Cys Gln Arg Gly Tyr Lys Gly Val Trp Arg Gly Asp770 775 780ggc atc atg cac act cgc tgc cac tgt gga gct gag atc act gga cat 4383Gly Ile Met His Thr Arg Cys His Cys Gly Ala Glu Ile Thr Gly His785 790 795gtc aaa aac ggg acg atg agg atc gtc ggt cct agg acc tgc agg aac 4431Val Lys Asn Gly Thr Met Arg Ile Val Gly Pro Arg Thr Cys Arg Asn800 805 810atg tgg agt ggg acc ttc ccc att aat gcc tac acc acg ggc ccc tgt 4479Met Trp Ser Gly Thr Phe Pro Ile Asn Ala Tyr Thr Thr Gly Pro Cys815 820 825 830acc ccc ctt cct gcg ccg aac tac acg ttc gcg cta tgg agg gtg tct 4527Thr Pro Leu Pro Ala Pro Asn Tyr Thr Phe Ala Leu Trp Arg Val Ser835 840 845gca gag gaa tac gtg gag ata agg cag gtg ggg gac ttc cac tac gtg 4575Ala Glu Glu Tyr Val Glu Ile Arg Gln Val Gly Asp Phe His Tyr Val
850 855 860acg ggt atg act act gac aat ctt aaa tgc ccg tgc cag gtc cca tcg 4623Thr Gly Met Thr Thr Asp Asn Leu Lys Cys Pro Cys Gln Val Pro Ser865 870 875ccc gaa ttt ttc aca gaa ttg gac ggg gtg cgc cta cat agg ttt gcg 4671Pro Glu Phe Phe Thr Glu Leu Asp Gly Val Arg Leu His Arg Phe Ala880 885 890ccc ccc tgc aag ccc ttg ctg cgg gag gag gta tca ttc aga gta gga 4719Pro Pro Cys Lys Pro Leu Leu Arg Glu Glu Val Ser Phe Arg Val Gly895 900 905 910ctc cac gaa tac ccg gta ggg tcg caa tta cct tgc gag ccc gaa ccg 4767Leu His Glu Tyr Pro Val Gly Ser Gln Leu Pro Cys Glu Pro Glu Pro915 920 925gac gtg gcc gtg ttg acg tcc atg ctc act gat ccc tcc cat ata aca 4815Asp Val Ala Val Leu Thr Ser Met Leu Thr Asp Pro Ser His Ile Thr930 935 940gca gag gcg gcc ggg cga agg ttg gcg agg gga tca ccc ccc tct gtg 4863Ala Glu Ala Ala Gly Arg Arg Leu Ala Arg Gly Ser Pro Pro Ser Val945 950 955gcc agc tcc tcg gct agc cag cra tcc gct cca tct ctc aag gca act 4911Ala Ser Ser Ser Ala Ser Gln Leu Ser Ala Pro Ser Leu Lys Ala Thr960 965 970tgc acc gct aac cat gac tcc cct gat gct gag ctc ata gag gcc aac 4959Cys Thr Ala Asn His Asp Ser Pro Asp Ala Glu Leu Ile Glu Ala Asn975 980 985 990ctc cta tgg agg cag gag atg ggc ggc aac atc acc agg gtt gag tca 5007Leu Leu Trp Arg Gln Glu Met Gly Gly Asn Ile Thr Arg Val Glu Ser99510001005gaa aac aaa gtg gtg att ctg gac tcc ttc gat ccg ctt gtg gcg gag 5055Glu Asn Lys Val Val Ile Leu Asp Ser Phe Asp Pro Leu Val Ala Glu101010151020gag gac gag cgg gag atc tcc gta ccc gca gaa atc ctg cgg aag tct 5103Glu Asp Glu Arg Glu Ile Ser Val Pro Ala Glu Ile Leu Arg Lys Ser102510301035cgg aga ttc gcc cag gcc ctg ccc gtt tgg gcg cgg ccg gac tat aac 5151Arg Arg Phe Ala Gln Ala Leu Pro Val Trp Ala Arg Pro Asp Tyr Asn104010451050ccc ccg cta gtg gag acg tgg aaa aag ccc gac tac gaa cca cct gtg 5199Pro Pro Leu Val Glu Thr Trp Lys Lys Pro Asp Tyr Glu Pro Pro Val1055 106010651070gtc cat ggc tgc ccg ctt cca cct cca aag tcc cct cct gtg cct ccg 5247Val His Gly Cys Pro Leu Pro Pro Pro Lys Ser Pro Pro Val Pro Pro107510801085cct cgg aag aag cgg acg gtg gtc ctc act gaa tca acc cta tct act 5295Pro Arg Lys Lys Arg Thr Val Val Leu Thr Glu Ser Thr Leu Ser Thr
109010951100gcc ttg gcc gag ctc gcc acc aga agc ttt ggc agc tcc tca act tcc 5343Ala Leu Ala Glu Leu Ala Thr Arg Ser Phe Gly Ser Ser Ser Thr Ser110511101115ggc att acg ggc gac aat acg aca aca tcc tct gag ccc gcc cct tct 5391Gly Ile Thr Gly Asp Asn Thr Thr Thr Set Ser Glu Pro Ala Pro Ser112011251130ggc tgc ccc ccc gac tcc gac gct gag tcc tat tcc tcc atg ccc ccc 5439Gly Cys Pro Pro Asp Ser Asp Ala Glu Ser Tyr Ser Ser Met Pro Pro1135 114011451150ctg gag ggg gag cct ggg gat ccg gat ctt agc gac ggg tca tgg tca 5487Leu Glu Gly Glu Pro Gly Asp Pro Asp Leu Ser Asp Gly Ser Trp Ser115511601165acg gtc agt agt gag gcc aac gcg gag gat gtc gtg tgc tgc tca atg 5535Thr Val Ser Ser Glu Ala Asn Ala Glu Asp Val Val Cys Cys Ser Met117011751180tct tac tct tgg aca ggc gca ctc gtc acc ccg tgc gcc gcg gaa gaa 5583Ser Tyr Ser Trp Thr Gly Ala Leu Val Thr Pro Cys Ala Ala Glu Glu118511901195cag aaa ctg ccc atc aat gca cta agc aac tcg ttg cta cgt cac cac 5631Gln Lys Leu Pro Ile Asn Ala Leu Ser Asn Ser Leu Leu Arg His His120012051210aat ttg gtg tat tcc acc acc tca cgc agt gct tgc caa agg cag aag 5679Asn Leu Val Tyr Ser Thr Thr Ser Arg Ser Ala Cys Gln Arg Gln Lys1215 122012251230aaa gtc aca ttt gac aga ctg caa gtt ctg gac agc cat tac cag gac 5727Lys Val Thr Phe Asp Arg Leu Gln Val Leu Asp Ser His Tyr Gln Asp123512401245gta ctc aag gag gtt aaa gca gcg gcg tca aaa gtg aag gct aac ttg 5775Val Leu Lys Glu Val Lys Ala Ala Ala Ser Lys Val Lys Ala Asn Leu125012551260cta tcc gta gag gaa gct tgc agc ctg acg ccc cca cac tca gcc aaa 5823Leu Ser Val Glu Glu Ala Cys Ser Leu Thr Pro Pro His Ser Ala Lys126512701275tcc aag ttt ggt tat ggg gca aaa gac gtc cgt tgc cat gcc aga aag 5871Ser Lys Phe Gly Tyr Gly Ala Lys Asp Val Arg Cys His Ala Arg Lys128012851290gcc gta acc cac atc aac tcc gtg tgg aaa gac ctt ctg gaa gac aat 5919Ala Val Thr His Ile Asn Ser Val Trp Lys Asp Leu Leu Glu Asp Asn1295 130013051310gta aca cca ata gac act acc atc atg gct aag aac gag gtt ttc tgc 5967Val Thr Pro Ile Asp Thr Thr Ile Met Ala Lys Asn Glu Val Phe Cys1315 13201325gtt cag cct gag aag ggg ggt cgt aag cca gct cgt ctc atc gtg ttc 6015Val Gln Pro Glu Lys Gly Gly Arg Lys Pro Ala Arg Leu Ile Val Phe
133013351340ccc gat ctg ggc gtg cgc gtg tgc gaa aag atg gct ttg tac gac gtg 6063Pro Asp Leu Gly Val Arg Val Cys Glu Lys Met Ala Leu Tyr Asp Val134513501355gtt aca aag ctc ccc ttg gcc gtg atg gga agc tcc tac gga ttc caa 6111Val Thr Lys Leu Pro Leu Ala Val Met Gly Ser Ser Tyr Gly Phe Gln136013651370tac tca cca gga cag cgg gtt gaa ttc ctc gtg caa gcg tgg aag tcc 6159Tyr Ser Pro Gly Gln Arg Val Glu Phe Leu Val Gln Ala Trp Lys Ser1375 138013851390aag aaa acc cca atg ggg ttc tcg tat gat acc cgc tgc ttt gac tcc 6207Lys Lys Thr Pro Met Gly Phe Ser Tyr Asp Thr Arg Cys Phe Asp Ser139514001405aca gtc act gag agc gac atc cgt acg gag gag gca atc tac caa tgt 6255Thr Val Thr Glu Ser Asp Ile Arg Thr Glu Glu Ala Ile Tyr Gln Cys141014151420tgt gac ctc gac ccc caa gcc cgc gtg gcc atc aag tcc ctc acc gag 6303Cys Asp Leu Asp Pro Gln Ala Arg Val Ala Ile Lys Ser Leu Thr Glu142514301435agg ctt tat gtt ggg ggc cct ctt acc aat tca agg ggg gag aac tgc 6351Arg Leu Tyr Val Gly Gly Pro Leu Thr Asn Ser Arg Gly Glu Asn Cys144014451450ggc tat cgc agg tgc cgc gcg agc ggc gta ctg aca act agc tgt ggt 6399Gly Tyr Arg Arg Cys Arg Ala Ser Gly Val Leu Thr Thr Ser Cys Gly1455 146014651470aac acc ctc act tgc tac atc aag gcc cgg gca gcc tgt cga gcc gca 6447Asn Thr Leu Thr Cys Tyr Ile Lys Ala Arg Ala Ala Cys Arg Ala Ala147514801485ggg ctc cag gac tgc acc atg ctc gtg tgt ggc gac gac tta gtc gtt 6495Gly Leu Gln Asp Cys Thr Met Leu Val Cys Gly Asp Asp Leu Val Val149014951500atc tgt gaa agc gcg ggg gtc cag gag gac gcg gcg agc ctg aga gcc 6543Ile Cys Glu Ser Ala Gly Val Gln Glu Asp Ala Ala Ser Leu Arg Ala150515101515ttc acg gag gct atg acc agg tac tcc gcc ccc cct ggg gac ccc cca 6591Phe Thr Glu Ala Met Thr Arg Tyr Ser Ala Pro Pro Gly Asp Pro Pro152015251530caa cca gaa tac gac ttg gag ctc ata aca tca tgc tcc tcc aac gtg 6639Gln Pro Glu Tyr Asp Leu Glu Leu Ile Thr Ser Cys Ser Ser Asn Val1535 154015451550tca gtc gcc cac gac ggc gct gga aag agg gtc tac tac ctc acc cgt 6687Ser Val Ala His Asp Gly Ala Gly Lys Arg Val Tyr Tyr Leu Thr Arg155515601565gac cct aca acc ccc ctc gcg aga gct gcg tgg gag aca gca aga cac 6735Asp Pro Thr Thr Pro Leu Ala Arg Ala Ala Trp Glu Thr Ala Arg His
157015751580act cca gtc aat tcc tgg cta ggc aac ata atc atg ttt gcc ccc aca 6783Thr Pro Val Asn Ser Trp Leu Gly Asn Ile Ile Met Phe Ala Pro Thr158515901595ctg tgg gcg agg atg ata ctg atg acc cat ttc ttt agc gtc ctt ata 6831Leu Trp Ala Arg Met Ile Leu Met Thr His Phe Phe Ser Val Leu Ile160016051610gcc agg gac cag ctt gaa cag gcc ctc gat tgc gag atc tac ggg gcc 6879Ala Arg Asp Gln Leu Glu Gln Ala Leu Asp Cys Glu Ile Tyr Gly Ala1615 162016251630tgc tac tcc ata gaa cca ctg gat cta cct cca atc att caa aga ctc 6927Cys Tyr Ser Ile Glu Pro Leu Asp Leu Pro Pro Ile Ile Gln Arg Leu163516401645cat ggc ctc agc gca ttt tca ctc cac agt tac tct cca ggt gaa atc 6975His Gly Leu Ser Ala Phe Ser Leu His Ser Tyr Ser Pro Gly Glu Ile165016551660aat agg gtg gcc gca tgc ctc aga aaa ctt ggg gta ccg ccc ttg cga 7023Asn Arg Val Ala Ala Cys Leu Arg Lys Leu Gly Val Pro Pro Leu Arg166516701675gct tgg aga cac cgg gcc cgg agc gtc cgc gct agg ctt ctg gcc aga 7071Ala Trp Arg His Arg Ala Arg Ser Val Arg Ala Arg Leu Leu Ala Arg168016851690gga ggc agg gct gcc ata tgt ggc aag tac ctc ttc aac tgg gca gta 7119Gly Gly Arg Ala Ala Ile Cys Gly Lys Tyr Leu Phe Asn Trp Ala Val1695 170017051710aga aca aag ctc aaa ctc act cca ata gcg gcc gct ggc cag ctg gac 7167Arg Thr Lys Leu Lys Leu Thr Pro Ile Ala Ala Ala Gly Gln Leu Asp171517201725ttg tcc ggc tgg ttc acg gct ggc tac agc ggg gga gac att tat cac 7215Leu Ser Gly Trp Phe Thr Ala Gly Tyr Ser Gly Gly Asp Ile Tyr His173017351740agc gtg tct cat gcc cgg ccc cgc tgg atc tgg ttt tgc cta ctc ctg 7263Ser Val Ser His Ala Arg Pro Arg Trp Ile Trp Phe Cys Leu Leu Leu174517501755ctt gct gca ggg gta ggc atc tac ctc ctc ccc aac cga tgaaggttgg7312Leu Ala Ala Gly Val Gly Ile Tyr Leu Leu Pro Asn Arg176017651770ggtaaacact ccggcctaaa aaaaaaaaaa aatctagaaa ggcgcgccaa gatatcaagg 7372atccactacg cgttagagct cgctgatcag cctcgactgt gccttctagt tgccagccat 7432ctgttgtttg cccctccccc gtgccttcct tgaccctgga aggtgccact cccactgtcc 7492tttcctaata aaatgaggaa attgcatcgc attgtctgag taggtgtcat tctattctgg 7552ggggtggggt ggggcaggac agcaaggggg aggattggga agacaatagc aggcatgctg 7612gggagctctt ccgcttcctc gctcactgac tcgctgcgct cggtcgttcg gctgcggcga 7672gcggtatcag ctcactcaaa ggcggtaata cggttatcca cagaatcagg ggataacgca 7732ggaaagaaca tgtgagcaaa aggccagcaa aaggccagga accgtaaaaa ggccgcgttg 7792ctggcgtttt tccataggct ccgcccccct gacgagcatc acaaaaatcg acgctcaagt 7852cagaggtggc gaaacccgac aggactataa agataccagg cgtttccccc tggaagctcc 7912ctcgtgcgct ctcctgttcc gaccctgccg cttaccggat acctgtccgc ctttctccct 7972tcgggaagcg tggcgctttc tcaatgctca cgctgtaggt atctcagttc ggtgtaggtc 8032gttcgctcca agctgggctg tgtgcacgaa ccccccgttc agcccgaccg ctgcgcctta 8092tccggtaact atcgtcttga gtccaacccg gtaagacacg acttatcgcc actggcagca 8152gccactggta acaggattag cagagcgagg tatgtaggcg gtgctacaga gttcttgaag 8212tggtggccta actacggcta cactagaagg acagtatttg gtatctgcgc tctgctgaag 8272ccagttacct tcggaaaaag agttggtagc tcttgatccg gcaaacaaac caccgctggt 8332agcggtggtt tttttgtttg caagcagcag attacgcgca gaaaaaaagg atctcaagaa 8392gatcctttga tcttttctac ggggtctgac gctcagtgga acgaaaactc acgttaaggg 8452attttggtca tgagattatc aaaaaggatc ttcacctaga tccttttaaa ttaaaaatga 8512agttttaaat caatctaaag tatatatgag taaacttggt ctgacagtta ccaatgctta 8572atcagtgagg cacctatctc agcgatctgt ctatttcgtt catccatagt tgcctgactc 8632cccgtcgtgt agataactac gatacgggag ggcttaccat ctggccccag tgctgcaatg 8692ataccgcgag acccacgctc accggctcca gatttatcag caataaacca gccagccgga 8752agggccgagc gcagaagtgg tcctgcaact ttatccgcct ccatccagtc tattaattgt 8812tgccgggaag ctagagtaag tagttcgcca gttaatagtt tgcgcaacgt tgttgccatt 8872gctacaggca tcgtggtgtc acgctcgtcg tttggtatgg cttcattcag ctccggttcc 8932caacgatcaa ggcgagttac atgatccccc atgttgtgca aaaaagcggt tagctccttc 8992ggtcctccga tcgttgtcag aagtaagttg gccgcagtgt tatcactcat ggttatggca 9052gcactgcata attctcttac tgtcatgcca tccgtaagat gcttttctgt gactggtgag 9112tactcaacca agtcattctg agaatagtgt atgcggcgac cgagttgctc ttgcccggcg 9172tcaatacggg ataataccgc gccacatagc agaactttaa aagtgctcat cattggaaaa 9232cgttcttcgg ggcgaaaact ctcaaggatc ttaccgctgt tgagatccag ttcgatgtaa 9292cccactcgtg cacccaactg atcttcagca tcttttactt tcaccagcgt ttctgggtga 9352gcaaaaacag gaaggcaaaa tgccgcaaaa aagggaataa gggcgacacg gaaatgttga 9412atactcatac tcttcctttt tcaatattat tgaagcattt atcagggtta ttgtctcatg 9472agcggataca tatttgaatg tatttagaaa aataaacaaa taggggttcc gcgcacattt 9532ccccgaaaag tgccacctga cgtctaagaa accattatta tcatgacatt aacctataaa 9592aataggcgta tcacgaggcc ctttcgtc96202l042111771212PRT213人工序列4004Met Ala Ala Tyr Ala Ala Gln Gly Tyr Lys Val Leu Val Leu Asn Pro1 5 10 15Ser Val Ala Ala Thr Leu Gly Phe Gly Ala Tyr Met Ser Lys Ala His20 25 30Gly Ile Asp Pro Asn Ile Arg Thr Gly Val Arg Thr Ile Thr Thr Gly35 40 45Ser Pro Ile Thr Tyr Ser Thr Tyr Gly Lys Phe Leu Ala Asp Gly Gly50 55 60Cys Ser Gly Gly Ala Tyr Asp Ile Ile Ile Cys Asp Glu Cys His Ser65 70 75 80Thr Asp Ala Thr Ser Ile Leu Gly Ile Gly Thr Val Leu Asp Gln Ala85 90 95Glu Thr Ala Gly Ala Arg Leu Val Val Leu Ala Thr Ala Thr Pro Pro100 105 110Gly Ser Val Thr Val Pro His Pro Asn Ile Glu Glu Val Ala Leu Ser115 120 125Thr Thr Gly Glu Ile Pro Phe Tyr Gly Lys Ala Ile Pro Leu Glu Val130 135 140Ile Lys Gly Gly Arg His Leu Ile Phe Cys His Ser Lys Lys Lys Cys145 150 155 160Asp Glu Leu Ala Ala Lys Leu Val Ala Leu Gly Ile Asn Ala Val Ala165 170 175Tyr Tyr Arg Gly Leu Asp Val Ser Val Ile Pro Thr Ser Gly Asp Val180 185 190Val Val Val Ala Thr Asp Ala Leu Met Thr Gly Tyr Thr Gly Asp Phe195 200 205Asp Ser Val Ile Asp Cys Asn Thr Cys Val Thr Gln Thr Val Asp Phe210 215 220Ser Leu Asp Pro Thr Phe Thr Ile Glu Thr Ile Thr Leu Pro Gln Asp225 230 235 240Ala Val Ser Arg Thr Gln Arg Arg Gly Arg Thr Gly Arg Gly Lys Pro245 250 255Gly Ile Tyr Arg Phe Val Ala Pro Gly Glu Arg Pro Ser Gly Met Phe260 265 270Asp Ser Ser Val Leu Cys Glu Cys Tyr Asp Ala Gly Cys Ala Trp Tyr275 280 285Glu Leu Thr Pro Ala Glu Thr Thr Val Arg Leu Arg Ala Tyr Met Asn290 295300Thr Pro Gly Leu Pro Val Cys Gln Asp His Leu Glu Phe Trp Glu Gly305 310 315 320Val Phe Thr Gly Leu Thr His Ile Asp Ala His Phe Leu Ser Gln Thr325 330 335Lys Gln Ser Gly Glu Asn Leu Pro Tyr Leu Val Ala Tyr Gln Ala Thr340 345 350Val Cys Ala Arg Ala Gln Ala Pro Pro Pro Ser Trp Asp Gln Met Trp355 360 365Lys Cys Leu Ile Arg Leu Lys Pro Thr Leu His Gly Pro Thr Pro Leu370 375 380Leu Tyr Arg Leu Gly Ala Val Gln Asn Glu Ile Thr Leu Thr His Pro385 390 395 400Val Thr Lys Tyr Ile Met Thr Cys Met Ser Ala Asp Leu Glu Val Val405 410 415Thr Ser Thr Trp Val Leu Val Gly Gly Val Leu Ala Ala Leu Ala Ala420 425 430Tyr Cys Leu Ser Thr Gly Cys Val Val Ile Val Gly Arg Val Val Leu435 440 445Ser Gly Lys Pro Ala Ile Ile Pro Asp Arg Glu Val Leu Tyr Arg Glu450 455 460Phe Asp Glu Met Glu Glu Cys Ser Gln His Leu Pro Tyr Ile Glu Gln465 470 475 480Gly Met Met Leu Ala Glu Gln Phe Lys Gln Lys Ala Leu Gly Leu Leu485 490 495Gln Thr Ala Ser Arg Gln Ala Glu Val Ile Ala Pro Ala Val Gln Thr500 505510Asn Trp Gln Lys Leu Glu Thr Phe Trp Ala Lys His Met Trp Asn Phe515 520 525Ile Ser Gly Ile Gln Tyr Leu Ala Gly Leu Ser Thr Leu Pro Gly Asn530 535 540Pro Ala Ile Ala Ser Leu Met Ala Phe Thr Ala Ala Val Thr Ser Pro545 550 555 560Leu Thr Thr Ser Gln Thr Leu Leu Phe Asn Ile Leu Gly Gly Trp Val565 570 575Ala Ala Gln Leu Ala Ala Pro Gly Ala Ala Thr Ala Phe Val Gly Ala580 585 590Gly Leu Ala Gly Ala Ala Ile Gly Ser Val Gly Leu Gly Lys Val Leu595 600605Ile Asp Ile Leu Ala Gly Tyr Gly Ala Gly Val Ala Gly Ala Leu Val610 615 620Ala Phe Lys Ile Met Ser Gly Glu Val Pro Ser Thr Glu Asp Leu Val625 630 635 640Asn Leu Leu Pro Ala Ile Leu Ser Pro Gly Ala Leu Val Val Gly Val645 650 655ValCys Ala Ala Ile Leu Arg Arg His Val Gly Pro Gly Glu Gly Ala660 665 670Val Gln Trp Met Asn Arg Leu Ile Ala Phe Ala Ser Arg Gly Asn His675 680 685Val Ser Pro Thr His Tyr Val Pro Glu Ser Asp Ala Ala Ala Arg Val690 695 700Thr Ala Ile Leu Ser Ser Leu Thr Val Thr Gln Leu Leu Arg Arg Leu705 710 715 720His Gln Trp Ile Ser Ser Glu Cys Thr Thr Pro Cys Ser Gly Ser Trp725 730 735Leu Arg Asp Ile Trp Asp Trp Ile Cys Glu Val Leu Ser Asp Phe Lys740 745 750Thr Trp Leu Lys Ala Lys Leu Met Pro Gln Leu Pro Gly Ile Pro Phe755 760 765Val Ser Cys Gln Arg Gly Tyr Lys Gly Val Trp Arg Gly Asp Gly Ile770 775 780Met His Thr Arg Cys His Cys Gly Ala Glu Ile Thr Gly His Val Lys785 790 795 800Asn Gly Thr Met Arg Ile Val Gly Pro Arg Thr Cys Arg Asn Met Trp805 810 815Ser Gly Thr Phe Pro Ile Asn Ala Tyr Thr Thr Gly Pro Cys Thr Pro820 825 830Leu Pro Ala Pro Asn Tyr Thr Phe Ala Leu Trp Arg Val Ser Ala Glu835 840 845Glu Tyr Val Glu Ile Arg Gln Val Gly Asp Phe His Tyr Val Thr Gly850 855 860Met Thr Thr Asp Asn Leu Lys Cys Pro Cys Gln Val Pro Ser Pro Glu865 870 875 880Phe Phe Thr Glu Leu Asp Gly Val Arg Leu His Arg Phe Ala Pro Pro885 890 895Cys Lys Pro Leu Leu Arg Glu Glu Val Ser Phe Arg Val Gly Leu His900 905 9l0Glu Tyr Pro Val Gly Ser Gln Leu Pro Cys Glu Pro Glu Pro Asp Val915 920 925Ala Val Leu Thr Ser Met Leu Thr Asp Pro Ser His Ile Thr Ala Glu930 935 940Ala Ala Gly Arg Arg Leu Ala Arg Gly Ser Pro Pro Ser Val Ala Ser945 950 955 960Ser Ser Ala Ser Gln Leu Ser Ala Pro Ser Leu Lys Ala Thr Cys Thr965 970 975Ala Asn His Asp Ser Pro Asp Ala Glu Leu Ile Glu Ala Asn Leu Leu980 985 990Trp Arg Gln Glu Met Gly Gly Asn Ile Thr Arg Val Glu Ser Glu Asn99510001005Lys Val Val Ile Leu Asp Ser Phe Asp Pro Leu Val Ala Glu Glu Aspl01010151020Glu Arg Glu Ile Ser Val Pro Ala Glu Ile Leu Arg Lys Ser Arg Arg025103010351040Phe Ala Gln Ala Leu Pro Val Trp Ala Arg Pro Asp Tyr Asn Pro Pro104510501055Leu Val Glu Thr Trp Lys Lys Pro Asp Tyr Glu Pro Pro Val Val His106010651070Gly Cys Pro Leu Pro Pro Pro Lys Ser Pro Pro Val Pro Pro Pro Arg107510801085Lys Lys Arg Thr Val Val Leu Thr Glu Ser Thr Leu Ser Thr Ala Leu109010951100Ala Glu Leu Ala Thr Arg Ser Phe Gly Ser Ser Ser Thr Ser Gly Ile105111011151120Thr Gly Asp Asn Thr Thr Thr Ser Ser Glu Pro Ala Pro Ser Gly Cys112511301135Pro Pro Asp Ser Asp Ala Glu Ser Tyr Ser Ser Met Pro Pro Leu Glu114011451150Gly Glu Pro Gly Asp Pro Asp Leu Ser Asp Gly Ser Trp Ser Thr Val115511601165Ser Ser Glu Ala Asn Ala Glu Asp Val Val Cys Cys Ser Met Ser Tyr117011751180Ser Trp Thr Gly Ala Leu Val Thr Pro Cys Ala Ala Glu Glu Gln Lys185119011951200Leu Pro Ile Asn Ala Leu Ser Asn Ser Leu Leu Arg His His Asn Leu120512101215Val Tyr Ser Thr Thr Ser Arg Ser Ala Cys Gln Arg Gln Lys Lys Val122012251230Thr Phe Asp Arg Leu Gln Val Leu Asp Ser His Tyr Gln Asp Val Leu123512401245Lys Glu Val Lys Ala Ala Ala Ser Lys Val Lys Ala Asn Leu Leu Ser125012551260Val Glu Glu Ala Cys Ser Leu Thr Pro Pro His Ser Ala Lys Ser Lys265127012751280Phe Gly Tyr Gly Ala Lys Asp Val Arg Cys His Ala Arg Lys Ala Val128512901295Thr His Ile Asn Ser Val Trp Lys Asp Leu Leu Glu Asp Asn Val Thr130013051310Pro Ile Asp Thr Thr Ile Met Ala Lys Asn Glu Val Phe Cys Val Gln131513201325Pro Glu Lys Gly Gly Arg Lys Pro Ala Arg Leu Ile Val Phe Pro Asp133013351340Leu Gly Val Arg Val Cys Glu Lys Met Ala Leu Tyr Asp Val Val Thr345135013551360Lys Leu Pro Leu Ala Val Met Gly Ser Ser Tyr Gly Phe Gln Tyr Ser136513701375Pro Gly Gln Arg Val Glu Phe Leu Val Gln Ala Trp Lys Ser Lys Lys138013851390Thr Pro Met Gly Phe Ser Tyr Asp Thr Arg Cys Phe Asp Ser Thr Val139514001405Thr Glu Ser Asp Ile Arg Thr Glu Glu Ala Ile Tyr Gln Cys Cys Asp141014151420Leu Asp Pro Gln Ala Arg Val Ala Ile Lys Ser Leu Thr Glu Arg Leu425143014351440Tyr Val Gly Gly Pro Leu Thr Asn Ser Arg Gly Glu Asn Cys Gly Tyr144514501455Arg Arg Cys Arg Ala Ser Gly Val Leu Thr Thr Ser Cys Gly Asn Thr146014651470Leu Thr Cys Tyr Ile Lys Ala Arg Ala Ala Cys Arg Ala Ala Gly Leu147514801485Gln Asp Cys Thr Met Leu Val Cys Gly Asp Asp Leu Val Val Ile Cys149014951500Glu Ser Ala Gly Val Gln Glu Asp Ala Ala Ser Leu Arg Ala Phe Thr505151015151520Glu Ala Met Thr Arg Tyr Ser Ala Pro Pro Gly Asp Pro Pro Gln Pro152515301535Glu Tyr Asp Leu Glu Leu Ile Thr Ser Cys Ser Ser Asn Val Ser Val154015451550Ala His Asp Gly Ala Gly Lys Arg Val Tyr Tyr Leu Thr Arg Asp Pro155515601565Thr Thr Pro Leu Ala Arg Ala Ala Trp Glu Thr Ala Arg His Thr Pro157015751580Val Asn Ser Trp Leu Gly Asn Ile Ile Met Phe Ala Pro Thr Leu Trp585159015951600Ala Arg Met Ile Leu Met Thr His Phe Phe Ser Val Leu Ile Ala Arg160516101615Asp Gln Leu Glu Gln Ala Leu Asp Cys Glu Ile Tyr Gly Ala Cys Tyr162016251630Ser Ile Glu Pro Leu Asp Leu Pro Pro Ile Ile Gln Arg Leu His Gly163516401645Leu Ser Ala Phe Ser Leu His Ser Tyr Ser Pro Gly Glu Ile Asn Arg165016551660Val Ala Ala Cys Leu Arg Lys Leu Gly Val Pro Pro Leu Arg Ala Trp665167016751680Arg His Arg Ala Arg Ser Val Arg Ala Arg Leu Leu Ala Arg Gly Gly168516901695Arg Ala Ala Ile Cys Gly Lys Tyr Leu Phe Asn Trp Ala Val Arg Thr170017051710Lys Leu Lys Leu Thr Pro lle Ala Ala Ala Gly Gln Leu Asp Leu Ser171517201725Gly Trp Phe Thr Ala Gly Tyr Ser Gly Gly Asp Ile Tyr His Ser Val173017351740Ser His Ala Arg Pro Arg Trp Ile Trp Phe Cys Leu Leu Leu Leu Ala74517501755 1760Ala Gly Val Gly Ile Tyr Leu Leu Pro Asn Arg1765177021052114282212DNA213人工序列220223人工序列的描述pCMVII4005tcgcgcgttt cggtgatgac ggtgaaaacc tctgacacat gcagctcccg gagacggtca 60cagcttgtct gtaagcggat gccgggagca gacaagcccg tcagggcgcg tcagcgggtg 120ttggcgggtg tcggggctgg cttaactatg cggcatcaga gcagattgta ctgagagtgc 180accatatgaa gctttttgca aaagcctagg cctccaaaaa agcctcctca ctacttctgg 240aatagctcag aggccgaggc ggcctcggcc tctgcataaa taaaaaaaat tagtcagcca 300tggggcggag aatgggcgga actgggcggg gagggaatta ttggctattg gccattgcat 360acgttgtatc tatatcataa tatgtacatt tatattggct catgtccaat atgaccgcca 420tgttgacatt gattattgac tagttattaa tagtaatcaa ttacggggtc attagttcat 480agcccatata tggagttccg cgttacataa cttacggtaa atggcccgcc tggctgaccg 540cccaacgacc cccgcccatt gacgtcaata atgacgtatg ttcccatagt aacgccaata 600gggactttcc attgacgtca atgggtggag tatttacggt aaactgccca cttggcagta 660catcaagtgt atcatatgcc aagtccgccc cctattgacg tcaatgacgg taaatggccc 720gcctggcatt atgcccagta catgacctta cgggactttc ctacttggca gtacatctac 780gtattagtca tcgctattac catggtgatg cggttttggc agtacaccaa tgggcgtgga 840tagcggtttg actcacgggg atttccaagt ctccacccca ttgacgtcaa tgggagtttg 900ttttggcacc aaaatcaacg ggactttcca aaatgtcgta ataaccccgc cccgttgacg 960caaatgggcg gtaggcgtgt acggtgggag gtctatataa gcagagctcg tttagtgaac 1020cgtcagatcg cctggagacg ccatccacgc tgttttgacc tccatagaag acaccgggac 1080cgatccagcc tccgcggccg ggaacggtgc attggaacgc ggattccccg tgccaagagt 1140gacgtaagta ccgcctatag actctatagg cacacccctt tggctcttat gcatgctata 1200ctgtttttgg cttggggcct atacaccccc gcttccttat gctataggtg atggtatagc 1260ttagcctata ggtgtgggtt attgaccatt attgaccact cccctattgg tgacgatact 1320ttccattact aatccataac atggctcttt gccacaacta tctctattgg ctatatgcca 1380atactctgtc cttcagagac tgacacggac tctgtatttt tacaggatgg ggtcccattt 1440attatttaca aattcacata tacaacaacg ccgtcccccg tgcccgcagt ttttattaaa 1500catagcgtgg gatctccacg cgaatctcgg gtacgtgttc cggacatggg ctcttctccg 1560gtagcggcgg agcttccaca tccgagccct ggtcccatgc ctccagcggc tcatggtcgc 1620tcggcagctc cttgctccta acagtggagg ccagacttag gcacagcaca atgcccacca 1680ccaccagtgt gccgcacaag gccgtggcgg tagggtatgt gtctgaaaat gagctcggag 1740attgggctcg caccgctgac gcagatggaa gacttaaggc agcggcagaa gaagatgcag 1800gcagctgagt tgttgtattc tgataagagt cagaggtaac tcccgttgcg gtgctgttaa 1860cggtggaggg cagtgtagtc tgagcagtac tcgttgctgc cgcgcgcgcc accagacata 1920atagctgaca gactaacaga ctgttccttt ccatgggtct tttctgcagt caccgtcgtc 1980gacctaagaa ttcagactcg agcaagtcta gaaaggcgcg ccaagatatc aaggatccac 2040tacgcgttag agctcgctga tcagcctcga ctgtgccttc tagttgccag ccatctgttg 2100tttgcccctc ccccgtgcct tccttgaccc tggaaggtgc cactcccact gtcctttcct 2160aataaaatga ggaaattgca tcgcattgtc tgagtaggtg tcattctatt ctggggggtg 2220gggtggggca ggacagcaag ggggaggatt gggaagacaa tagcaggcat gctggggagc 2280tcttccgctt cctcgctcac tgactcgctg cgctcggtcg ttcggctgcg gcgagcggta 2340tcagctcact caaaggcggt aatacggtta tccacagaat caggggataa cgcaggaaag 2400aacatgtgag caaaaggcca gcaaaaggcc aggaaccgta aaaaggccgc gttgctggcg 2460tttttccata ggctccgccc ccctgacgag catcacaaaa atcgacgctc aagtcagagg 2520tggcgaaacc cgacaggact ataaagatac caggcgtttc cccctggaag ctccctcgtg 2580cgctctcctg ttccgaccct gccgcttacc ggatacctgt ccgcctttct cccttcggga 2640agcgtggcgc tttctcaatg ctcacgctgt aggtatctca gttcggtgta ggtcgttcgc 2700tccaagctgg gctgtgtgca cgaacccccc gttcagcccg accgctgcgc cttatccggt 2760aactatcgtc ttgagtccaa cccggtaaga cacgacttat cgccactggc agcagccact 2820ggtaacagga ttagcagagc gaggtatgta ggcggtgcta cagagttctt gaagtggtgg 2880cctaactacg gctacactag aaggacagta tttggtatct gcgctctgct gaagccagtt 2940accttcggaa aaagagttgg tagctcttga tccggcaaac aaaccaccgc tggtagcggt 3000ggtttttttg tttgcaagca gcagattacg cgcagaaaaa aaggatctca agaagatcct 3060ttgatctttt ctacggggtc tgacgctcag tggaacgaaa actcacgtta agggattttg 3120gtcatgagat tatcaaaaag gatcttcacc tagatccttt taaattaaaa atgaagtttt 3180aaatcaatct aaagtatata tgagtaaact tggtctgaca gttaccaatg cttaatcagt 3240gaggcaccta tctcagcgat ctgtctattt cgttcatcca tagttgcctg actccccgtc 3300gtgtagataa ctacgatacg ggagggctta ccatctggcc ccagtgctgc aatgataccg 3360cgagacccac gctcaccggc tccagattta tcagcaataa accagccagc cggaagggcc 3420gagcgcagaa gtggtcctgc aactttatcc gcctccatcc agtctattaa ttgttgccgg 3480gaagctagag taagtagttc gccagttaat agtttgcgca acgttgttgc cattgctaca 3540ggcatcgtgg tgtcacgctc gtcgtttggt atggcttcat tcagctccgg ttcccaacga 3600tcaaggcgag ttacatgatc ccccatgttg tgcaaaaaag cggttagctc cttcggtcct 3660ccgatcgttg tcagaagtaa gttggccgca gtgttatcac tcatggttat ggcagcactg 3720cataattctc ttactgtcat gccatccgta agatgctttt ctgtgactgg tgagtactca 3780accaagtcat tctgagaata gtgtatgcgg cgaccgagtt gctcttgccc ggcgtcaata 3840cgggataata ccgcgccaca tagcagaact ttaaaagtgc tcatcattgg aaaacgttct 3900tcggggcgaa aactctcaag gatcttaccg ctgttgagat ccagttcgat gtaacccact 3960cgtgcaccca actgatcttc agcatctttt actttcacca gcgtttctgg gtgagcaaaa 4020acaggaaggc aaaatgccgc aaaaaaggga ataagggcga cacggaaatg ttgaatactc 4080atactcttcc tttttcaata ttattgaagc atttatcagg gttattgtct catgagcgga 4140tacatatttg aatgtattta gaaaaataaa caaatagggg ttccgcgcac atttccccga 4200aaagtgccac ctgacgtcta agaaaccatt attatcatga cattaaccta taaaaatagg 4260cgtatcacga ggccctttcg tc 42822l062116299212DNA213人工序列220223人工序列的描述pNS34a220221CDS222(1990)..(4047)400 6cgcgcgtttc ggtgatgacg gtgaaaacct ctgacacatg cagctcccgg agacggtcac 60agcttgtctg taagcggatg ccgggagcag acaagcccgt cagggcgcgt cagcgggtgt 120tggcgggtgt cggggctggc ttaactatgc ggcatcagag cagattgtac tgagagtgca 180ccatatgaag ctttttgcaa aagcctaggc ctccaaaaaa gcctcctcac tacttctgga 240atagctcaga ggccgaggcg gcctcggcct ctgcataaat aaaaaaaatt agtcagccat 300ggggcggaga atgggcggaa ctgggcgggg agggaattat tggctattgg ccattgcata 360cgttgtatct atatcataat atgtacattt atattggctc atgtccaata tgaccgccat 420gttgacattg attattgact agttattaat agtaatcaat tacggggtca ttagttcata 480gcccatatat ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc 540ccaacgaccc ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag 600ggactttcca ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac 660atcaagtgta tcatatgcca agtccgcccc ctattgacgt caatgacggt aaatggcccg 720cctggcatta tgcccagtac atgaccttac gggactttcc tacttggcag tacatctacg 780tattagtcat cgctattacc atggtgatgc ggttttggca gtacaccaat gggcgtggat 840agcggtttga ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt 900tttggcacca aaatcaacgg gactttccaa aatgtcgtaa taaccccgcc ccgttgacgc 960aaatgggcgg taggcgtgta cggtgggagg tctatataag cagagctcgt ttagtgaacc 1020gtcagatcgc ctggagacgc catccacgct gttttgacct ccatagaaga caccgggacc 1080gatccagcct ccgcggccgg gaacggtgca ttggaacgcg gattccccgt gccaagagtg 1140acgtaagtac cgcctataga ctctataggc acaccccttt ggctcttatg catgctatac 1200tgtttttggc ttggggccta tacacccccg ctccttatgc tataggtgat ggtatagctt 1260agcctatagg tgtgggttat tgaccattat tgaccactcc cctattggtg acgatacttt 1320ccattactaa tccataacat ggctctttgc cacaactatc tctattggct atatgccaat 1380actctgtcct tcagagactg acacggactc tgtattttta caggatgggg tccatttatt 1440atttacaaat tcacatatac aacaacgccg tcccccgtgc ccgcagtttt tattaaacat 1500agcgtgggat ctccgacatc tcgggtacgt gttccggaca tgggctcttc tccggtagcg 1560gcggagcttc cacatccgag ccctggtccc atccgtccag cggctcatgg tcgctcggca 1620gctccttgct cctaacagtg gaggccagac ttaggcacag cacaatgccc accaccacca 1680gtgtgccgca caaggccgtg gcggtagggt atgtgtctga aaatgagctc ggagattggg 1740ctcgcacctg gacgcagatg gaagacttaa ggcagcggca gaagaagatg caggcagctg 1800agttgttgta ttctgataag agtcagaggt aactcccgtt gcggtgctgt taacggtgga 1860gggcagtgta gtctgagcag tactcgttgc tgccgcgcgc gccaccagac ataatagctg 1920acagactaac agactgttcc tttccatggg tcttttctgc agtcaccgtc gtcgacctaa 1980gaattcacc atg gcg ccc atc acg gcg tac gcc cag cag aca agg ggc ctc 2031Met Ala Pro Ile Thr Ala Tyr Ala Gln Gln Thr Arg Gly Leu1 5 10cta ggg tgc ata atc acc agc cta act ggc cgg gac aaa aac caa gtg 2079Leu Gly Cys Ile Ile Thr Ser Leu Thr Gly Arg Asp Lys Asn Gln Val15 20 25 30gag ggt gag gtc cag att gtg tca act gct gcc caa acc ttc ctg gca 2127Glu Gly Glu Val Gln Ile Val Ser Thr Ala Ala Gln Thr Phe Leu Ala
35 40 45acg tgc atc aat ggg gtg tgc tag act gtc tac cac ggg gcc gga acg 2175Thr Cys Ile Asn Gly Val Cys Trp Thr Val Tyr His Gly Ala Gly Thr50 55 60agg acc atc gcg tca ccc aag ggt cct gtc atc cag atg tat acc aat 2223Arg Thr Ile Ala Ser Pro Lys Gly Pro Val Ile Gln Met Tyr Thr Asn65 70 75gta gac caa gac ctt gtg ggc tgg ccc gct tcg caa ggt acc cgc tca 2271Val Asp Gln Asp Leu Val Gly Trp Pro Ala Ser Gln Gly Thr Arg Ser80 85 90ttg aca ccc tgc act tgc ggc tcc tcg gac ctt tac ctg gtc acg agg 2319Leu Thr Pro Cys Thr Cys Gly Ser Ser Asp Leu Tyr Leu Val Thr Arg95 100 105 110cac gcc gat gtc att ccc gtg cgc cgg cgg ggt gat agc agg ggc agc 2367His Ala Asp Val Ile Pro Val Arg Arg Arg Gly Asp Ser Arg Gly Ser115 120 125ctg ctg tcg ccc cgg ccc att tcc tac ttg aaa ggc tcc tcg ggg ggt 2415Leu Leu Ser Pro Arg Pro Ile Ser Tyr Leu Lys Gly Ser Ser Gly Gly130 135 140ccg ctg ttg tgc ccc gcg ggg cac gcc gtg ggc ata ttt agg gcc gcg 2463Pro Leu Leu Cys Pro Ala Gly His Ala Val Gly Ile Phe Arg Ala Ala145 150 155gtg tgc acc cgt gga gtg gct aag gcg gtg gac ttt atc cct gtg gag 2511Val Cys Thr Arg Gly Val Ala Lys Ala Val Asp Phe Ile Pro Val Glu160 165 170aac cta gag aca acc atg agg tcc ccg gtg ttc acg gat aac tcc tct 2559Asn Leu Glu Thr Thr Met Arg Ser Pro Val Phe Thr Asp Asn Ser Ser175 180 185 190cca cca gta gtg ccc cag agc ttc cag gtg gct cac ctc cat gct ccc 2607Pro Pro Val Val Pro Gln Ser Phe Gln Val Ala His Leu His Ala Pro195 200 205aca ggc agc ggc aaa agc acc aag gtc ccg gct gca tat gca gct cag 2655Thr Gly Ser Gly Lys Ser Thr Lys Val Pro Ala Ala Tyr Ala Ala Gln210 215 220ggc tat aag gtg cta gta ctc aac ccc tct gtt gct gca aca ctg ggc 2703Gly Tyr Lys Val Leu Val Leu Asn Pro Ser Val Ala Ala Thr Leu Gly225 230 235ttt ggt gct tac atg tcc aag gct cat ggg atc gat cct aac atc agg 2751Phe Gly Ala Tyr Met Ser Lys Ala His Gly Ile Asp Pro Asn Ile Arg240 245 250acc ggg gtg aga aca att acc act ggc agc ccc atc acg tac tcc acc 2799Thr Gly Val Arg Thr Ile Thr Thr Gly Ser Pro Ile Thr Tyr Ser Thr255 260 265 270tac ggc aag ttc ctt gcc gac ggc ggg tgc tcg ggg ggc gct tat gac 2847Tyr Gly Lys Phe Leu Ala Asp Gly Gly Cys Ser Gly Gly Ala Tyr Asp275 280 285ata ata att tgt gac gag tgc cac tcc acg gat gcc aca tcc atc ttg 2895Ile Ile Ile Cys Asp G1u Cys His Ser Thr Asp Ala Thr Ser Ile Leu290 295 300ggc att ggc act gtc ctt gac caa gca gag act gcg ggg gcg aga ctg 2943Gly Ile Gly Thr Val Leu Asp Gln Ala Glu Thr Ala Gly Ala Arg Leu305 310 315gtt gtg ctc gcc acc gcc acc cct ccg ggc tcc gtc act gtg ccc cat 2991Val Val Leu Ala Thr Ala Thr Pro Pro Gly Ser Val Thr Val Pro His320 325 330ccc aac atc gag gag gtt gct ctg tcc acc acc gga gag atc cct ttt 3039Pro Asn Ile Glu Glu Val Ala Leu Ser Thr Thr Gly Glu Ile Pro Phe335 340 345 350tac ggc aag gct atc ccc ctc gaa gta atc aag ggg ggg aga cat ctc 3087Tyr Gly Lys Ala Ile Pro Leu Glu Val Ile Lys Gly Gly Arg His Leu355 360 365atc ttc tgt cat tea aag aag aag tgc gac gaa ctc gcc gca aag ctg 3135Ile Phe Cys His Ser Lys Lys Lys Cys Asp Glu Leu Ala Ala Lys Leu370 375 380gtc gca ttg ggc atc aat gcc gtg gcc tac tac cgc ggt ctt gac gtg 3183Val Ala Leu Gly Ile Asn Ala Val Ala Tyr Tyr Arg Gly Leu Asp Val385 390 395tcc gtc atc ccg acc agc ggc gat gtt gtc gtc gtg gca acc gat gcc 3231Ser Val Ile Pro Thr Ser Gly Asp Val Val Val Val Ala Thr Asp Ala400 405 410ctc atg acc ggc tat acc ggc gac ttc gac tcg gtg ata gac tgc aat 3279Leu Met Thr Gly Tyr Thr Gly Asp Phe Asp Ser Val Ile Asp Cys Asn415 420 425 430acg tgt gtc acc cag aca gtc gat ttc agc ctt gac cct acc ttc acc 3327Thr Cys Val Thr Gln Thr Val Asp Phe Ser Leu Asp Pro Thr Phe Thr435 440 445att gag aca arc acg ctc ccc caa gat gct gtc tcc cgc act caa cgt 3375Ile Glu Thr Ile Thr Leu Pro Gln Asp Ala Val Ser Arg Thr Gln Arg450 455 460cgg ggc agg act ggc agg ggg aag cca ggc atc tac aga ttt gtg gca 3423Arg Gly Arg Thr Gly Arg Gly Lys Pro Gly Ile Tyr Arg Phe Val Ala465 470 475ccg ggg gag cgc ccc tcc ggc atg ttc gac tcg tcc gtc ctc tgt gag 3471Pro Gly Glu Arg Pro Ser Gly Met Phe Asp Ser Ser Val Leu Cys Glu480 485 490tgc tat gac gca ggc tgt gct tgg tat gag ctc acg ccc gcc gag act 3519Cys Tyr Asp Ala Gly Cys Ala Trp Tyr Glu Leu Thr Pro Ala Glu Thr495 500 505 510aca gtt agg cta cga gcg tac atg aac acc ccg ggg ctt ccc gtg tgc 3567Thr Val Arg Leu Arg Ala Tyr Met Asn Thr Pro Gly Leu Pro Val Cys515 520 525cag gac cat ctt gaa ttt tag gag ggc gtc ttt aca ggc ctc act cat 3615Gln Asp His Leu Glu Phe Trp Glu Gly Val Phe Thr Gly Leu Thr His530 535 540ata gat gcc cac ttt cta tcc cag aca aag cag agt gag gag aac ctt 3663Ile Asp Ala His Phe Leu Ser Gln Thr Lys Gln Ser Gly Glu Asn Leu545 550 555cct tac ctg gta gcg tac caa gcc acc gtg tgc gct agg gct caa gcc 3711Pro Tyr Leu Val Ala Tyr Gln Ala Thr Val Cys Ala Arg Ala Gln Ala560 565 570cct ccc cca tcg tag gac cag atg tgg aaa tat ttg att cgc ctc aaa 3759Pro Pro Pro Ser Trp Asp Gln Met Trp Lys Cys Leu Ile Ara Leu Lys575 580 585 590ccc acc ctc cat ggg cca aca ccc ctg cta tac aaa ctg ggc act att 3807Pro Thr Leu His Gly Pro Thr Pro Leu Leu Tyr Ara Leu Gly Ala Val595 600 605cag aat gaa atc acc ctg acg cac cca gtc acc aaa tac atc atg aca 3855Gln Asn Glu Ile Thr Leu Thr His Pro Val Thr Lys Tyr Ile Met Thr610 615 620tgc atg tcg gcc gac ctg gag gtc gtc acg agc acc tag gtg ctc gtt 3903Cys Met Ser Ala Asp Leu Glu Val Val Thr Ser Thr Trp Val Leu Val625 630 635ggc ggc gtc ctg gct act ttg gcc gcg tat tgc ctg tca aca ggc tgc 3951Gly Gly Val Leu Ala Ala Leu Ala Ala Tyr Cys Leu Ser Thr Gly Cys640 645 650gtg gtc ata gtg ggc agg gtc gtc ttg tcc gag aaa ccg gca atc ata 3999Val Val Ile Val Gly Ara Val Val Leu Ser Gly Lys Pro Ala Ile Ile655 660 665 670cct gac agg aaa gtc ctc tac cga gag ttc gat gag atg aaa gag tgc 4047Pro Asp Ara Glu Val Leu Tyr Ara Glu Phe Asp Glu Met Glu Glu Cys675 680 685taggatccac tacgcgttag agctcgctga tcagcctcga ctgtgccttc tagttgccag 4107ccatctgttg tttgcccctc ccccgtgcct tccttgaccc tggaaggtgc cactcccact 4167gtcctttcct aataaaatga ggaaattgca tcgcattgtc tgagtaggtg tcattctatt 4227ctggggggtg gggtggggca ggacagcaag ggggaggatt gggaagacaa tagcaggcat 4287gctggggagc tcttccgctt cctcgctcac tgactcgctg cgctcggtcg ttcggctgcg 4347gcgagcggta tcagctcact caaaggcggt aatacggtta tccacagaat caggggataa 4407cgcaggaaag aacatgtgag caaaaggcca gcaaaaggcc aggaaccgta aaaaggccgc 4467gttgctggcg tttttccata ggctccgccc ccctgacgag catcacaaaa atcgacgctc 4527aagtcagagg tggcgaaacc cgacaggact ataaagatac caggcgtttc cccctggaag 4587ctccctcgtg cgctctcctg ttccgaccct gccgcttacc ggatacctgt ccgcctttct 4647cccttcggga agcgtggcgc tttctcaatg ctcacgctgt aggtatctca gttcggtgta 4707ggtcgttcgc tccaagctgg gctgtgtgca cgaacccccc gttcagcccg accgctgcgc 4767cttatccggt aactatcgtc ttgagtccaa cccggtaaga cacgacttat cgccactggc 4827agcagccact ggtaacagga ttagcagagc gaggtatgta ggcggtgcta cagagttctt 4887gaagtggtgg cctaactacg gctacactag aaggacagta tttggtatct gcgctctgct 4947gaagccagtt accttcggaa aaagagttgg tagctcttga tccggcaaac aaaccaccgc 5007tggtagcggt ggtttttttg tttgcaagca gcagattacg cgcagaaaaa aaggatctca 5067agaagatcct ttgatctttt ctacggggtc tgacgctcag tggaacgaaa actcacgtta 5127agggattttg gtcatgagat tatcaaaaag gatcttcacc tagatccttt taaattaaaa 5187atgaagtttt aaatcaatct aaagtatata tgagtaaact tggtctgaca gttaccaatg 5247cttaatcagt gaggcaccta tctcagcgat ctgtctattt cgttcatcca tagttgcctg 5307actccccgtc gtgtagataa ctacgatacg ggagggctta ccatctggcc ccagtgctgc 5367aatgataccg cgagacccac gctcaccggc tccagattta tcagcaataa accagccagc 5427cggaagggcc gagcgcagaa gtggtcctgc aactttatcc gcctccatcc agtctattaa 5487ttgttgccgg gaagctagag taagtagttc gccagttaat agtttgcgca acgttgttgc 5547cattgctaca ggcatcgtgg tgtcacgctc gtcgtttggt atggcttcat tcagctccgg 5607ttcccaacga tcaaggcgag ttacatgatc ccccatgttg tgcaaaaaag cggttagctc 5667cttcggtcct ccgatcgttg tcagaagtaa gttggccgca gtgttatcac tcatggttat 5727ggcagcactg cataattctc ttactgtcat gccatccgta agatgctttt ctgtgactgg 5787tgagtactca accaagtcat tctgagaata gtgtatgcgg cgaccgagtt gctcttgccc 5847ggcgtcaata cgggataata ccgcgccaca tagcagaact ttaaaagtgc tcatcattgg 5907aaaacgttct tcggggcgaa aactctcaag gatcttaccg ctgttgagat ccagttcgat 5967gtaacccact cgtgcaccca actgatcttc agcatctttt actttcacca gcgtttctgg 6027gtgagcaaaa acaggaaggc aaaatgccgc aaaaaaggga ataagggcga cacggaaatg 6087ttgaatactc atactcttcc tttttcaata ttattgaagc atttatcagg gttattgtct 6147catgagcgga tacatatttg aatgtattta gaaaaataaa caaatagggg ttccgcgcac 6207atttccccga aaagtgccac ctgacgtcta agaaaccatt attatcatga cattaaccta 6267taaaaatagg cgtatcacga ggccctttcg tc 62992107211686212PRT213人工序列220223人工序列的描述pNS34a4007Met Ala Pro Ile Thr Ala Tyr Ala Gln Gln Thr Arg Gly Leu Leu Gly1 5 10 15Cys Ile Ile Thr Ser Leu Thr Gly Arg Asp Lys Asn Gln Val Glu Gly20 25 30Glu Val Gln Ile Val Ser Thr Ala Ala Gln Thr Phe Leu Ala Thr Cys35 40 45Ile Asn Gly Val Cys Trp Thr Val Tyr His Gly Ala Gly Thr Arg Thr50 55 60Ile Ala Ser Pro Lys Gly Pro Val Ile Gln Met Tyr Thr Asn Val Asp65 70 75 80Gln Asp Leu Val Gly Trp Pro Ala Ser Gln Gly Thr Arg Ser Leu Thr85 90 95Pro Cys Thr Cys Gly Ser Ser Asp Leu Tyr Leu Val Thr Arg His Ala100 105 110Asp Val Ile Pro Val Arg Arg Arg Gly Asp Ser Arg Gly Ser Leu Leu115 120 125Ser Pro Arg Pro Ile Ser Tyr Leu Lys Gly Ser Ser Gly Gly Pro Leu130 135 140Leu Cys Pro Ala Gly His Ala Val Gly Ile Phe Arg Ala Ala Val Cys145 150 155 160Thr Arg Gly Val Ala Lys Ala Val Asp Phe Ile Pro Val Glu Asn Leu165 170 175Glu Thr Thr Met Arg Ser Pro Val Phe Thr Asp Asn Ser Ser Pro Pro180 185 190Val Val Pro Gln Ser Phe Gln Val Ala His Leu His Ala Pro Thr Gly195 200 205Ser Gly Lys Ser Thr Lys Val Pro Ala Ala Tyr Ala Ala Gln Gly Tyr210 215 220Lys Val Leu Val Leu Asn Pro Ser Val Ala Ala Thr Leu Gly Phe Gly225 230 235 240Ala Tyr Met Ser Lys Ala His Gly Ile Asp Pro Asn Ile Arg Thr Gly245 250 255Val Arg Thr Ile Thr Thr Gly Ser Pro Ile Thr Tyr Ser Thr Tyr Gly260 265 270Lys Phe Leu Ala Asp Gly Gly Cys Ser Gly Gly Ala Tyr Asp Ile lle275 280 285Ile Cys Asp Glu Cys His Ser Thr Asp Ala Thr Ser Ile Leu Gly Ile290 295 300Gly Thr Val Leu Asp Gln Ala Glu Thr Ala Gly Ala Arg Leu Val Val305 310 315 320Leu Ala Thr Ala Thr Pro Pro Gly Ser Val Thr Val Pro His Pro Asn325 330 335Ile Glu Glu Val Ala Leu Ser Thr Thr Gly Glu Ile Pro Phe Tyr Gly340 345 350Lys Ala Ile Pro Leu Glu Val Ile Lys Gly Gly Arg His Leu Ile Phe355 360 365Cys His Ser Lys Lys Lys Cys Asp Glu Leu Ala Ala Lys Leu Val Ala370 375 380Leu Gly Ile Asn Ala Val Ala Tyr Tyr Arg Gly Leu Asp Val Ser Val385 390 395 400Ile Pro Thr Ser Gly Asp Val Val Val Val Ala Thr Asp Ala Leu Met405 410 415Thr Gly Tyr Thr Gly Asp Phe Asp Ser Val Ile Asp Cys Asn Thr Cys420 425 430Val Thr Gln Thr Val Asp Phe Ser Leu Asp Pro Thr Phe Thr Ile Glu435 440 445Thr Ile Thr Leu Pro Gln Asp Ala Val Ser Arg Thr Gln Arg Arg Gly450 455 460Arg Thr Gly Arg Gly Lys Pro Gly Ile Tyr Arg Phe Val Ala Pro Gly465 470 475 480Glu Arg Pro Ser Gly Met Phe Asp Ser Ser Val Leu Cys Glu Cys Tyr485 490 495Asp Ala Gly Cys Ala Trp Tyr Glu Leu Thr Pro Ala Glu Thr Thr Val500 505 510Arg Leu Arg Ala Tyr Met Asn Thr Pro Gly Leu Pro Val Cys Gln Asp515 520 525His Leu Glu Phe Trp Glu Gly Val Phe Thr Gly Leu Thr His Ile Asp530 535 540Ala His Phe Leu Ser Gln Thr Lys Gln Ser Gly Glu Asn Leu Pro Tyr545 550 555 560Leu Val Ala Tyr Gln Ala Thr Val Cys Ala Arg Ala Gln Ala Pro Pro565 570 575Pro Ser Trp Asp Gln Met Trp Lys Cys Leu Ile Arg Leu Lys Pro Thr580 585 590Leu His Gly Pro Thr Pro Leu Leu Tyr Arg Leu Gly Ala Val Gln Asn595 600 605Glu Ile Thr Leu Thr His Pro Val Thr Lys Tyr Ile Met Thr Cys Met610 615 620Ser Ala Asp Leu Glu Val Val Thr Ser Thr Trp Val Leu Val Gly Gly625 630 635 640Val Leu Ala Ala Leu Ala Ala Tyr Cys Leu Ser Thr Gly Cys Val Val645 650 655Ile Val Gly Arg Val Val Leu Ser Gly Lys Pro Ala Ile Ile Pro Asp660 665 670Arg Glu Val Leu Tyr Arg Glu Phe Asp Glu Met Glu Glu Cys675 680 68521082ll19912212DNA213人工序列220223人工序列的描述pd.deltaNS3NS5220221CDS222(12745)..(18057)4008atcgatccta ccccttgcgc taaagaagta tatgtgccta ctaacgcttg tctttgtctc 60tgtcactaaa cactggatta ttactcccag atacttattt tggactaatt taaatgattt 120cggatcaacg ttcttaatat cgctgaatct tccacaattg atgaaagtag ctaggaagag 180gaattggtat aaagtttttg tttttgtaaa tctcgaagta tactcaaacg aatttagtat 240tttctcagtg atctcccaga tgctttcacc ctcacttaga agtgctttaa gcattttttt 300actgtggcta tttcccttat ctgcttcttc cgatgattcg aactgtaatt gcaaactact 360tacaatatca gtgatatcag attgatgttt ttgtccatag taaggaataa ttgtaaattc 420ccaagcagga atcaatttct ttaatgaggc ttccagaatt gttgcttttt gcgtcttgta 480tttaaactgg agtgatttat tgacaatatc gaaactcagc gaattgctta tgatagtatt 540atagctcatg aatgtggctc tcttgattgc tgttccgtta tgtgtaatca tccaacataa 600ataggttagt tcagcagcac ataatgctat tttctcacct gaaggtcttt caaacctttc 660cacaaactga cgaacaagca ccttaggtgg tgttttacat aatatatcaa attgtggcat 720gcttagcgcc gatcttgtgt gcaattgata tctagtttca actactctat ttatcttgta 780tcttgcagta ttcaaacacg ctaactcgaa aaactaactt taattgtcct gtttgtctcg 840cgttctttcg aaaaatgcac cggccgcgca ttatttgtac tgcgaaaata attggtactg 900cggtatcttc atttcatatt ttaaaaatgc acctttgctg cttttcctta atttttagac 960ggcccgcagg ttcgttttgc ggtactatct tgtgataaaa agttgttttg acatgtgatc 1020tgcacagatt ttataatgta ataagcaaga atacattatc aaacgaacaa tactggtaaa 1080agaaaaccaa aatggacgac attgaaacag ccaagaatct gacggtaaaa gcacgtacag 1140cttatagcgt ctgggatgta tgtcggctgt ttattgaaat gattgctcct gatgtagata 1200ttgatataga gagtaaacgt aagtctgatg agctactctt tccaggatat gtcataaggc 1260ccatggaatc tctcacaacc ggtaggccgt atggtcttga ttctagcgca gaagattcca 1320gcgtatcttc tgactccagt gctgaggtaa ttttgcctgc tgcgaagatg gttaaggaaa 1380ggtttgattc gattggaaat ggtatgctct cttcacaaga agcaagtcag gctgccatag 1440atttgatgct acagaataac aagctgttag acaatagaaa gcaactatac aaatctattg 1500ctataataat aggaagattg cccgagaaag acaagaagag agctaccgaa atgctcatga 1560gaaaaatgga ttgtacacag ttattagtcc caccagctcc aacggaagaa gatgttatga 1620agctcgtaag cgtcgttacc caattgctta ctttagttcc accagatcgt caagctgctt 1680taataggtga tttattcatc ccggaatctc taaaggatat attcaatagt ttcaatgaac 1740tggcggcaga gaatcgttta cagcaaaaaa agagtgagtt ggaaggaagg actgaagtga 1800accatgctaa tacaaatgaa gaagttccct ccaggcgaac aagaagtaga gacacaaatg 1860caagaggagc atataaatta caaaacacca tcactgaggg ccctaaagcg gttcccacga 1920aaaaaaggag agtagcaacg agggtaaggg gcagaaaatc acgtaatact tctagggtat 1980gatccaatat caaaggaaat gatagcattg aaggatgaga ctaatccaat tgaggagtgg 2040cagcatatag aacagctaaa gggtagtgct gaaggaagca tacgataccc cgcatggaat2100gggataatat cacaggaggt actagactac ctttcatcct acataaatag acgcatataa 2160gtacgcattt aagcataaac acgcactatg ccgttcttct catgtatata tatatacagg 2220caacacgcag atataggtgc gacgtgaaca gtgagctgta tgtgcgcagc tcgcgttgca 2280ttttcggaag cgctcgtttt cggaaacgct ttgaagttcc tattccgaag ttcctattct 2340ctagaaagta taggaacttc agagcgcttt tgaaaaccaa aagcgctctg aagacgcact 2400ttcaaaaaac caaaaacgca ccggactgta acgagctact aaaatattgc gaataccgct 2460tccacaaaca ttgctcaaaa gtatctcttt gctatatatc tctgtgctat atccctatat 2520aacctaccca tccacctttc gctccttgaa cttgcatcta aactcgacct ctacatcaac 2580aggcttccaa tgctcttcaa attttactgt caagtagacc catacggctg taatatgctg 2640ctcttcataa tgtaagctta tctttatcga atcgtgtgaa aaactactac cgcgataaac 2700ctttacggtt ccctgagatt gaattagttc ctttagtata tgatacaaga cacttttgaa 2760ctttgtacga cgaattttga ggttcgccat cctctggcta tttccaatta tcctgtcggc 2820gaaacatgct gcttaaaact ccaagcggta ggagaccgat aaaggttaat aggacagccg 2880tattatctcc gcctcagttt gatcttccgc ttcagactgc catttttcac ataatgaatc 2940tatttcaccc cacaatcctt catccgcctc cgcatcttgt tccgttaaac tattgacttc 3000atgttgtaca ttgtttagtt cacgagaagg gtcctcttca ggcggtagct cctgatctcc 3060tatatgacct ttatcctgtt ctctttccac aaacttagaa atgtattcat gaattatgga 3120gcacctaata acattcttca aggcggagaa gtttgggcca gatgcccaat atgcttgaca 3180tgaaaacgtg agaatgaatt tagtattatt gtgatattct gaggcaattt tattataatc 3240tcgaagataa gagaagaatg cagtgacctt tgtattgaca aatggagatt ccatgtatct 3300aaaaaatacg cctttaggcc ttctgatacc ctttcccctg cggtttagcg tgccttttac 3360attaatatct aaaccctctc cgatggtggc ctttaactga ctaataaatg caaccgatat 3420aaactgtgat aattctgggt gatttatgat tcgatcgaca attgtattgt acactagtgc 3480aggatcaggc caatccagtt ctttttcaat taccggtgtg tcgtctgtat tcagtacatg 3540tccaacaaat gcaaatgcta acgttttgta tttcttataa ttgtcaggaa ctggaaaagt 3600cccccttgtc gtctcgatta cacacctact ttcatcgtac accataggtt ggaagtgctg 3660cataatacat tgcttaatac aagcaagcag tctctcgcca ttcatatttc agttattttc 3720cattacagct gatgtcattg tatatcagcg ctgtaaaaat ctatctgtta cagaaggttt 3780tcgcggtttt tataaacaaa actttcgtta cgaaatcgag caatcacccc agctgcgtat 3840ttggaaattc gggaaaaagt agagcaacgc gagttgcatt ttttacacca taatgcatga 3900ttaacttcga gaagggatta aggctaattt cactagtatg tttcaaaaac ctcaatctgt 3960ccattgaatg ccttataaaa cagctataga ttgcatagaa gagttagcta ctcaatgctt 4020tttgtcaaag cttactgatg atgatgtgtc tactttcagg cgggtctgta gtaaggagaa 4080tgacattata aagctggcac ttagaattcc acggactata gactatacta gtatactccg 4140tctactgtac gatacacttc cgctcaggtc cttgtccttt aacgaggcct taccactctt 4200ttgttactct attgatccag ctcagcaaag gcagtgtgat ctaagattct atcttcgcga 4260tgtagtaaaa ctagctagac cgagaaagag actagaaatg caaaaggcac ttctacaatg 4320gctgccatca ttattatccg atgtgacgct gcattttttt tttttttttt tttttttttt 4380tttttttttt tttttttttt ttttttggta caaatatcat aaaaaaagag aatcttttta 4440agcaaggatt ttcttaactt cttcggcgac agcatcaccg acttcggtgg tactgttgga 4500accacctaaa tcaccagttc tgatacctgc atccaaaacc tttttaactg catcttcaat 4560ggctttacct tcttcaggca agttcaatga caatttcaac atcattgcag cagacaagat 4620agtggcgata gggttgacct tattctttgg caaatctgga gcggaaccat ggcatggttc 4680gtacaaacca aatgcggtgt tcttgtctgg caaagaggcc aaggacgcag atggcaacaa 4740acccaaggag cctgggataa cggaggcttc atcggagatg atatcaccaa acatgttgct 4800ggtgattata ataccattta ggtgggttgg gttcttaact aggatcatgg cggcagaatc 4860aatcaattga tgttgaactt tcaatgtagg gaattcgttc ttgatggttt cctccacagt 4920ttttctccat aatcttgaag aggccaaaac attagcttta tccaaggacc aaataggcaa 4980tggtggctca tgttgtaggg ccatgaaagc ggccattctt gtgattcttt gcacttctgg 5040aacggtgtat tgttcactat cccaagcgac accatcacca tcgtcttcct ttctcttacc 5100aaagtaaata cctcccacta attctctaac aacaacgaag tcagtacctt tagcaaattg 5160tggcttgatt ggagataagt ctaaaagaga gtcggatgca aagttacatg gtcttaagtt 5220ggcgtacaat tgaagttctt tacggatttt tagtaaacct tgttcaggtc taacactacc 5280ggtaccccat ttaggaccac ccacagcacc taacaaaacg gcatcagcct tcttggaggc 5340ttccagcgcc tcatctggaa gtggaacacc tgtagcatcg atagcagcac caccaattaa 5400atgattttcg aaatcgaact tgacattgga acgaacatca gaaatagctt taagaacctt 5460aatggcttcg gctgtgattt cttgaccaac gtggtcacct ggcaaaacga cgatcttctt 5520aggggcagac attacaatgg tatatccttg aaatatatat aaaaaaaaaa aaaaaaaaaa 5580aaaaaaaaaa atgcagcttc tcaatgatat tcgaatacgc tttgaggaga tacagcctaa 5640tatccgacaa actgttttac agatttacga tcgtacttgt tacccatcat tgaattttga 5700acatccgaac ctgggagttt tccctgaaac agatagtata tttgaacctg tataataata 5760tatagtctag cgctttacgg aagacaatgt atgtatttcg gttcctggag aaactattgc 5820atctattgca taggtaatct tgcacgtcgc atccccggtt cattttctgc gtttccatct 5880tgcacttcaa tagcatatct ttgttaacga agcatctgtg cttcattttg tagaacaaaa 5940atgcaacgcg agagcgctaa tttttcaaac aaagaatctg agctgcattt ttacagaaca 6000gaaatgcaac gcgaaagcgc tattttacca acgaagaatc tgtgcttcat ttttgtaaaa 6060caaaaatgca acgcgagagc gctaattttt caaacaaaga atctgagctg catttttaca 6120gaacagaaat gcaacgcgag agcgctattt taccaacaaa gaatctatac ttcttttttg 6180ttctacaaaa atgcatcccg agagcgctat ttttctaaca aagcatctta gattactttt 6240tttctccttt gtgcgctcta taatgcagtc tcttgataac tttttgcact gtaggtccgt 6300taaggttaga agaaggctac tttggtgtct attttctctt ccataaaaaa agcctgactc 6360cacttcccgc gtttactgat tactagcgaa gctgcgggtg cattttttca agataaaggc 6420atccccgatt atattctata ccgatgtgga ttgcgcatac tttgtgaaca gaaagtgata 6480gcgttgatga ttcttcattg gtcagaaaat tatgaacggt ttcttctatt ttgtctctat 6540atactacgta taggaaatgt ttacattttc gtattgtttt cgattcactc tatgaatagt 6600tcttactaca atttttttgt ctaaagagta atactagaga taaacataaa aaatgtagag 6660gtcgagttta gatgcaagtt caaggagcga aaggtggatg ggtaggttat atagggatat 6720agcacagaga tatatagcaa agagatactt ttgagcaatg tttgtggaag cggtattcgc 6780aatattttag tagctcgtta cagtccggtg cgtttttggt tttttgaaag tgcgtcttca 6840gagcgctttt ggttttcaaa agcgctctga agttcctata ctttctagag aataggaact 6900tcggaatagg aacttcaaag cgtttccgaa aacgagcgct tccgaaaatg caacgcgagc 6960tgcgcacata cagctcactg ttcacgtcgc acctatatct gcgtgttgcc tgtatatata 7020tatacatgag aagaacggca tagtgcgtgt ttatgcttaa atgcgtactt atatgcgtct 7080atttatgtag gatgaaaggt agtctagtac ctcctgtgat attatcccat tccatgcggg 7140gtatcgtatg cttccttcag cactaccctt tagctgttct atatgctgcc actcctcaat 7200tggattagtc tcatccttca atgctatcat ttcctttgat attggatcat atgcatagta 7260ccgagaaact agtgcgaagt agtgatcagg tattgctgtt atctgatgag tatacgttgt 7320cctggccacg gcagaagcac gcttatcgct ccaatttccc acaacattag tcaactccgt 7380taggcccttc attgaaagaa atgaggtcat caaatgtctt ccaatgtgag attttgggcc 7440attttttata gcaaagattg aataaggcgc atttttcttc aaagctttat tgtacgatct 7500gactaagtta tcttttaata attggtattc ctgtttattg cttgaagaat tgccggtcct 7560atttactcgt tttaggactg gttcagaatt cctcaaaaat tcatccaaat atacaagtgg 7620atcgatgata agctgtcaaa catgagaatt cttgaagacg aaagggcctc gtgatacgcc 7680tatttttata ggttaatgtc atgataataa tggtttctta gacgtcaggt ggcacttttc 7740ggggaaatgt gcgcggaacc cctatttgtt tatttttcta aatacattca aatatgtatc 7800cgctcatgag acaataaccc tgataaatgc ttcaataata ttgaaaaagg aagagtatga 7860gtattcaaca tttccgtgtc gcccttattc ccttttttgc ggcattttgc cttcctgttt 7920ttgctcaccc agaaacgctg gtgaaagtaa aagatgctga agatcagttg ggtgcacgag 7980tgggttacat cgaactggat ctcaacagcg gtaagatcct tgagagtttt cgccccgaag 8040aacgttttcc aatgatgagc acttttaaag ttctgctatg tggcgcggta ttatcccgtg 8100ttgacgccgg gcaagagcaa ctcggtcgcc gcatacacta ttctcagaat gacttggttg 8160agtactcacc agtcacagaa aagcatctta cggatggcat gacagtaaga gaattatgca 8220gtgctgccat aaccatgagt gataacactg cggccaactt acttctgaca acgatcggag 8280gaccgaagga gctaaccgct tttttgcaca acatggggga tcatgtaact cgccttgatc 8340gttgggaacc ggagctgaat gaagccatac caaacgacga gcgtgacacc acgatgcctg 8400cagcaatggc aacaacgttg cgcaaactat taactggcga actacttact ctagcttccc 8460ggcaacaatt aatagactgg atggaggcgg ataaagttgc aggaccactt ctgcgctcgg 8520cccttccggc tggctggttt attgctgata aatctggagc cggtgagcgt gggtctcgcg 8580gtatcattgc agcactgggg ccagatggta agccctcccg tatcgtagtt atctacacga 8640cggggagtca ggcaactatg gatgaacgaa atagacagat cgctgagata ggtgcctcac 8700tgattaagca ttggtaactg tcagaccaag tttactcata tatactttag attgatttaa 8760aacttcattt ttaatttaaa aggatctagg tgaagatcct ttttgataat ctcatgacca 8820aaatccctta acgtgagttt tcgttccact gagcgtcaga ccccgtagaa aagatcaaag 8880gatcttcttg agatcctttt tttctgcgcg taatctgctg cttgcaaaca aaaaaaccac 8940cgctaccagc ggtggtttgt ttgccggatc aagagctacc aactcttttt ccgaaggtaa 9000ctggcttcag cagagcgcag ataccaaata ctgtccttct agtgtagccg tagttaggcc 9060accacttcaa gaactctgta gcaccgccta catacctcgc tctgctaatc ctgttaccag 9120tggctgctgc cagtggcgat aagtcgtgtc ttaccgggtt ggactcaaga cgatagttac 9180cggataaggc gcagcggtcg ggctgaacgg ggggttcgtg cacacagccc agcttggagc 9240gaacgaccta caccgaactg agatacctac agcgtgagct atgagaaagc gccacgcttc 9300ccgaagggag aaaggcggac aggtatccgg taagcggcag ggtcggaaca ggagagcgca 9360cgagggagct tccaggggga aacgcctggt atctttatag tcctgtcggg tttcgccacc 9420tctgacttga gcgtcgattt ttgtgatgct cgtcaggggg gcggagccta tggaaaaacg 9480ccagcaacgc ggccttttta cggttcctgg ccttttgctg gccttttgct cacatgttct 9540ttcctgcgtt atcccctgat tctgtggata accgtattac cgcctttgag tgagctgata 9600ccgctcgccg cagccgaacg accgagcgca gcgagtcagt gagcgaggaa gcggaagagc 9660gcctgatgcg gtattttctc cttacgcatc tgtgcggtat ttcacaccgc atatggtgca 9720ctctcagtac aatctgctct gatgccgcat agttaagcca gtatacactc cgctatcgct 9780acgtgactgg gtcatggctg cgccccgaca cccgccaaca cccgctgacg cgccctgacg 9840ggcttgtctg ctcccggcat ccgcttacag acaagctgtg accgtctccg ggagctgcat 9900gtgtcagagg ttttcaccgt catcaccgaa acgcgcgagg cagctgcggt aaagctcatc 9960agcgtggtcg tgaagcgatt cacagatgtc tgcctgttca tccgcgtcca gctcgttgag 10020tttctccaga agcgttaatg tctggcttct gataaagcgg gccatgttaa gggcggtttt 10080ttcctgtttg gtcactgatg cctccgtgta agggggattt ctgttcatgg gggtaatgat 10140accgatgaaa cgagagagga tgctcacgat acgggttact gatgatgaac atgcccggtt 10200actggaacgt tgtgagggta aacaactggc ggtatggatg cggcgggacc agagaaaaat 10260cactcagggt caatgccagc gcttcgttaa tacagatgta ggtgttccac agggtagcca 10320gcagcatcct gcgatgcaga tccggaacat aatggtgcag ggcgctgact tccgcgtttc 10380cagactttac gaaacacgga aaccgaagac cattcatgtt gttgctcagg tcgcagacgt 10440tttgcagcag cagtcgcttc acgttcgctc gcgtatcggt gattcattct gctaaccagt 10500aaggcaaccc cgccagccta gccgggtcct caacgacagg agcacgatca tgcgcacccg 10560tggccaggac ccaacgctgc ccgagatgcg ccgcgtgcgg ctgctggaga tggcggacgc 10620gatggatatg ttctgccaag ggttggtttg cgcattcaca gttctccgca agaattgatt 10680ggctccaatt cttggagtgg tgaatccgtt agcgaggtgc cgccggcttc cattcaggtc 10740gaggtggccc ggctccatgc accgcgacgc aacgcgggga ggcagacaag gtatagggcg 10800gcgcctacaa tccatgccaa cccgttccat gtgctcgccg aggcggcata aatcgccgtg 10860acgatcagcg gtccaatgat cgaagttagg ctggtaagag ccgcgagcga tccttgaagc 10920tgtccctgat ggtcgtcatc tacctgcctg gacagcatgg cctgcaacgc gggcatcccg 10980atgccgccgg aagcgagaag aatcataatg gggaaggcca tccagcctcg cgtcgcgaac 11040gccagcaaga cgtagcccag cgcgtcggcc gccatgccgg cgataatggc ctgcttctcg 11100ccgaaacgtt tggtggcggg accagtgacg aaggcttgag cgagggcgtg caagattccg 11160aataccgcaa gcgacaggcc gatcatcgtc gcgctccagc gaaagcggtc ctcgccgaaa 11220atgacccaga gcgctgccgg cacctgtcct acgagttgca tgataaagaa gacagtcata 11280agtgcggcga cgatagtcat gccccgcgcc caccggaagg agctgactgg gttgaaggct 11340ctcaagggca tcggtcgagg atccttcaat atgcgcacat acgctgttat gttcaaggtc 11400ccttcgttta agaacgaaag cggtcttcct tttgagggat gtttcaagtt gttcaaatct 11460atcaaatttg caaatcccca gtctgtatct agagcgttga atcggtgatg cgatttgtta 11520attaaattga tggtgtcacc attaccaggt ctagatatac caatggcaaa ctgagcacaa 11580caataccagt ccggatcaac tggcaccatc tctcccgtag tctcatctaa tttttcttcc 11640ggatgaggtt ccagatatac cgcaacacct ttattatggt ttccctgagg gaataataga 11700atgtcccatt cgaaatcacc aattctaaac ctgggcgaat tgtatttcgg gtttgttaac 11760tcgttccagt caggaatgtt ccacgtgaag ctatcttcca gcaaagtctc cacttcttca 11820tcaaattgtg gagaatactc ccaatgctct tatctatggg acttccggga aacacagtac 11880cgatacttcc caattcgtct tcagagctca ttgtttgttt gaagagacta atcaaagaat 11940cgttttctca aaaaaattaa tatcttaact gatagtttga tcaaaggggc aaaacgtagg 12000ggcaaacaaa cggaaaaatc gtttctcaaa ttttctgatg ccaagaactc taaccagtct 12060tatctaaaaa ttgccttatg atccgtctct ccggttacag cctgtgtaac tgattaatcc 12120tgcctttcta atcaccattc taatgtttta attaagggat tttgtcttca ttaacggctt 12180tcgctcataa aaatgttatg acgttttgcc cgcaggcggg aaaccatcca cttcacgaga 12240ctgatctcct ctgccggaac accgggcatc tccaacttat aagttggaga aataagagaa 12300tttcagattg agagaatgaa aaaaaaaaac ccttagttca taggtccatt ctcttagcgc 12360aactacagag aacaggggca caaacaggca aaaaacgggc acaacctcaa tggagtgatg 12420caacctgcct ggagtaaatg atgacacaag gcaattgacc cacgcatgta tctatctcat 12480tttcttacac cttctattac cttctgctct ctctgatttg gaaaaagctg aaaaaaaagg 12540ttgaaaccag ttccctgaaa ttattcccct acttgactaa taagtatata aagacggtag 12600gtattgattg taattctgta aatctatttc ttaaacttct taaattctac ttttatagtt 12660agtctttttt ttagttttaa aacaccaaga acttagtttc gaataaacac acataaacaa 12720acaagcttac aaaacaaatt cacc atg gct gca tat gca gct cag ggc tat12771Met Ala Ala Tyr Ala Ala Gln Gly Tyr1 5aag gtg cta gta ctc aac ccc tct gtt gct gca aca ctg ggc ttt ggt 12819Lys Val Leu Val Leu Asn Pro Ser Val Ala Ala Thr Leu Gly Phe Gly10 15 20 25gct tac atg tcc aag gct cat ggg atc gat cct aac atc agg acc ggg 12867Ala Tyr Met Ser Lys Ala His Gly Ile Asp Pro Asn Ile Arg Thr Gly30 35 40gtg aga aca att acc act ggc agc ccc atc acg tac tcc acc tac ggc 12915Val Arg Thr Ile Thr Thr Gly Ser Pro Ile Thr Tyr Ser Thr Tyr Gly
45 50 55aag ttc ctt gcc gac ggc ggg tgc tcg ggg ggc gct tat gac ata ata 12963Lys Phe Leu Ala Asp Gly Gly Cys Ser Gly Gly Ala Tyr Asp Ile Ile60 65 70att tgt gac gag tgc cac tcc acg gat gcc aca tcc atc ttg ggc att 13011Ile Cys Asp Glu Cys His Ser Thr Asp Ala Thr Ser Ile Leu Gly Ile75 80 85ggc act gtc ctt gac caa gca gag act gcg ggg gcg aga ctg gtt gtg 13059Gly Thr Val Leu Asp Gln Ala Glu Thr Ala Gly Ala Arg Leu Val Val90 95 100 105ctc gcc acc gcc acc cct ccg ggc tcc gtc act gtg ccc cat ccc aac 13107Leu Ala Thr Ala Thr Pro Pro Gly Ser Val Thr Val Pro His Pro Asn110 115 120atc gag gag gtt gct ctg tcc acc acc gga gag atc cct ttt tac ggc 13155Ile Glu Glu Val Ala Leu Ser Thr Thr Gly Glu Ile Pro Phe Tyr Gly125 130 135aag gct atc ccc ctc gaa gta atc aag ggg ggg aga cat ctc atc ttc 13203Lys Ala Ile Pro Leu Glu Val Ile Lys Gly Gly Arg His Leu Ile Phe140 145 150tgt cat tca aag aag aag tgc gac gaa ctc gcc gca aag ctg gtc gca 13251Cys His Ser Lys Lys Lys Cys Asp Glu Leu Ala Ala Lys Leu Val Ala155 160 165ttg ggc atc aat gcc gtg gcc tac tac cgc ggt ctt gac gtg tcc gtc 13299Leu Gly Ile Asn Ala Val Ala Tyr Tyr Arg Gly Leu Asp Val Ser Val170 175 180 185atc ccg acc agc ggc gat gtt gtc gtc gtg gca acc gat gcc ctc atg 13347Ile Pro Thr Ser Gly Asp Val Val Val Val Ala Thr Asp Ala Leu Met190 195 200acc ggc tat acc ggc gac ttc gac tcg gtg ata gac tgc aat acg tgt 13395Thr Gly Tyr Thr Gly Asp Phe Asp Ser Val Ile Asp Cys Asn Thr Cys205 210 215gtc acc cag aca gtc gat ttc agc ctt gac cct acc ttc acc att gag 13443Val Thr Gln Thr Val Asp Phe Ser Leu Asp Pro Thr Phe Thr Ile Glu220 225 230aca atc acg ctc ccc caa gat gct gtc tcc cgc act caa cgt cgg ggc 13491Thr Ile Thr Leu Pro Gln Asp Ala Val Ser Arg Thr Gln Arg Arg Gly235 240 245agg act ggc agg ggg aag cca ggc atc tac aga ttt gtg gca ccg ggg 13539Arg Thr Gly Arg Gly Lys Pro Gly Ile Tyr Arg Phe Val Ala Pro Gly250 255 260 265gag cgc ccc tcc ggc atg ttc gac tcg tcc gtc ctc tgt gag tgc tat 13587Glu Arg Pro Ser Gly Met Phe Asp Ser Ser Val Leu Cys Glu Cys Tyr270 275 280gac gca ggc tgt gct tgg tat gag ctc acg ccc gcc gag act aca gtt 13635Asp Ala Gly Cys Ala Trp Tyr Glu Leu Thr Pro Ala Glu Thr Thr Val285 290 295agg cta cga gcg tac atg aac acc ccg ggg ctt ccc gtg tgc cag gac 13683Arg Leu Arg Ala Tyr Met Asn Thr Pro Gly Leu Pro Val Cys Gln Asp300 305 310cat ctt gaa ttt tgg gag ggc gtc ttt aca ggc ctc act cat ata gat 13731His Leu Glu Phe Trp Glu Gly Val Phe Thr Gly Leu Thr His Ile Asp315 320 325gcc cac ttt cta tcc cag aca aag cag agt ggg gag aac ctt cct tac 13779Ala His Phe Leu Ser Gln Thr Lys Gln Ser Gly Glu Asn Leu Pro Tyr330 335 340 345ctg gta gcg tac caa gcc acc gtg tgc gct agg gct caa gcc cct ccc 13827Leu Val Ala Tyr Gln Ala Thr Val Cys Ala Arg Ala Gln Ala Pro Pro350 355 360cca tcg tgg gac cag atg tgg aag tgt ttg att cgc ctc aag ccc acc 13875Pro Ser Trp Asp Gln Met Trp Lys Cys Leu lle Arg Leu Lys Pro Thr365 370 375ctc cat ggg cca aca ccc ctg cta tac aga ctg ggc gct gtt cag aat 13923Leu His Gly Pro Thr Pro Leu Leu Tyr Arg Leu Gly Ala Val Gln Asn380 385 390gaa atc acc ctg acg cac cca gtc acc aaa tac atc atg aca tgc atg 13971Glu Ile Thr Leu Thr His Pro Val Thr Lys Tyr Ile Met Thr Cys Met395 400 405tcg gcc gac ctg gag gtc gtc acg agc acc tgg gtg ctc gtt ggc ggc 14019Ser Ala Asp Leu Glu Val Val Thr Ser Thr Trp Val Leu Val Gly Gly410 415 420 425gtc ctg gct gct ttg gcc gcg tat tgc ctg tca aca ggc tgc gtg gtc 14067Val Leu Ala Ala Leu Ala Ala Tyr Cys Leu Ser Thr Gly Cys Val Val430 435 440ata gtg ggc agg gtc gtc ttg tcc ggg aag ccg gca atc ata cct gac 14115Ile Val Gly Arg Val Val Leu Ser Gly Lys Pro Ala Ile Ile Pro Asp445 450 455agg gaa gtc ctc tac cga gag ttc gat gag atg gaa gag tgc tct cag 14163Arg Glu Val Leu Tyr Arg Glu Phe Asp Glu Met Glu Glu Cys Ser Gln460 465 470cac tta ccg tac atc gag caa ggg atg atg ctc gcc gag cag ttc aag 14211His Leu Pro Tyr Ile Glu Gln Gly Met Met Leu Ala Glu Gln Phe Lys475 480 485cag aag gcc ctc ggc crc ctg cag acc gcg tcc cgt cag gca gag gtt 14259Gln Lys Ala Leu Gly Leu Leu Gln Thr Ala Ser Arg Gln Ala Glu Val490 495 500 505atc gcc cct gct gtc cag acc aac tgg caa aaa ctc gag acc ttc tgg 14307Ile Ala Pro Ala Val Gln Thr Asn Trp Gln Lys Leu Glu Thr Phe Trp510 515 520gcg aag cat atg tgg aac ttc atc agt ggg ata caa tac ttg gcg ggc 14355Ala Lys His Met Trp Asn Phe Ile Ser Gly Ile Gln Tyr Leu Ala Gly525 530 535ttg tca acg ctg cct ggt aac ccc gcc att gct tca ttg atg gct ttt 14403Leu Ser Thr Leu Pro Gly Asn Pro Ala Ile Ala Ser Leu Met Ala Phe540 545 550aca gct gct gtc acc agc cca cta acc act agc caa acc ctc ctc ttc 14451Thr Ala Ala Val Thr Ser Pro Leu Thr Thr Ser Gln Thr Leu Leu Phe555 560 565aac ata ttg ggg ggg tgg gtg gct gcc cag ctc gcc gcc ccc ggt gcc 14499Asn Ile Leu Gly Gly Trp Val Ala Ala Gln Leu Ala Ala Pro Gly Ala570 575 580 585gct act gcc ttt gtg ggc gct ggc tta gct ggc gcc gcc atc ggc agt 14547Ala Thr Ala Phe Val Gly Ala Gly Leu Ala Gly Ala Ala Ile Gly Ser590 595 600gtt gga ctg ggg aag gtc ctc ata gac atc ctt gca ggg tat ggc gcg 14595Val Gly Leu Gly Lys Val Leu Ile Asp Ile Leu Ala Gly Tyr Gly Ala605 610 615ggc gtg gcg gga gct ctt gtg gca ttc aag atc atg agc ggt gag gtc 14643Gly Val Ala Gly Ala Leu Val Ala Phe Lys Ile Met Ser Gly Glu Val620 625 630ccc tcc acg gag gac ctg gtc aat cta ctg ccc gcc atc ctc tcg ccc 14691Pro Ser Thr Glu Asp Leu Val Asn Leu Leu Pro Ala Ile Leu Ser Pro635 640 645gga gcc ctc gta gtc ggc gtg gtc tgt gca gca ata ctg cgc cgg cac 14739Gly Ala Leu Val Val Gly Val Val Cys Ala Ala Ile Leu Arg Arg His650 655 660 665gtt ggc ccg ggc gag ggg gca gtg cag tgg atg aac cgg ctg ata gcc 14787Val Gly Pro Gly Glu Gly Ala Val Gln Trp Met Asn Arg Leu Ile Ala670 675 680ttc gcc tcc cgg ggg aac cat gtt tcc ccc acg cac tac gtg ccg gag 14835Phe Ala Ser Arg Gly Asn His Val Ser Pro Thr His Tyr Val Pro Glu685 690 695agc gat gca gct gcc cgc gtc act gcc ata ctc agc agc ctc act gta 14883Ser Asp Ala Ala Ala Arg Val Thr Ala Ile Leu Ser Ser Leu Thr Val700 705 710acc cag ctc ctg agg cga ctg cac cag tgg ata agc tcg gag tgt acc 14931Thr Gln Leu Leu Arg Arg Leu His Gln Trp Ile Ser Ser Glu Cys Thr715 720 725act cca tgc tcc ggt tcc tgg cta agg gac atc tgg gac tgg ata tgc 14979Thr Pro Cys Ser Gly Ser Trp Leu Arg Asp Ile Trp Asp Trp Ile Cys730 735 740 745gag gtg ttg agc gac ttt aag acc tgg cta aaa gct aag ctc atg cca 15027Glu Val Leu Ser Asp Phe Lys Thr Trp Leu Lys Ala Lys Leu Met Pro750 755 760cag ctg cct ggg atc ccc ttt gtg tcc tgc cag cgc ggg tat aag ggg 15075Gln Leu Pro Gly Ile Pro Phe Val Ser Cys Gln Arg Gly Tyr Lys Gly765 770 775gtc tgg cga ggg gac ggc atc atg cac act cgc tgc cac tgt gga gct 15123Val Trp Arg Gly Asp Gly Ile Met His Thr Arg Cys His Cys Gly Ala780 785 790gag atc act gga cat gtc aaa aac ggg acg atg agg atc gtc ggt cct 15171Glu Ile Thr Gly His Val Lys Asn Gly Thr Met Arg Ile Val Gly Pro795 800 805agg acc tgc agg aac atg tgg agt ggg acc ttc ccc att aat gcc tac 15219Arg Thr Cys Arg Asn Met Trp Ser Gly Thr Phe Pro Ile Asn Ala Tyr810 815 820 825acc acg ggc ccc tgt acc ccc ctt cct gcg ccg aac tac acg ttc gcg 15267Thr Thr Gly Pro Cys Thr Pro Leu Pro Ala Pro Asn Tyr Thr Phe Ala830 835 840cta tgg agg gtg tct gca gag gaa tac gtg gag ata agg cag gtg ggg 15315Leu Trp Arg Val Ser Ala Glu Glu Tyr Val Glu Ile Arg Gln Val Gly845 850 855gac ttc cac tac gtg acg ggt atg act act gac aat ctt aaa tgc ccg 15363Asp Phe His Tyr Val Thr Gly Met Thr Thr Asp Asn Leu Lys Cys Pro860 865 870tgc cag gtc cca tcg ccc gaa ttt ttc aca gaa ttg gac ggg gtg cgc 15411Cys Gln Val Pro Ser Pro Glu Phe Phe Thr Glu Leu Asp Gly Val Arg875 880 885cta cat agg ttt gcg ccc ccc tgc aag ccc ttg ctg cgg gag gag gta 15459Leu His Arg Phe Ala Pro Pro Cys Lys Pro Leu Leu Arg Glu Glu Val890 895 900 905tca ttc aga gta gga ctc cac gaa tac ccg gta ggg tcg caa tta cct 15507Ser Phe Arg Val Gly Leu His Glu Tyr Pro Val Gly Ser Gln Leu Pro910 915 920tgc gag ccc gaa ccg gac gtg gcc gtg ttg acg tcc atg ctc act gat 15555Cys Glu Pro Glu Pro Asp Val Ala Val Leu Thr Ser Met Leu Thr Asp925 930 935ccc tcc cat ata aca gca gag gcg gcc ggg cga agg ttg gcg agg gga 15603Pro Ser His Ile Thr Ala Glu Ala Ala Gly Arg Arg Leu Ala Arg Gly940 945 950tca ccc ccc tct gtg gcc agc tcc tcg gct agc cag cta tcc gct cca 15651Ser Pro Pro Ser Val Ala Ser Ser Ser Ala Ser Gln Leu Ser Ala Pro955 960 965tct ctc aag gca act tgc acc gct aac cat gac tcc cct gat gct gag 15699Ser Leu Lys Ala Thr Cys Thr Ala Asn His Asp Ser Pro Asp Ala Glu970 975 980 985ctc ata gag gcc aac ctc cta tgg agg cag gag atg ggc ggc aac atc 15747Leu Ile Glu Ala Asn Leu Leu Trp Arg Gln Glu Met Gly Gly Asn Ile990 9951000acc agg gtt gag tca gaa aac aaa gtg gtg att ctg gac tcc ttc gat 15795Thr Arg Val Glu Ser Glu Asn Lys Val Val Ile Leu Asp Ser Phe Asp100510101015ccg ctt gtg gcg gag gag gac gag cgg gag atc tcc gta ccc gca gaa 15843Pro Leu Val Ala Glu Glu Asp Glu Arg Glu Ile Ser Val Pro Ala Glu102010251030atc ctg cgg aag tct cgg aga ttc gcc cag gcc ctg ccc gtt tgg gcg 15891Ile Leu Arg Lys Ser Arg Arg Phe Ala Gln Ala Leu Pro Val Trp Ala103510401045cgg ccg gac tat aac ccc ccg cta gtg gag acg tgg aaa aag ccc gac 15939Arg Pro Asp Tyr Asn Pro Pro Leu Val Glu Thr Trp Lys Lys Pro Asp1050 105510601065tac gaa cca cct gtg gtc cat ggc tgc ccg ctt cca cct cca aag tcc 15987Tyr Glu Pro Pro Val Val His Gly Cys Pro Leu Pro Pro Pro Lys Ser107010751080cct cct gtg cct ccg cct cgg aag aag cgg acg gtg gtc ctc act gaa 16035Pro Pro Val Pro Pro Pro Arg Lys Lys Arg Thr Val Val Leu Thr Glu108510901095tca acc cta tct act gcc ttg gcc gag ctc gcc acc aga agc ttt ggc 16083Ser Thr Leu Ser Thr Ala Leu Ala Glu Leu Ala Thr Arg Ser Phe Gly110011051110agc tcc tca act tcc ggc att acg ggc gac aat acg aca aca tcc tct 16131Ser Ser Ser Thr Ser Gly Ile Thr Gly Asp Asn Thr Thr Thr Ser Ser111511201125gag ccc gcc cct tct ggc tgc ccc ccc gac tcc gac gct gag tcc tat 16179Glu Pro Ala Pro Ser Gly Cys Pro Pro Asp Ser Asp Ala Glu Ser Tyr1130 113511401145tcc tcc atg ccc ccc ctg gag ggg gag cct ggg gat ccg gat ctt agc 16227Ser Ser Met Pro Pro Leu Glu Gly Glu Pro Gly Asp Pro Asp Leu Ser115011551160gac ggg tca tgg tca acg gtc agt agt gag gcc aac gcg gag gat gtc 16275Asp Gly Ser Trp Ser Thr Val Ser Ser Glu Ala Asn Ala Glu Asp Val116511701175gtg tgc tgc tca atg tct tac tct tgg aca ggc gca ctc gtc acc ccg 16323Val Cys Cys Ser Met Ser Tyr Ser Trp Thr Gly Ala Leu Val Thr Pro118011851190tgc gcc gcg gaa gaa cag aaa ctg ccc atc aat gca cta agc aac tcg 16371Cys Ala Ala Glu Glu Gln Lys Leu Pro Ile Asn Ala Leu Ser Asn Ser119512001205ttg cta cgt cac cac aat ttg gtg tat tcc acc acc tca cgc agt gct 16419Leu Leu Arg His His Asn Leu Val Tyr Ser Thr Thr Ser Arg Ser Ala1210 121512201225tgc caa agg cag aag aaa gtc aca ttt gac aga ctg caa gtt ctg gac 16467Cys Gln Arg Gln Lys Lys Val Thr Phe Asp Arg Leu Gln Val Leu Asp123012351240agc cat tac cag gac gta ctc aag gag gtt aaa gca gcg gcg tca aaa 16515Ser His Tyr Gln Asp Val Leu Lys Glu Val Lys Ala Ala Ala Ser Lys124512501255gtg aag gct aac ttg cta tcc gta gag gaa gct tgc agc ctg acg ccc 16563Val Lys Ala Asn Leu Leu Ser Val Glu Glu Ala Cys Ser Leu Thr Pro126012651270cca cac tca gcc aaa tcc aag ttt ggt tat ggg gca aaa gac gtc cgt 16611Pro His Ser Ala Lys Ser Lys Phe Gly Tyr Gly Ala Lys Asp Val Arg127512801285tgc cat gcc aga aag gcc gta acc cac atc aac tcc gtg tgg aaa gac 16659Cys His Ala Arg Lys Ala Val Thr His Ile Asn Ser Val Trp Lys Asp1290 129513001305ctt ctg gaa gac aat gta aca cca ata gac act acc atc atg gct aag 16707Leu Leu Glu Asp Asn Val Thr Pro Ile Asp Thr Thr Ile Met Ala Lys131013151320aac gag gtt ttc tgc gtt cag cct gag aag ggg ggt cgt aag cca gct 16755Asn Glu Val Phe Cys Val Gln Pro Glu Lys Gly Gly Arg Lys Pro Ala132513301335cgt ctc atc gtg ttc ccc gat ctg ggc gtg cgc gtg tgc gaa aag atg 16803Arg Leu Ile Val Phe Pro Asp Leu Gly Val Arg Val Cys Glu Lys Met134013451350gct ttg tac gac gtg gtt aca aag ctc ccc ttg gcc gtg atg gga agc 16851Ala Leu Tyr Asp Val Val Thr Lys Leu Pro Leu Ala Val Met Gly Ser135513601365tcc tac gga ttc caa tac tca cca gga cag cgg gtt gaa ttc ctc gtg 16899Ser Tyr Gly Phe Gln Tyr Ser Pro Gly Gln Arg Val Glu Phe Leu Val1370 137513801385caa gcg tgg aag tcc aag aaa acc cca atg ggg ttc tcg tat gat acc 16947Gln Ala Trp Lys Ser Lys Lys Thr Pro Met Gly Phe Ser Tyr Asp Thr139013951400cgc tgc ttt gac tcc aca gtc act gag agc gac atc cgt acg gag gag 16995Arg Cys Phe Asp Ser Thr Val Thr Glu Ser Asp Ile Arg Thr Glu Glu140514101415gca atc tac caa tgt tgt gac ctc gac ccc caa gcc cgc gtg gcc atc 17043Ala Ile Tyr Gln Cys Cys Asp Leu Asp Pro Gln Ala Arg Val Ala Ile142014251430aag tcc ctc acc gag agg ctt tat gtt ggg ggc cct ctt acc aat tca 17091Lys Ser Leu Thr Glu Arg Leu Tyr Val Gly Gly Pro Leu Thr Asn Ser143514401445agg ggg gag aac tgc ggc tat cgc agg tgc cgc gcg agc ggc gta ctg 17139Arg Gly Glu Asn Cys Gly Tyr Arg Arg Cys Arg Ala Ser Gly Val Leu1450 145514601465aca act agc tgt ggt aac acc ctc act tgc tac atc aag gcc cgg gca 17187Thr Thr Ser Cys Gly Asn Thr Leu Thr Cys Tyr Ile Lys Ala Arg Ala147014751480gcc tgt cga gcc gca ggg ctc cag gac tgc acc atg ctc gtg tgt ggc 17235Ala Cys Arg Ala Ala Gly Leu Gln Asp Cys Thr Met Leu Val Cys Gly148514901495gac gac tta gtc gtt atc tgt gaa agc gcg ggg gtc cag gag gac gcg 17283Asp Asp Leu Val Val lle Cys Glu Ser Ala Gly Val Gln Glu Asp Ala150015051510gcg agc ctg aga gcc ttc acg gag gct atg acc agg tac tcc gcc ccc 17331Ala Ser Leu Arg Ala Phe Thr Glu Ala Met Thr Arg Tyr Ser Ala Pro151515201525cct ggg gac ccc cca caa cca gaa tac gac ttg gag crc ata aca rca 17379Pro Gly Asp Pro Pro Gln Pro Glu Tyr Asp Leu Glu Leu Ile Thr Ser1530 153515401545tgc tcc tcc aac gtg tca gtc gcc cac gac ggc gct gga aag agg gtc 17427Cys Ser Ser Asn Val Ser Val Ala His Asp Gly Ala Gly Lys Arg Val155015551560tac tac ctc acc cgt gac cct aca acc ccc ctc gcg aga gct gcg tgg 17475Tyr Tyr Leu Thr Arg Asp Pro Thr Thr Pro Leu Ala Arg Ala Ala Trp156515701575gag aca gca aga cac act cca gtc aat tcc tgg cta ggc aac ata atc 17523Glu Thr Ala Arg His Thr Pro Val Asn Ser Trp Leu Gly Asn Ile Ile158015851590atg ttt gcc ccc aca ctg tgg gcg agg atg ata ctg atg acc cat ttc 17571Met Phe Ala Pro Thr Leu Trp Ala Arg Met Ile Leu Met Thr His Phe159516001605ttt agc gtc ctt ata gcc agg gac cag ctt gaa cag gcc ctc gat tgc 17619Phe Ser Val Leu Ile Ala Arg Asp Gln Leu Glu Gln Ala Leu Asp Cys1610 161516201625gag atc tac ggg gcc tgc tac tcc ata gaa cca ctg gat cta cct cca 17667Glu Ile Tyr Gly Ala Cys Tyr Ser Ile Glu Pro Leu Asp Leu Pro Pro163016351640atc att caa aga ctc cat ggc ctc agc gca ttt tca ctc cac agt tac 17715Ile Ile Gln Arg Leu His Gly Leu Ser Ala Phe Ser Leu His Ser Tyr164516501655tct cca ggt gaa atc aat agg gtg gcc gca tgc ctc aga aaa ctt ggg 17763Ser Pro Gly Glu Ile Asn Arg Val Ala Ala Cys Leu Arg Lys Leu Gly166016651670gta ccg ccc ttg cga gct tgg aga cac cgg gcc cgg agc gtc cgc gct 17811Val Pro Pro Leu Arg Ala Trp Arg His Arg Ala Arg Ser Val Arg Ala167516801685agg ctt ctg gcc aga gga ggc agg gct gcc ata tgt ggc aag tac ctc 17859Arg Leu Leu Ala Arg Gly Gly Arg Ala Ala Ile Cys Gly Lys Tyr Leu1690 169517001705ttc aac tgg gca gta aga aca aag ctc aaa ctc act cca ata gcg gcc 17907Phe Asn Trp Ala Val Arg Thr Lys Leu Lys Leu Thr Pro Ile Ala Ala171017151720gct ggc cag ctg gac ttg tcc ggc tgg ttc acg gct ggc tac agc ggg 17955Ala Gly Gln Leu Asp Leu Ser Gly Trp Phe Thr Ala Gly Tyr Ser Gly172517301735gga gac att tat cac agc gtg tct cat gcc cgg ccc cgc tgg atc tgg 18003Gly Asp Ile Tyr His Ser Val Ser His Ala Arg Pro Arg Trp Ile Trp174017451750ttt tgc cta ctc ctg ctt gct gca ggg gta ggc atc tac ctc ctc ccc 18051Phe Cys Leu Leu Leu Leu Ala Ala Gly Val Gly Ile Tyr Leu Leu Pro175517601765aac cga tgaaggttgg ggtaaacact ccggcctaaa aaaaaaaaaa aatctagaac18107Asn Arg1770ccgagtcgac tttgttccca ctgtactttt agctcgtaca aaatacaata tacttttcat 18167ttctccgtaa acaacatgtt ttcccatgta atatcctttt ctatttttcg ttccgttacc 18227aactttacac atactttata tagctattca cttctataca ctaaaaaact aagacaattt 18287taattttgct acctgccata tttcaatttg ttataaattc ctataattta tcctattagt 18347agctaaaaaa agatgaatgt gaatcgaatc ctaagagaat tggatctgat ccacaggacg 18407ggtgtggtcg ccatgatcgc gtagtcgata gtggctccaa gtagcgaagc gagcaggact 18467gggcggcggc caaagcggtc ggacagtgct ccgagaacgg gtgcgcatag aaattgcatc 18527aacgcatata gcgctagcag cacgccatag tgactggcga tgctgtcgga atggacgata 18587tcccgcaaga ggcccggcag taccggcata accaagccta tgcctacagc atccagggtg 18647acggtgccga ggatgacgat gagcgcattg ttagatttca tacacggtgc ctgactgcgt 18707tagcaattta actgtgataa actaccgcat taaagctttt tctttccaat tttttttttt 18767tcgtcattat aaaaatcatt acgaccgaga ttcccgggta ataactgata taattaaatt 18827gaagctctaa tttgtgagtt tagtatacat gcatttactt ataatacagt tttttagttt 18887tgctggccgc atcttctcaa atatgcttcc cagcctgctt ttctgtaacg ttcaccctct 18947accttagcat cccttccctt tgcaaatagt cctcttccaa caataataat gtcagatcct 19007gtagagacca catcatccac ggttctatac tgttgaccca atgcgtctcc cttgtcatct 19067aaacccacac cgggtgtcat aatcaaccaa tcgtaacctt catctcttcc acccatgtct 19127ctttgagcaa taaagccgat aacaaaatct ttgtcgctct tcgcaatgtc aacagtaccc 19187ttagtatatt ctccagtaga tagggagccc ttgcatgaca attctgctaa catcaaaagg 19247cctctaggtt cctttgttac ttcttctgcc gcctgcttca aaccgctaac aatacctggg 19307cccaccacac cgtgtgcatt cgtaatgtct gcccattctg ctattctgta tacacccgca 19367gagtactgca atttgactgt attaccaatg tcagcaaatt ttctgtcttc gaagagtaaa 19427aaattgtact tggcggataa tgcctttagc ggcttaactg tgccctccat ggaaaaatca 19487gtcaagatat ccacatgtgt ttttagtaaa caaattttgg gacctaatgc ttcaactaac 19547tccagtaatt ccttggtggt acgaacatcc aatgaagcac acaagtttgt ttgcttttcg 19607tgcatgatat taaatagctt ggcagcaaca ggactaggat gagtagcagc acgttcctta 19667tatgtagctt tcgacatgat ttatcttcgt ttcctgcagg tttttgttct gtgcagttgg 19727gttaagaata ctgggcaatt tcatgtttct tcaacactac atatgcgtat atataccaat 19787ctaagtctgt gctccttcct tcgttcttcc ttctgttcgg agattaccga atcaaaaaaa 19847tttcaaggaa accgaaatca aaaaaaagaa taaaaaaaaa atgatgaatt gaaaagctta 19907tcgat 1991221092111771212PRT213人工序列220223人工序列的描述pd.deltaNS3NS54009Met Ala Ala Tyr Ala Ala Gln Gly Tyr Lys Val Leu Val Leu Asn Pro1 5 10 15Ser Val Ala Ala Thr Leu Gly Phe Gly Ala Tyr Met Ser Lys Ala His20 25 30Gly Ile Asp Pro Asn Ile Arg Thr Gly Val Arg Thr Ile Thr Thr Gly35 40 45Ser Pro Ile Thr Tyr Ser Thr Tyr Gly Lys Phe Leu Ala Asp Gly Gly50 55 60Cys Ser Gly Gly Ala Tyr Asp Ile Ile Ile Cys Asp Glu Cys His Ser65 70 75 80Thr Asp Ala Thr Ser Ile Leu Gly Ile Gly Thr Val Leu Asp Gln Ala85 90 95Glu Thr Ala Gly Ala Arg Leu Val Val Leu Ala Thr Ala Thr Pro Pro100 105 110Gly Ser Val Thr Val Pro His Pro Asn Ile Glu Glu Val Ala Leu Ser115 120 125Thr Thr Gly Glu Ile Pro Phe Tyr Gly Lys Ala Ile Pro Leu Glu Val130 135 140Ile Lys Gly Gly Arg His Leu Ile Phe Cys His Ser Lys Lys Lys Cys145 150 155 160Asp Glu Leu Ala Ala Lys Leu Val Ala Leu Gly Ile Asn Ala Val Ala165 170 175Tyr Tyr Arg Gly Leu Asp Val Ser Val Ile Pro Thr Ser Gly Asp Val180 185 190Val Val Val Ala Thr Asp Ala Leu Met Thr Gly Tyr Thr Gly Asp Phe195 200 205Asp Ser Val Ile Asp Cys Asn Thr Cys Val Thr Gln Thr Val Asp Phe210 215 220Ser Leu Asp Pro Thr Phe Thr Ile Glu Thr Ile Thr Leu Pro Gln Asp225 230 235 240Ala Val Ser Arg Thr Gln Arg Arg Gly Arg Thr Gly Arg Gly Lys Pro245 250 255Gly Ile Tyr Arg Phe Val Ala Pro Gly Glu Arg Pro Ser Gly Met Phe260 265 270Asp Ser Ser Val Leu Cys Glu Cys Tyr Asp Ala Gly Cys Ala Trp Tyr275 280 285Glu Leu Thr Pro Ala Glu Thr Thr Val Arg Leu Arg Ala Tyr Met Asn290 295 300Thr Pro Gly Leu Pro Val Cys Gln Asp His Leu Glu Phe Trp Glu Gly305 310 315 320Val Phe Thr Gly Leu Thr His Ile Asp Ala His Phe Leu Ser Gln Thr325 330 335Lys Gln Ser Gly Glu Asn Leu Pro Tyr Leu Val Ala Tyr Gln Ala Thr340 345 350Val Cys Ala Arg Ala Gln Ala Pro Pro Pro Ser Trp Asp Gln Met Trp355 360 365Lys Cys Leu Ile Arg Leu Lys Pro Thr Leu His Gly Pro Thr Pro Leu370 375 380Leu Tyr Arg Leu Gly Ala Val Gln Asn Glu Ile Thr Leu Thr His Pro385 390 395 400Val Thr Lys Tyr Ile Met Thr Cys Met Ser Ala Asp Leu Glu Val Val405 410 415Thr Ser Thr Trp Val Leu Val Gly Gly Val Leu Ala Ala Leu Ala Ala420 425 430Tyr Cys Leu Ser Thr Gly Cys Val Val Ile Val Gly Arg Val Val Leu435 440 445Ser Gly Lys Pro Ala Ile Ile Pro Asp Arg Glu Val Leu Tyr Arg Glu450 455 460Phe Asp Glu Met Glu Glu Cys Ser Gln His Leu Pro Tyr Ile Glu Gln465 470 475 480Gly Met Met Leu Ala Glu Gln Phe Lys Gln Lys Ala Leu Gly Leu Leu485 490 495Gln Thr Ala Ser Arg Gln Ala Glu Val Ile Ala Pro Ala Val Gln Thr500 505 510Asn Trp Gln Lys Leu Glu Thr Phe Trp Ala Lys His Met Trp Asn Phe515 520 525Ile Ser Gly Ile Gln Tyr Leu Ala Gly Leu Ser Thr Leu Pro Gly Asn530 535 540Pro Ala Ile Ala Ser Leu Met Ala Phe Thr Ala Ala Val Thr Ser Pro545 550 555 560Leu Thr Thr Ser Gln Thr Leu Leu Phe Asn Ile Leu Gly Gly Trp Val565 570 575Ala Ala Gln Leu Ala Ala Pro Gly Ala Ala Thr Ala Phe Val Gly Ala580 585 590Gly Leu Ala Gly Ala Ala Ile Gly Ser Val Gly Leu Gly Lys Val Leu595 600 605Ile Asp Ile Leu Ala Gly Tyr Gly Ala Gly Val Ala Gly Ala Leu Val610 615 620Ala Phe Lys Ile Met Ser Gly Glu Val Pro Ser Thr Glu Asp Leu Val625 630 635 640Asn Leu Leu Pro Ala Ile Leu Ser Pro Gly Ala Leu Val Val Gly Val645 650 655Val Cys Ala Ala Ile Leu Arg Arg His Val Gly Pro Gly Glu Gly Ala660 665 670Val Gln Trp Met Asn Arg Leu Ile Ala Phe Ala Ser Arg Gly Asn His675 680 685Val Ser Pro Thr His Tyr Val Pro Glu Ser Asp Ala Ala Ala Arg Val690 695 700Thr Ala Ile Leu Ser Ser Leu Thr Val Thr Gln Leu Leu Arg Arg Leu705 710 715 720His Gln Trp Ile Ser Ser Glu Cys Thr Thr Pro Cys Ser Gly Ser Trp725 730 735Leu Arg Asp Ile Trp Asp Trp Ile Cys Glu Val Leu Ser Asp Phe Lys740 745 750Thr Trp Leu Lys Ala Lys Leu Met Pro Gln Leu Pro Gly Ile Pro Phe755 760 765Val Ser Cys Gln Arg Gly Tyr Lys Gly Val Trp Arg Gly Asp Gly Ile770 775 780Met His Thr Arg Cys His Cys Gly Ala Glu Ile Thr Gly His Val Lys785 790 795 800Asn Gly Thr Met Arg Ile Val Gly Pro Arg Thr Cys Arg Asn Met Trp805 810 815Ser Gly Thr Phe Pro Ile Asn Ala Tyr Thr Thr Gly Pro Cys Thr Pro820 825 830Leu Pro Ala Pro Asn Tyr Thr Phe Ala Leu Trp Arg Val Ser Ala Glu835 840 845Glu Tyr Val Glu Ile Arg Gln Val Gly Asp Phe His Tyr Val Thr Gly850 855 860Met Thr Thr Asp Asn Leu Lys Cys Pro Cys Gln Val Pro Ser Pro Glu865 870 875 880Phe Phe Thr Glu Leu Asp Gly Val Arg Leu His Arg Phe Ala Pro Pro885 890 895Cys Lys Pro Leu Leu Arg Glu Glu Val Ser Phe Arg Val Gly Leu His900 905 910Glu Tyr Pro Val Gly Ser Gln Leu Pro Cys Glu Pro Glu Pro Asp Val915 920 925Ala Val Leu Thr Ser Met Leu Thr Asp Pro Ser His Ile Thr Ala Glu930 935 940Ala Ala Gly Arg Arg Leu Ala Arg Gly Ser Pro Pro Ser Val Ala Ser945 950 955 960Ser Ser Ala Ser Gln Leu Ser Ala Pro Ser Leu Lys Ala Thr Cys Thr965 970 975Ala Asn His Asp Ser Pro Asp Ala Glu Leu Ile Glu Ala Asn Leu Leu980 985 990Trp Arg Gln Glu Met Gly Gly Asn Ile Thr Arg Val Glu Ser Glu Asn99510001005Lys Val Val Ile Leu Asp Ser Phe Asp Pro Leu Val Ala Glu Glu Asp101010151020Glu Arg Glu Ile Ser Val Pro Ala Glu Ile Leu Arg Lys Ser Arg Arg025103010351040Phe Ala Gln Ala Leu Pro Val Trp Ala Arg Pro Asp Tyr Asn Pro Pro104510501055Leu ValGlu Thr Trp Lys Lys Pro Asp Tyr Glu Pro Pro Val Val His106010651070Gly Cys Pro Leu Pro Pro Pro Lys Ser Pro Pro Val Pro Pro Pro Arg107510801085Lys Lys Arg Thr Val Val Leu Thr Glu Ser Thr Leu Ser Thr Ala Leu109010951100Ala Glu Leu Ala Thr Arg Ser Phe Gly Ser Ser Ser Thr Ser Gly Ile105111011151120Thr Gly Asp Asn Thr Thr Thr Ser Ser Glu Pro Ala Pro Ser Gly Cys112511301135Pro Pro Asp Ser Asp Ala Glu Ser Tyr Ser Ser Met Pro Pro Leu Glu114011451150Gly Glu Pro Gly Asp Pro Asp Leu Ser Asp Gly Ser Trp Ser Thr Val115511601165Ser Ser Glu Ala Asn Ala Glu Asp Val Val Cys Cys Ser Met Ser Tyr117011751180Ser Trp Thr Gly Ala Leu Val Thr Pro Cys Ala Ala Glu Glu Gln Lys185119011951200Leu Pro Ile Asn Ala Leu Ser Asn Ser Leu Leu Arg His His Asn Leu120512101215Val Tyr Ser Thr Thr Ser Arg Ser Ala Cys Gln Arg Gln Lys Lys Val122012251230Thr Phe Asp Arg Leu Gln Val Leu Asp Ser His Tyr Gln Asp Val Leu123512401245Lys Glu Val Lys Ala Ala Ala Ser Lys Val Lys Ala Asn Leu Leu Ser125012551260Val Glu Glu Ala Cys Ser Leu Thr Pro Pro His Ser Ala Lys Ser Lys265127012751280Phe Gly Tyr Gly Ala Lys Asp Val Arg Cys His Ala Arg Lys Ala Val128512901295Thr His Ile Asn Ser Val Trp Lys Asp Leu Leu Glu Asp Asn Val Thr130013051310Pro Ile Asp Thr Thr Ile Met Ala Lys Asn Glu Val Phe Cys Val Gln131513201325Pro Glu Lys Gly Gly Arg Lys Pro Ala Arg Leu Ile Val Phe Pro Asp133013351340Leu Gly Val Arg Val Cys Glu Lys Met Ala Leu Tyr Asp Val Val Thr345135013551360Lys Leu Pro Leu Ala Val Met Gly Ser Ser Tyr Gly Phe Gln Tyr Ser136513701375Pro Gly Gln Arg Val Glu Phe Leu Val Gln Ala Trp Lys Ser Lys Lys138013851390Thr Pro Met Gly Phe Ser Tyr Asp Thr Arg Cys Phe Asp Ser Thr Val139514001405Thr Glu Ser Asp Ile Arg Thr Glu Glu Ala Ile Tyr Gln Cys Cys Asp141014151420Leu Asp Pro Gln Ala Arg Val Ala Ile Lys Ser Leu Thr Glu Arg Leu425143014351440Tyr Val Gly Gly Pro Leu Thr Asn Ser Arg Gly Glu Asn Cys Gly Tyr144514501455Arg Arg Cys Arg Ala Ser Gly Val Leu Thr Thr Ser Cys Gly Asn Thr146014651470Leu Thr Cys Tyr Ile Lys Ala Arg Ala Ala Cys Arg Ala Ala Gly Leu147514801485Gln Asp Cys Thr Met Leu Val Cys Gly Asp Asp Leu Val Val Ile Cys149014951500Glu Ser Ala Gly Val Gln Glu Asp Ala Ala Ser Leu Arg Ala Phe Thr505151015151520Glu Ala Met Thr Arg Tyr Ser Ala Pro Pro Gly Asp Pro Pro Gln Pro152515301535Glu Tyr Asp Leu Glu Leu Ile Thr Ser Cys Ser Ser Asn Val Ser Val154015451550Ala His Asp Gly Ala Gly Lys Arg Val Tyr Tyr Leu Thr Arg Asp Pro155515601565Thr Thr Pro Leu Ala Arg Ala Ala Trp Glu Thr Ala Arg His Thr Pro157015751580Val Asn Ser Trp Leu Gly Asn Ile Ile Met Phe Ala Pro Thr Leu Trp585159015951600Ala Arg Met Ile Leu Met Thr His Phe Phe Ser Val Leu Ile Ala Arg160516101615Asp Gln Leu Glu Gln Ala Leu Asp Cys Glu Ile Tyr Gly Ala Cys Tyr162016251630Ser Ile Glu Pro Leu Asp Leu Pro Pro Ile Ile Gln Arg Leu His Gly163516401645Leu Ser Ala Phe Ser Leu His Ser Tyr Ser Pro Gly Glu Ile Asn Arg165016551660Val Ala Ala Cys Leu Arg Lys Leu Gly Val Pro Pro Leu Arg Ala Trp665167016751680Arg His Arg Ala Arg Ser Val Arg Ala Arg Leu Leu Ala Arg Gly Gly168516901695Arg Ala Ala Ile Cys Gly Lys Tyr Leu Phe Asn Trp Ala Val Arg Thr170017051710Lys Leu Lys Leu Thr Pro Ile Ala Ala Ala Gly Gln Leu Asp Leu Ser171517201725Gly Trp Phe Thr Ala Gly Tyr Ser Gly Gly Asp Ile Tyr His Ser Val173017351740Ser His Ala Arg Pro Arg Trp Ile Trp Phe Cys Leu Leu Leu Leu Ala745175017551760Ala Gly Val Gly Ile Tyr Leu Leu Pro Asn Arg176517702101021119798212DNA213人工序列220223人工序列的描述pd.deltaNS3NS5.pj22022lCDS222(12679)..(17991)40010atcgatccta ccccttgcgc taaagaagta tatgtgccta ctaacgcttg tctttgtctc 60tgtcactaaa cactggatta ttactcccag atacttattt tggactaatt taaatgattt 120cggatcaacg ttcttaatat cgctgaatct tccacaattg atgaaagtag ctaggaagag 180gaattggtat aaagtttttg tttttgtaaa tctcgaagta tactcaaacg aatttagtat 240tttctcagtg atctcccaga tgctttcacc ctcacttaga agtgctttaa gcattttttt 300actgtggcta tttcccttat ctgcttcttc cgatgattcg aactgtaatt gcaaactact 360tacaatatca gtgatatcag attgatgttt ttgtccatag taaggaataa ttgtaaattc 420ccaagcagga atcaatttct ttaatgaggc ttccagaatt gttgcttttt gcgtcttgta 480tttaaactgg agtgatttat tgacaatatc gaaactcagc gaattgctta tgatagtatt 540atagctcatg aatgtggctc tcttgattgc tgttccgtta tgtgtaatca tccaacataa 600ataggttagt tcagcagcac ataatgctat tttctcacct gaaggtcttt caaacctttc 660cacaaactga cgaacaagca ccttaggtgg tgttttacat aatatatcaa attgtggcat 720gcttagcgcc gatcttgtgt gcaattgata tctagtttca actactctat ttatcttgta 780tcttgcagta ttcaaacacg ctaactcgaa aaactaactt taattgtcct gtttgtctcg 840cgttctttcg aaaaatgcac cggccgcgca ttatttgtac tgcgaaaata attggtactg 900cggtatcttc atttcatatt ttaaaaatgc acctttgctg cttttcctta atttttagac 960ggcccgcagg ttcgttttgc ggtactatct tgtgataaaa agttgttttg acatgtgatc 1020tgcacagatt ttataatgta ataagcaaga atacattatc aaacgaacaa tactggtaaa 1080agaaaaccaa aatggacgac attgaaacag ccaagaatct gacggtaaaa gcacgtacag 1140cttatagcgt ctgggatgta tgtcggctgt ttattgaaat gattgctcct gatgtagata 1200ttgatataga gagtaaacgt aagtctgatg agctactctt tccaggatat gtcataaggc 1260ccatggaatc tctcacaacc ggtaggccgt atggtcttga ttctagcgca gaagattcca 1320gcgtatcttc tgactccagt gctgaggtaa ttttgcctgc tgcgaagatg gttaaggaaa 1380ggtttgattc gattggaaat ggtatgctct cttcacaaga agcaagtcag gctgccatag 1440atttgatgct acagaataac aagctgttag acaatagaaa gcaactatac aaatctattg 1500ctataataat aggaagattg cccgagaaag acaagaagag agctaccgaa atgctcatga 1560gaaaaatgga ttgtacacag ttattagtcc caccagctcc aacggaagaa gatgttatga 1620agctcgtaag cgtcgttacc caattgctta ctttagttcc accagatcgt caagctgctt 1680taataggtga tttattcatc ccggaatctc taaaggatat attcaatagt ttcaatgaac 1740tggcggcaga gaatcgttta cagcaaaaaa agagtgagtt ggaaggaagg actgaagtga 1800accatgctaa tacaaatgaa gaagttccct ccaggcgaac aagaagtaga gacacaaatg 1860caagaggagc atataaatta caaaacacca tcactgaggg ccctaaagcg gttcccacga 1920aaaaaaggag agtagcaacg agggtaaggg gcagaaaatc acgtaatact tctagggtat 1980gatccaatat caaaggaaat gatagcattg aaggatgaga ctaatccaat tgaggagtgg 2040cagcatatag aacagctaaa gggtagtgct gaaggaagca tacgataccc cgcatggaat 2100gggataatat cacaggaggt actagactac ctttcatcct acataaatag acgcatataa 2160gtacgcattt aagcataaac acgcactatg ccgttcttct catgtatata tatatacagg 2220caacacgcag atataggtgc gacgtgaaca gtgagctgta tgtgcgcagc tcgcgttgca 2280ttttcggaag cgctcgtttt cggaaacgct ttgaagttcc tattccgaag ttcctattct 2340ctagaaagta taggaacttc agagcgcttt tgaaaaccaa aagcgctctg aagacgcact 2400ttcaaaaaac caaaaacgca ccggactgta acgagctact aaaatattgc gaataccgct 2460tccacaaaca ttgctcaaaa gtatctcttt gctatatatc tctgtgctat atccctatat 2520aacctaccca tccacctttc gctccttgaa cttgcatcta aactcgacct ctacatcaac 2580aggcttccaa tgctcttcaa attttactgt caagtagacc catacggctg taatatgctg 2640ctcttcataa tgtaagctta tctttatcga atcgtgtgaa aaactactac cgcgataaac 2700ctttacggtt ccctgagatt gaattagttc ctttagtata tgatacaaga cacttttgaa 2760ctttgtacga cgaattttga ggttcgccat cctctggcta tttccaatta tcctgtcggc 2820tattatctcc gcctcagttt gatcttccgc ttcagactgc catttttcac ataatgaatc 2880tatttcaccc cacaatcctt catccgcctc cgcatcttgt tccgttaaac tattgacttc 2940atgttgtaca ttgtttagtt cacgagaagg gtcctcttca ggcggtagct cctgatctcc 3000tatatgacct ttatcctgtt ctctttccac aaacttagaa atgtattcat gaattatgga 3060gcacctaata acattcttca aggcggagaa gtttgggcca gatgcccaat atgcttgaca 3120tgaaaacgtg agaatgaatt tagtattatt gtgatattct gaggcaattt tattataatc 3180tcgaagataa gagaagaatg cagtgacctt tgtattgaca aatggagatt ccatgtatct 3240aaaaaatacg cctttaggcc ttctgatacc ctttcccctg cggtttagcg tgccttttac 3300attaatatct aaaccctctc cgatggtggc ctttaactga ctaataaatg caaccgatat 3360aaactgtgat aattctgggt gatttatgat tcgatcgaca attgtattgt acactagtgc 3420aggatcaggc caatccagtt ctttttcaat taccggtgtg tcgtctgtat tcagtacatg 3480tccaacaaat gcaaatgcta acgttttgta tttcttataa ttgtcaggaa ctggaaaagt 3540cccccttgtc gtctcgatta cacacctact ttcatcgtac accataggtt ggaagtgctg 3600cataatacat tgcttaatac aagcaagcag tctctcgcca ttcatatttc agttattttc 3660cattacagct gatgtcattg tatatcagcg ctgtaaaaat ctatctgtta cagaaggttt 3720tcgcggtttt tataaacaaa actttcgtta cgaaatcgag caatcacccc agctgcgtat 3780ttggaaattc gggaaaaagt agagcaacgc gagttgcatt ttttacacca taatgcatga 3840ttaacttcga gaagggatta aggctaattt cactagtatg tttcaaaaac ctcaatctgt 3900ccattgaatg ccttataaaa cagctataga ttgcatagaa gagttagcta ctcaatgctt 3960tttgtcaaag cttactgatg atgatgtgtc tactttcagg cgggtctgta gtaaggagaa 4020tgacattata aagctggcac ttagaattcc acggactata gactatacta gtatactccg 4080tctactgtac gatacacttc cgctcaggtc cttgtccttt aacgaggcct taccactctt 4140ttgttactct attgatccag ctcagcaaag gcagtgtgat ctaagattct atcttcgcga 4200tgtagtaaaa ctagctagac cgagaaagag actagaaatg caaaaggcac ttctacaatg 4260gctgccatca ttattatccg atgtgacgct gcattttttt tttttttttt tttttttttt 4320tttttttttt tttttttttt ttttttggta caaatatcat aaaaaaagag aatcttttta 4380agcaaggatt ttcttaactt cttcggcgac agcatcaccg acttcggtgg tactgttgga 4440accacctaaa tcaccagttc tgatacctgc atccaaaacc tttttaactg catcttcaat 4500ggctttacct tcttcaggca agttcaatga caatttcaac atcattgcag cagacaagat 4560agtggcgata gggttgacct tattctttgg caaatctgga gcggaaccat ggcatggttc 4620gtacaaacca aatgcggtgt tcttgtctgg caaagaggcc aaggacgcag atggcaacaa 4680acccaaggag cctgggataa cggaggcttc atcggagatg atatcaccaa acatgttgct 4740ggtgattata ataccattta ggtgggttgg gttcttaact aggatcatgg cggcagaatc 4800aatcaattga tgttgaactt tcaatgtagg gaattcgttc ttgatggttt cctccacagt 4860ttttctccat aatcttgaag aggccaaaac attagcttta tccaaggacc aaataggcaa 4920tggtggctca tgttgtaggg ccatgaaagc ggccattctt gtgattcttt gcacttctgg 4980aacggtgtat tgttcactat cccaagcgac accatcacca tcgtcttcct ttctcttacc 5040aaagtaaata cctcccacta attctctaac aacaacgaag tcagtacctt tagcaaattg 5100tggcttgatt ggagataagt ctaaaagaga gtcggatgca aagttacatg gtcttaagtt 5160ggcgtacaat tgaagttctt tacggatttt tagtaaacct tgttcaggtc taacactacc 5220ggtaccccat ttaggaccac ccacagcacc taacaaaacg gcatcagcct tcttggaggc 5280ttccagcgcc tcatctggaa gtggaacacc tgtagcatcg atagcagcac caccaattaa 5340atgattttcg aaatcgaact tgacattgga acgaacatca gaaatagctt taagaacctt 5400aatggcttcg gctgtgattt cttgaccaac gtggtcacct ggcaaaacga cgatcttctt 5460aggggcagac attacaatgg tatatccttg aaatatatat aaaaaaaaaa aaaaaaaaaa 5520aaaaaaaaaa atgcagcttc tcaatgatat tcgaatacgc tttgaggaga tacagcctaa 5580tatccgacaa actgttttac agatttacga tcgtacttgt tacccatcat tgaattttga 5640acatccgaac ctgggagttt tccctgaaac agatagtata tttgaacctg tataataata 5700tatagtctag cgctttacgg aagacaatgt atgtatttcg gttcctggag aaactattgc 5760atctattgca taggtaatct tgcacgtcgc atccccggtt cattttctgc gtttccatct 5820tgcacttcaa tagcatatct ttgttaacga agcatctgtg cttcattttg tagaacaaaa 5880atgcaacgcg agagcgctaa tttttcaaac aaagaatctg agctgcattt ttacagaaca 5940gaaatgcaac gcgaaagcgc tattttacca acgaagaatc tgtgcttcat ttttgtaaaa 6000caaaaatgca acgcgagagc gctaattttt caaacaaaga atctgagctg catttttaca 6060gaacagaaat gcaacgcgag agcgctattt taccaacaaa gaatctatac ttcttttttg 6120ttctacaaaa atgcatcccg agagcgctat ttttctaaca aagcatctta gattactttt 6180tttctccttt gtgcgctcta taatgcagtc tcttgataac tttttgcact gtaggtccgt 6240taaggttaga agaaggctac tttggtgtct attttctctt ccataaaaaa agcctgactc 6300cacttcccgc gtttactgat tactagcgaa gctgcgggtg cattttttca agataaaggc 6360atccccgatt atattctata ccgatgtgga ttgcgcatac tttgtgaaca gaaagtgata 6420gcgttgatga ttcttcattg gtcagaaaat tatgaacggt ttcttctatt ttgtctctat 6480atactacgta taggaaatgt ttacattttc gtattgtttt cgattcactc tatgaatagt 6540tcttactaca atttttttgt ctaaagagta atactagaga taaacataaa aaatgtagag 6600gtcgagttta gatgcaagtt caaggagcga aaggtggatg ggtaggttat atagggatat 6660agcacagaga tatatagcaa agagatactt ttgagcaatg tttgtggaag cggtattcgc 6720aatattttag tagctcgtta cagtccggtg cgtttttggt tttttgaaag tgcgtcttca 6780gagcgctttt ggttttcaaa agcgctctga agttcctata ctttctagag aataggaact 6840tcggaatagg aacttcaaag cgtttccgaa aacgagcgct tccgaaaatg caacgcgagc 6900tgcgcacata cagctcactg ttcacgtcgc acctatatct gcgtgttgcc tgtatatata 6960tatacatgag aagaacggca tagtgcgtgt ttatgcttaa atgcgtactt atatgcgtct 7020atttatgtag gatgaaaggt agtctagtac ctcctgtgat attatcccat tccatgcggg 7080gtatcgtatg cttccttcag cactaccctt tagctgttct atatgctgcc actcctcaat 7140tggattagtc tcatccttca atgctatcat ttcctttgat attggatcat atgcatagta 7200ccgagaaact agtgcgaagt agtgatcagg tattgctgtt atctgatgag tatacgttgt 7260cctggccacg gcagaagcac gcttatcgct ccaatttccc acaacattag tcaactccgt 7320taggcccttc attgaaagaa atgaggtcat caaatgtctt ccaatgtgag attttgggcc 7380attttttata gcaaagattg aataaggcgc atttttcttc aaagctttat tgtacgatct 7440gactaagtta tcttttaata attggtattc ctgtttattg cttgaagaat tgccggtcct 7500atttactcgt tttaggactg gttcagaatt cctcaaaaat tcatccaaat atacaagtgg 7560atcgatgata agctgtcaaa catgagaatt cttgaagacg aaagggcctc gtgatacgcc 7620tatttttata ggttaatgtc atgataataa tggtttctta gacgtcaggt ggcacttttc 7680ggggaaatgt gcgcggaacc cctatttgtt tatttttcta aatacattca aatatgtatc 7740cgctcatgag acaataaccc tgataaatgc ttcaataata ttgaaaaagg aagagtatga 7800gtattcaaca tttccgtgtc gcccttattc ccttttttgc ggcattttgc cttcctgttt 7860ttgctcaccc agaaacgctg gtgaaagtaa aagatgctga agatcagttg ggtgcacgag 7920tgggttacat cgaactggat ctcaacagcg gtaagatcct tgagagtttt cgccccgaag 7980aacgttttcc aatgatgagc acttttaaag ttctgctatg tggcgcggta ttatcccgtg 8040ttgacgccgg gcaagagcaa ctcggtcgcc gcatacacta ttctcagaat gacttggttg 8100agtactcacc agtcacagaa aagcatctta cggatggcat gacagtaaga gaattatgca 8160gtgctgccat aaccatgagt gataacactg cggccaactt acttctgaca acgatcggag 8220gaccgaagga gctaaccgct tttttgcaca acatggggga tcatgtaact cgccttgatc 8280gttgggaacc ggagctgaat gaagccatac caaacgacga gcgtgacacc acgatgcctg 8340cagcaatggc aacaacgttg cgcaaactat taactggcga actacttact ctagcttccc 8400ggcaacaatt aatagactgg atggaggcgg ataaagttgc aggaccactt ctgcgctcgg 8460cccttccggc tggctggttt attgctgata aatctggagc cggtgagcgt gggtctcgcg 8520gtatcattgc agcactgggg ccagatggta agccctcccg tatcgtagtt atctacacga 8580cggggagtca ggcaactatg gatgaacgaa atagacagat cgctgagata ggtgcctcac 8640tgattaagca ttggtaactg tcagaccaag tttactcata tatactttag attgatttaa 8700aacttcattt ttaatttaaa aggatctagg tgaagatcct ttttgataat ctcatgacca 8760aaatccctta acgtgagttt tcgttccact gagcgtcaga ccccgtagaa aagatcaaag 8820gatcttcttg agatcctttt tttctgcgcg taatctgctg cttgcaaaca aaaaaaccac 8880cgctaccagc ggtggtttgt ttgccggatc aagagctacc aactcttttt ccgaaggtaa 8940ctggcttcag cagagcgcag ataccaaata ctgtccttct agtgtagccg tagttaggcc 9000accacttcaa gaactctgta gcaccgccta catacctcgc tctgctaatc ctgttaccag 9060tggctgctgc cagtggcgat aagtcgtgtc ttaccgggtt ggactcaaga cgatagttac 9120cggataaggc gcagcggtcg ggctgaacgg ggggttcgtg cacacagccc agcttggagc 9180gaacgaccta caccgaactg agatacctac agcgtgagct atgagaaagc gccacgcttc 9240ccgaagggag aaaggcggac aggtatccgg taagcggcag ggtcggaaca ggagagcgca 9300cgagggagct tccaggggga aacgcctggt atctttatag tcctgtcggg tttcgccacc 9360tctgacttga gcgtcgattt ttgtgatgct cgtcaggggg gcggagccta tggaaaaacg 9420ccagcaacgc ggccttttta cggttcctgg ccttttgctg gccttttgct cacatgttct 9480ttcctgcgtt atcccctgat tctgtggata accgtattac cgcctttgag tgagctgata 9540ccgctcgccg cagccgaacg accgagcgca gcgagtcagt gagcgaggaa gcggaagagc 9600gcctgatgcg gtattttctc cttacgcatc tgtgcggtat ttcacaccgc atatggtgca 9660ctctcagtac aatctgctct gatgccgcat agttaagcca gtatacactc cgctatcgct 9720acgtgactgg gtcatggctg cgccccgaca cccgccaaca cccgctgacg cgccctgacg 9780ggcttgtctg ctcccggcat ccgcttacag acaagctgtg accgtctccg ggagctgcat 9840gtgtcagagg ttttcaccgt catcaccgaa acgcgcgagg cagctgcggt aaagctcatc 9900agcgtggtcg tgaagcgatt cacagatgtc tgcctgttca tccgcgtcca gctcgttgag 9960tttctccaga agcgttaatg tctggcttct gataaagcgg gccatgttaa gggcggtttt 10020ttcctgtttg gtcactgatg cctccgtgta agggggattt ctgttcatgg gggtaatgat 10080accgatgaaa cgagagagga tgctcacgat acgggttact gatgatgaac atgcccggtt 10140actggaacgt tgtgagggta aacaactggc ggtatggatg cggcgggacc agagaaaaat 10200cactcagggt caatgccagc gcttcgttaa tacagatgta ggtgttccac agggtagcca 10260gcagcatcct gcgatgcaga tccggaacat aatggtgcag ggcgctgact tccgcgtttc 10320cagactttac gaaacacgga aaccgaagac cattcatgtt gttgctcagg tcgcagacgt 10380tttgcagcag cagtcgcttc acgttcgctc gcgtatcggt gattcattct gctaaccagt 10440aaggcaaccc cgccagccta gccgggtcct caacgacagg agcacgatca tgcgcacccg 10500tggccaggac ccaacgctgc ccgagatgcg ccgcgtgcgg ctgctggaga tggcggacgc 10560gatggatatg ttctgccaag ggttggtttg cgcattcaca gttctccgca agaattgatt 10620ggctccaatt cttggagtgg tgaatccgtt agcgaggtgc cgccggcttc cattcaggtc 10680gaggtggccc ggctccatgc accgcgacgc aacgcgggga ggcagacaag gtatagggcg 10740gcgcctacaa tccatgccaa cccgttccat gtgctcgccg aggcggcata aatcgccgtg 10800acgatcagcg gtccaatgat cgaagttagg ctggtaagag ccgcgagcga tccttgaagc 10860tgtccctgat ggtcgtcatc tacctgcctg gacagcatgg cctgcaacgc gggcatcccg 10920atgccgccgg aagcgagaag aatcataatg gggaaggcca tccagcctcg cgtcgcgaac 10980gccagcaaga cgtagcccag cgcgtcggcc gccatgccgg cgataatggc ctgcttctcg ll040ccgaaacgtt tggtggcggg accagtgacg aaggcttgag cgagggcgtg caagattccg lll00aataccgcaa gcgacaggcc gatcatcgtc gcgctccagc gaaagcggtc ctcgccgaaa 11160atgacccaga gcgctgccgg cacctgtcct acgagttgca tgataaagaa gacagtcata 11220agtgcggcga cgatagtcat gccccgcgcc caccggaagg agctgactgg gttgaaggct 11280ctcaagggca tcggtcgagg atccttcaat atgcgcacat acgctgttat gttcaaggtc 11340ccttcgttta agaacgaaag cggtcttcct tttgagggat gtttcaagtt gttcaaatct 11400atcaaatttg caaatcccca gtctgtatct agagcgttga atcggtgatg cgatttgtta 11460attaaattga tggtgtcacc attaccaggt ctagatatac caatggcaaa ctgagcacaa 11520caataccagt ccggatcaac tggcaccatc tctcccgtag tctcatctaa tttttcttcc 11580ggatgaggtt ccagatatac cgcaacacct ttattatggt ttccctgagg gaataataga 11640atgtcccatt cgaaatcacc aattctaaac ctgggcgaat tgtatttcgg gtttgttaac 11700tcgttccagt caggaatgtt ccacgtgaag ctatcttcca gcaaagtctc cacttcttca 11760tcaaattgtg gagaatactc ccaatgctct tatctatggg acttccggga aacacagtac 11820cgatacttcc caattcgtct tcagagctca ttgtttgttt gaagagacta atcaaagaat 11880cgttttctca aaaaaattaa tatcttaact gatagtttga tcaaaggggc aaaacgtagg 11940ggcaaacaaa cggaaaaatc gtttctcaaa ttttctgatg ccaagaactc taaccagtct 12000tatctaaaaa ttgccttatg atccgtctct ccggttacag cctgtgtaac tgattaatcc 12060tgcctttcta atcaccattc taatgtttta attaagggat tttgtcttca ttaacggctt 12120tcgctcataa aaatgttatg acgttttgcc cgcaggcggg aaaccatcca cttcacgaga 12180ctgatctcct ctgccggaac accgggcatc tccaacttat aagttggaga aataagagaa 12240tttcagattg agagaatgaa aaaaaaaaac ccttagttca taggtccatt ctcttagcgc 12300aactacagag aacaggggca caaacaggca aaaaacgggc acaacctcaa tggagtgatg 12360caacctgcct ggagtaaatg atgacacaag gcaattgacc cacgcatgta tctatctcat 12420tttcttacac cttctattac cttctgctct ctctgatttg gaaaaagctg aaaaaaaagg 12480ttgaaaccag ttccctgaaa ttattcccct acttgactaa taagtatata aagacggtag 12540gtattgattg taattctgta aatctatttc ttaaacttct taaattctac ttttatagtt 12600agtctttttt ttagttttaa aacaccaaga acttagtttc gaataaacac acataaacaa 12660acaagcttac aaaacaaa atg gct gca tat gca gct cag ggc tat aag gtg 12711Met Ala Ala Tyr Ala Ala Gln Gly Tyr Lys Val1 5 10cta gta ctc aac ccc tct gtt gct gca aca ctg ggc ttt ggt gct tac 12759Leu Val Leu Asn Pro Ser Val Ala Ala Thr Leu Gly Phe Gly Ala Tyr15 20 25atg tcc aag gct cat ggg atc gat cct aac atc agg acc ggg gtg aga 12807Met Ser Lys Ala His Gly Ile Asp Pro Asn Ile Arg Thr Gly Val Arg30 35 40aca att acc act ggc agc ccc atc acg tac tcc acc tac ggc aag ttc 12855Thr Ile Thr Thr Gly Ser Pro Ile Thr Tyr Ser Thr Tyr Gly Lys Phe45 50 55ctt gcc gac ggc ggg tgc tcg ggg ggc gct tat gac ata ata att tgt 12903Leu Ala Asp Gly Gly Cys Ser Gly Gly Ala Tyr Asp Ile Ile Ile Cys60 65 70 75gac gag tgc cac tcc acg gat gcc aca tcc atc ttg ggc att ggc act 12951Asp Glu Cys His Ser Thr Asp Ala Thr Ser Ile Leu Gly Ile Gly Thr80 85 90gtc ctt gac caa gca gag act gcg ggg gcg aga ctg gtt gtg ctc gcc 12999Val Leu Asp Gln Ala Glu Thr Ala Gly Ala Arg Leu Val Val Leu Ala95 100 105acc gcc acc cct ccg ggc tcc gtc act gtg ccc cat ccc aac atc gag 13047Thr Ala Thr Pro Pro Gly Ser Val Thr Val Pro His Pro Asn Ile Glu110 115 120gag gtt gct ctg tcc acc acc gga gag atc cct ttt tac ggc aag gct 13095Glu Val Ala Leu Ser Thr Thr Gly Glu Ile Pro Phe Tyr Gly Lys Ala125 130 135atc ccc ctc gaa gta atc aag ggg ggg aga cat ctc atc ttc tgt cat 13143Ile Pro Leu Glu Val Ile Lys Gly Gly Arg His Leu Ile Phe Cys His140 145 150 155tca aag aag aag tgc gac gaa ctc gcc gca aag ctg gtc gca ttg ggc 13191Ser Lys Lys Lys Cys Asp Glu Leu Ala Ala Lys Leu Val Ala Leu Gly160 165 170atc aat gcc gtg gcc tac tac cgc ggt ctt gac gtg tcc gtc atc ccg 13239Ile Asn Ala Val Ala Tyr Tyr Arg Gly Leu Asp Val Ser Val Ile Pro175 180 185acc agc ggc gat gtt gtc gtc gtg gca acc gat gcc ctc atg acc ggc 13287Thr Ser Gly Asp Val Val Val Val Ala Thr Asp Ala Leu Met Thr Gly190 195 200tat acc ggc gac ttc gac tcg gtg ata gac tgc aat acg tgt gtc acc 13335Tyr Thr Gly Asp Phe Asp Ser Val Ile Asp Cys Asn Thr Cys Val Thr205 210 215cag aca gtc gat ttc agc ctt gac cct acc ttc acc att gag aca atc 13383Gln Thr Val Asp Phe Ser Leu Asp Pro Thr Phe Thr Ile Glu Thr Ile220 225 230 235acg ctc ccc caa gat gct gtc tcc cgc act caa cgt cgg ggc agg act 13431Thr Leu Pro Gln Asp Ala Val Ser Arg Thr Gln Arg Arg Gly Arg Thr240 245 250ggc agg ggg aag cca ggc atc tac aga ttt gtg gca ccg ggg gag cgc 13479Gly Arg Gly Lys Pro Gly Ile Tyr Arg Phe Val Ala Pro Gly Glu Arg255 260 265ccc tcc ggc atg ttc gac tcg tcc gtc ctc tgt gag tgc tat gac gca 13527Pro Ser Gly Met Phe Asp Ser Ser Val Leu Cys Glu Cys Tyr Asp Ala270 275 280ggc tgt gct tgg tat gag ctc acg ccc gcc gag act aca gtt agg cta 13575Gly Cys Ala Trp Tyr Glu Leu Thr Pro Ala Glu Thr Thr Val Arg Leu285 290 295cga gcg tac atg aac acc ccg ggg ctt ccc gtg tgc cag gac cat ctt 13623Arg Ala Tyr Met Asn Thr Pro Gly Leu Pro Val Cys Gln Asp His Leu300 305 310 315gaa ttt tgg gag ggc gtc ttt aca ggc ctc act cat ata gat gcc cac 13671Glu Phe Trp Glu Gly Val Phe Thr Gly Leu Thr His Ile Asp Ala His320 325 330ttt cta tcc cag aca aag cag agt ggg gag aac ctt cct tac ctg gta 13719Phe Leu Ser Gln Thr Lys Gln Ser Gly Glu Asn Leu Pro Tyr Leu Val335 340 345gcg tac caa gcc acc gtg tgc gct agg gct caa gcc cct ccc cca tcg 13767Ala Tyr Gln Ala Thr Val Cys Ala Arg Ala Gln Ala Pro Pro Pro Ser350 355 360tgg gac cag atg tgg aag tgt ttg att cgc ctc aag ccc acc ctc cat 13815Trp Asp Gln Met Trp Lys Cys Leu Ile Arg Leu Lys Pro Thr Leu His365 370 375ggg cca aca ccc ctg cta tac aga ctg ggc gct gtt cag aat gaa atc 13863Gly Pro Thr Pro Leu Leu Tyr Arg Leu Gly Ala Val Gln Asn Glu Ile380 385 390 395acc ctg acg cac cca gtc acc aaa tac atc atg aca tgc atg tcg gcc 13911Thr Leu Thr His Pro Val Thr Lys Tyr Ile Met Thr Cys Met Ser Ala400 405 410gac ctg gag gtc gtc acg agc acc tgg gtg ctc gtt ggc ggc gtc ctg 13959Asp Leu Glu Val Val Thr Ser Thr Trp Val Leu Val Gly Gly Val Leu415 420 425gct gct ttg gcc gcg tat tgc ctg tca aca ggc tgc gtg gtc ata gtg 14007Ala Ala Leu Ala Ala Tyr Cys Leu Ser Thr Gly Cys Val Val Ile Val430 435 440ggc agg gtc gtc ttg tcc ggg aag ccg gca atc ata cct gac agg gaa 14055Gly Arg Val Val Leu Ser Gly Lys Pro Ala Ile Ile Pro Asp Arg Glu445 450 455gtc ctc tac cga gag ttc gat gag atg gaa gag tgc tct cag cac tta 14103Val Leu Tyr Arg Glu Phe Asp Glu Met Glu Glu Cys Ser Gln His Leu460 465 470 475ccg tac atc gag caa ggg atg atg ctc gcc gag cag ttc aag cag aag 14151Pro Tyr Ile Glu Gln Gly Met Met Leu Ala Glu Gln Phe Lys Gln Lys480 485 490gcc ctc ggc ctc ctg cag acc gcg tcc cgt cag gca gag gtt atc gcc 14199Ala Leu Gly Leu Leu Gln Thr Ala Ser Arg Gln Ala Glu Val Ile Ala495 500 505cct gct gtc cag acc aac tgg caa aaa ctc gag acc ttc tgg gcg aag 14247Pro Ala Val Gln Thr Asn Trp Gln Lys Leu Glu Thr Phe Trp Ala Lys510 515 520cat atg tgg aac ttc atc agt ggg ata caa tac ttg gcg ggc ttg tca 14295His Met Trp Asn Phe Ile Ser Gly Ile Gln Tyr Leu Ala Gly Leu Ser525 530 535acg ctg cct ggt aac ccc gcc att gct tca ttg atg gct ttt aca gct 14343Thr Leu Pro Gly Asn Pro Ala Ile Ala Ser Leu Met Ala Phe Thr Ala540 545 550 555gct gtc acc agc cca cta acc act agc caa acc ctc ctc ttc aac ata 14391Ala Val Thr Ser Pro Leu Thr Thr Ser Gln Thr Leu Leu Phe Asn Ile560 565 570ttg ggg ggg tgg gtg gct gcc cag ctc gcc gcc ccc ggt gcc gct act 14439Leu Gly Gly Trp Val Ala Ala Gln Leu Ala Ala Pro Gly Ala Ala Thr575 580 585gcc ttt gtg ggc gct ggc tta gct ggc gcc gcc atc ggc agt gtt gga 14487Ala Phe Val Gly Ala Gly Leu Ala Gly Ala Ala Ile Gly Ser Val Gly590 595 600ctg ggg aag gtc ctc ata gac atc ctt gca ggg tat ggc gcg ggc gtg 14535Leu Gly Lys Val Leu Ile Asp Ile Leu Ala Gly Tyr Gly Ala Gly Val605 610 615gcg gga gct ctt gtg gca ttc aag atc atg agc ggt gag gtc ccc tcc 14583Ala Gly Ala Leu Val Ala Phe Lys Ile Met Ser Gly Glu Val Pro Ser620 625 630 635acg gag gac ctg gtc aat cta ctg ccc gcc atc ctc tcg ccc gga gcc 14631Thr Glu Asp Leu Val Asn Leu Leu Pro Ala Ile Leu Ser Pro Gly Ala640 645 650ctc gta gtc ggc gtg gtc tgt gca gca ata ctg cgc cgg cac gtt ggc 14679Leu Val Val Gly Val Val Cys Ala Ala Ile Leu Arg Arg His Val Gly655 660 665ccg ggc gag ggg gca gtg cag tgg atg aac cgg ctg ata gcc ttc gcc 14727Pro Gly Glu Gly Ala Val Gln Trp Met Asn Arg Leu Ile Ala Phe Ala670 675 680tcc cgg ggg aac cat gtt tcc ccc acg cac tac gtg ccg gag agc gat 14775Ser Arg Gly Asn His Val Ser Pro Thr His Tyr Val Pro Glu Ser Asp685 690 695gca gct gcc cgc gtc act gcc ata ctc agc agc ctc act gta acc cag 14823Ala Ala Ala Arg Val Thr Ala Ile Leu Ser Ser Leu Thr Val Thr Gln700 705 710 715ctc ctg agg cga ctg cac cag tgg ata agc tcg gag tgt acc act cca 14871Leu Leu Arg Arg Leu His Gln Trp Ile Ser Ser Glu Cys Thr Thr Pro720 725 730tgc tcc ggt tcc tgg cta agg gac atc tgg gac tgg ata tgc gag gtg 14919Cys Ser Gly Ser Trp Leu Arg Asp Ile Trp Asp Trp Ile Cys Glu Val735 740 745ttg agc gac ttt aag acc tgg cta aaa gct aag ctc atg cca cag ctg 14967Leu Ser Asp Phe Lys Thr Trp Leu Lys Ala Lys Leu Met Pro Gln Leu750 755 760cct ggg atc ccc ttt gtg tcc tgc cag cgc ggg tat aag ggg gtc tgg 15015Pro Gly Ile Pro Phe Val Ser Cys Gln Arg Gly Tyr Lys Gly Val Trp765 770 775cga ggg gac ggc atc atg cac act cgc tgc cac tgt gga gct gag atc 15063Arg Gly Asp Gly Ile Met His Thr Arg Cys His Cys Gly Ala Glu Ile780 785 790 795act gga cat gtc aaa aac ggg acg atg agg atc gtc ggt cct agg acc 15111Thr Gly His Val Lys Asn Gly Thr Met Arg Ile Val Gly Pro Arg Thr800 805 810tgc agg aac atg tgg agt ggg acc ttc ccc att aat gcc tac acc acg 15159Cys Arg Asn Met Trp Ser Gly Thr Phe Pro Ile Asn Ala Tyr Thr Thr815 820 825ggc ccc tgt acc ccc ctt cct gcg ccg aac tac acg ttc gcg cta tgg 15207Gly Pro Cys Thr Pro Leu Pro Ala Pro Asn Tyr Thr Phe Ala Leu Trp830 835 840agg gtg tct gca gag gaa tac gtg gag ata agg cag gtg ggg gac ttc 15255Arg Val Ser Ala Glu Glu Tyr Val Glu Ile Arg Gln ValGly Asp Phe845 850 855cac tac gtg acg ggt atg act act gac aat ctt aaa tgc ccg tgc cag 15303His Tyr Val Thr Gly Met Thr Thr Asp Asn Leu Lys Cys Pro Cys Gln860 865 870 875gtc cca tcg ccc gaa ttt ttc aca gaa ttg gac ggg gtg cgc cta cat 15351Val Pro Ser Pro Glu Phe Phe Thr Glu Leu Asp Gly Val Arg Leu His880 885 890agg ttt gcg ccc ccc tgc aag ccc ttg ctg cgg gag gag gta tca ttc 15399Arg Phe Ala Pro Pro Cys Lys Pro Leu Leu Arg Glu Glu Val Ser Phe895 900 905aga gta gga ctc cac gaa tac ccg gta ggg tcg caa tta cct tgc gag 15447Arg Val Gly Leu His Glu Tyr Pro Val Gly Ser Gln Leu Pro Cys Glu910 915 920ccc gaa ccg gac gtg gcc gtg ttg acg tcc atg ctc act gat ccc tcc 15495Pro Glu Pro Asp Val Ala Val Leu Thr Ser Met Leu Thr Asp Pro Ser925 930 935cat ata aca gca gag gcg gcc ggg cga agg ttg gcg agg gga tca ccc 15543His Ile Thr Ala Glu Ala Ala Gly Arg Arg Leu Ala Arg Gly Ser Pro940 945 950 955ccc tct gtg gcc agc tcc tcg gct agc cag cta tcc gct cca tct ctc 15591Pro Ser Val Ala Ser Ser Ser Ala Ser Gln Leu Ser Ala Pro Ser Leu960 965 970aag gca act tgc acc gct aac cat gac tcc cct gat gct gag ctc ata 15639Lys Ala Thr Cys Thr Ala Asn His Asp Ser Pro Asp Ala Glu Leu Ile975 980 985gag gcc aac ctc cta tgg agg cag gag atg ggc ggc aac atc acc agg 15687Glu Ala Asn Leu Leu Trp Arg Gln Glu Met Gly Gly Asn Ile Thr Arg990 995 1000gtt gag tca gaa aac aaa gtg gtg att ctg gac tcc ttc gat ccg ctt 15735Val Glu Ser Glu Asn Lys Val Val Ile Leu Asp Ser Phe Asp Pro Leu100510101015gtg gcg gag gag gac gag cgg gag atc tcc gta ccc gca gaa atc ctg 15783Val Ala Glu Glu Asp Glu Arg Glu Ile Ser Val Pro Ala Glu Ile Leu1020 102510301035cgg aag tct cgg aga ttc gcc cag gcc ctg ccc gtt tgg gcg cgg ccg 15831Arg Lys Ser Arg Arg Phe Ala Gln Ala Leu Pro Val Trp Ala Arg Pro104010451050gac tat aac ccc ccg cta gtg gag acg tgg aaa aag ccc gac tac gaa 15879Asp Tyr Asn Pro Pro Leu Val Glu Thr Trp Lys Lys Pro Asp Tyr Glu105510601065cca cct gtg gtc cat ggc tgc ccg ctt cca cct cca aag tcc cct cct 15927Pro Pro Val Val His Gly Cys Pro Leu Pro Pro Pro Lys Ser Pro Pro107010751080gtg cct ccg cct cgg aag aag cgg acg gtg gtc ctc act gaa tca acc 15975Val Pro Pro Pro Arg Lys Lys Arg Thr Val Val Leu Thr Glu Ser Thr108510901095cta tct act gcc ttg gcc gag ctc gcc acc aga agc ttt ggc agc tcc 16023Leu Ser Thr Ala Leu Ala Glu Leu Ala Thr Arg Ser Phe Gly Ser Ser1100 110511101115tca act tcc ggc att acg ggc gac aat acg aca aca tcc tct gag ccc 16071Ser Thr Ser Gly Ile Thr Gly Asp Asn Thr Thr Thr Ser Ser Glu Pro112011251130gcc cct tct ggc tgc ccc ccc gac tcc gac gct gag tcc tat tcc tcc 16119Ala Pro Ser Gly Cys Pro Pro Asp Ser Asp Ala Glu Ser Tyr Ser Ser113511401145atg ccc ccc ctg gag ggg gag cct ggg gat ccg gat ctt agc gac ggg 16167Met Pro Pro Leu Glu Gly Glu Pro Gly Asp Pro Asp Leu Ser Asp Gly115011551160tca tgg tca acg gtc agt agt gag gcc aac gcg gag gat gtc gtg tgc 16215Ser Trp Ser Thr Val Ser Ser Glu Ala Asn Ala Glu Asp Val Val Cys116511701175tgc tca atg tct tac tct tgg aca ggc gca ctc gtc acc ccg tgc gcc 16263Cys Ser Met Ser Tyr Ser Trp Thr Gly Ala Leu Val Thr Pro Cys Ala1180 118511901195gcg gaa gaa cag aaa ctg ccc atc aat gca cta agc aac tcg ttg cta 16311Ala Glu Glu Gln Lys Leu Pro Ile Asn Ala Leu Ser Asn Ser Leu Leu120012051210cgt cac cac aat ttg gtg tat tcc acc acc tca cgc agt gct tgc caa 16359Arg His His Asn Leu Val Tyr Ser Thr Thr Ser Arg Ser Ala Cys Gln121512201225agg cag aag aaa gtc aca ttt gac aga ctg caa gtt ctg gac agc cat 16407Arg Gln Lys Lys Val Thr Phe Asp Arg Leu Gln Val Leu Asp Ser His123012351240tac cag gac gta ctc aag gag gtt aaa gca gcg gcg tca aaa gtg aag 16455Tyr Gln Asp Val Leu Lys Glu Val Lys Ala Ala Ala Ser Lys Val Lys124512501255gct aac ttg cta tcc gta gag gaa gct tgc agc ctg acg ccc cca cac 16503Ala Asn Leu Leu Ser Val Glu Glu Ala Cys Ser Leu Thr Pro Pro His1260 126512701275tca gcc aaa tcc aag ttt ggt tat ggg gca aaa gac gtc cgt tgc cat 16551Ser Ala Lys Ser Lys Phe Gly Tyr Gly Ala Lys Asp Val Arg Cys His128012851290gcc aga aag gcc gta acc cac atc aac tcc gtg tgg aaa gac ctt ctg 16599Ala Arg Lys Ala Val Thr His Ile Asn Ser Val Trp Lys Asp Leu Leu129513001305gaa gac aat gta aca cca ata gac act acc atc atg gct aag aac gag 16647Glu Asp Asn Val Thr Pro Ile Asp Thr Thr Ile Met Ala Lys Asn Glu131013151320gtt ttc tgc gtt cag cct gag aag ggg ggt cgt aag cca gct cgt ctc 16695Val Phe Cys Val Gln Pro Glu Lys Gly Gly Arg Lys Pro Ala Arg Leu132513301335atc gtg ttc ccc gat ctg ggc gtg cgc gtg tgc gaa aag atg gct ttg 16743Ile Val Phe Pro Asp Leu Gly Val Arg Val Cys Glu Lys Met Ala Leu1340 134513501355tac gac gtg gtt aca aag ctc ccc ttg gcc gtg atg gga agc tcc tac 16791Tyr Asp Val Val Thr Lys Leu Pro Leu Ala Val Met Gly Ser Ser Tyr136013651370gga ttc caa tac tca cca gga cag cgg gtt gaa ttc ctc gtg caa gcg 16839Gly Phe Gln Tyr Ser Pro Gly Gln Arg Val Glu Phe Leu Val Gln Ala137513801385tgg aag tcc aag aaa acc cca atg ggg ttc tcg tat gat acc cgc tgc 16887Trp Lys Ser Lys Lys Thr Pro Met Gly Phe Ser Tyr Asp Thr Arg Cys139013951400ttt gac tcc aca gtc act gag agc gac atc cgt acg gag gag gca atc 16935Phe Asp Ser Thr Val Thr Glu Ser Asp Ile Arg Thr Glu Glu Ala Ile140514101415tac caa tgt tgt gac ctc gac ccc caa gcc cgc gtg gcc atc aag tcc 16983Tyr Gln Cys Cys Asp Leu Asp Pro Gln Ala Ara Val Ala Ile Lys Ser1420 142514301435ctc acc gag agg ctt tat gtt ggg ggc cct ctt acc aat tca agg ggg 17031Leu Thr Glu Arg Leu Tyr Val Gly Gly Pro Leu Thr Asn Ser Arg Gly144014451450gag aac tgc ggc tat cgc agg tgc cgc gcg agc ggc gta ctg aca act 17079Glu Asn Cys Gly Tyr Arg Arg Cys Arg Ala Ser Gly Val Leu Thr Thr145514601465agc tgt ggt aac acc ctc act tgc tac atc aag gcc cgg gca gcc tgt 17127Ser Cys Gly Asn Thr Leu Thr Cys Tyr Ile Lys Ala Arg Ala Ala Cys147014751480cga gcc gca ggg ctc cag gac tgc acc atg ctc gtg tgt ggc gac gac 17175Arg Ala Ala Gly Leu Gln Asp Cys Thr Met Leu Val Cys Gly Asp Asp148514901495tta gtc gtt atc tgt gaa agc gcg ggg gtc cag gag gac gcg gcg agc 17223Leu Val Val Ile Cys Glu Ser Ala Gly Val Gln Glu Asp Ala Ala Ser1500 150515101515ctg aga gcc ttc acg gag gct atg acc agg tac tcc gcc ccc cct ggg 17271Leu Arg Ala Phe Thr Glu Ala Met Thr Arg Tyr Ser Ala Pro Pro Gly152015251530gac ccc cca caa cca gaa tac gac ttg gag ctc ata aca tca tgc tcc 17319Asp Pro Pro Gln Pro Glu Tyr Asp Leu Glu Leu Ile Thr Ser Cys Ser153515401545tcc aac gtg tca gtc gcc cac gac ggc gct gga aag agg gtc tac tac 17367Ser Asn Val Ser Val Ala His Asp Gly Ala Gly Lys Arg Val Tyr Tyr155015551560ctc acc cgt gac cct aca acc ccc ctc gcg aga gct gcg tgg gag aca 17415Leu Thr Arg Asp Pro Thr Thr Pro Leu Ala Arg Ala Ala Trp Glu Thr156515701575gca aga cac act cca gtc aat tcc tgg cta ggc aac ata atc atg ttt 17463Ala Arg His Thr Pro Val Asn Ser Trp Leu Gly Asn lle lle Met Phe1580 158515901595gcc ccc aca ctg tgg gcg agg atg ata ctg atg acc cat ttc ttt agc 17511Ala Pro Thr Leu Trp Ala Arg Met Ile Leu Met Thr His Phe Phe Ser160016051610gtc ctt ata gcc agg gac cag ctt gaa cag gcc ctc gat tgc gag atc 17559Val Leu Ile Ala Arg Asp Gln Leu Glu Gln Ala Leu Asp Cys Glu Ile161516201625tac ggg gcc tgc tac tcc ata gaa cca ctg gat cta cct cca atc att 17607Tyr Gly Ala Cys Tyr Ser Ile Glu Pro Leu Asp Leu Pro Pro Ile Ile163016351640caa aga ctc cat ggc ctc agc gca ttt tca ctc cac agt tac tct cca 17655Gln Arg Leu His Gly Leu Ser Ala Phe Ser Leu His Ser Tyr Ser Pro164516501655ggt gaa atc aat agg gtg gcc gca tgc ctc aga aaa ctt ggg gta ccg 17703Gly Glu Ile Asn Arg Val Ala Ala Cys Leu Arg Lys Leu Gly Val Pro1660 166516701675ccc ttg cga gct tgg aga cac cgg gcc cgg agc gtc cgc gct agg ctt 17751Pro Leu Arg Ala Trp Arg His Arg Ala Arg Ser Val Arg Ala Arg Leu168016851690ctg gcc aga gga ggc agg gct gcc ata tgt ggc aag tac ctc ttc aac 17799Leu Ala Arg Gly Gly Arg Ala Ala Ile Cys Gly Lys Tyr Leu Phe Asn169517001705tgg gca gta aga aca aag ctc aaa ctc act cca ata gcg gcc get ggc 17847Trp Ala Val Arg Thr Lys Leu Lys Leu Thr Pro Ile Ala Ala Ala Gly171017151720cag ctg gac ttg tcc ggc tgg ttc acg gct ggc tac agc ggg gga gac 17895Gln Leu Asp Leu Ser Gly Trp Phe Thr Ala Gly Tyr Ser Gly Gly Asp172517301735att tat cac agc gtg tct cat gcc cgg ccc cgc tgg atc tgg ttt tgc 17943Ile Tyr His Ser Val Ser His Ala Arg Pro Arg Trp Ile Trp Phe Cys1740 1745 17501755cta ctc ctg ctt gct gca ggg gta ggc atc tac ctc ctc ccc aac cga 17991Leu Leu Leu Leu Ala Ala Gly Val Gly Ile Tyr Leu Leu Pro Asn Arg176017651770tgaatagtcg actttgttcc cactgtactt ttagctcgta caaaatacaa tatacttttc 18051atttctccgt aaacaacatg ttttcccatg taatatcctt ttctattttt cgttccgtta 18111ccaactttac acatacttta tatagctatt cacttctata cactaaaaaa ctaagacaat 18171tttaattttg ctgcctgcca tatttcaatt tgttataaat tcctataatt tatcctatta 18231gtagctaaaa aaagatgaat gtgaatcgaa tcctaagaga attggatctg atccacagga 18291cgggtgtggt cgccatgatc gcgtagtcga tagtggctcc aagtagcgaa gcgagcagga 18351ctgggcggcg gccaaagcgg tcggacagtg ctccgagaac gggtgcgcat agaaattgca 18411tcaacgcata tagcgctagc agcacgccat agtgactggc gatgctgtcg gaatggacga 18471tatcccgcaa gaggcccggc agtaccggca taaccaagcc tatgcctaca gcatccaggg 18531tgacggtgcc gaggatgacg atgagcgcat tgttagattt catacacggt gcctgactgc 18591gttagcaatt taactgtgat aaactaccgc attaaagctt tttctttcca attttttttt 18651tttcgtcatt ataaaaatca ttacgaccga gattcccggg taataactga tataattaaa 18711ttgaagctct aatttgtgag tttagtatac atgcatttac ttataataca gttttttagt 18771tttgctggcc gcatcttctc aaatatgctt cccagcctgc ttttctgtaa cgttcaccct 18831ctaccttagc atcccttccc tttgcaaata gtcctcttcc aacaataata atgtcagatc 18891ctgtagagac cacatcatcc acggttctat actgttgacc caatgcgtct cccttgtcat 18951ctaaacccac accgggtgtc ataatcaacc aatcgtaacc ttcatctctt ccacccatgt 19011ctctttgagc aataaagccg ataacaaaat ctttgtcgct cttcgcaatg tcaacagtac 19071ccttagtata ttctccagta gatagggagc ccttgcatga caattctgct aacatcaaaa 19131ggcctctagg ttcctttgtt acttcttctg ccgcctgctt caaaccgcta acaatacctg 19191ggcccaccac accgtgtgca ttcgtaatgt ctgcccattc tgctattctg tatacacccg 19251cagagtactg caatttgact gtattaccaa tgtcagcaaa ttttctgtct tcgaagagta 19311aaaaattgta cttggcggat aatgccttta gcggcttaac tgtgccctcc atggaaaaat 19371cagtcaagat atccacatgt gtttttagta aacaaatttt gggacctaat gcttcaacta 19431actccagtaa ttccttggtg gtacgaacat ccaatgaagc acacaagttt gtttgctttt 19491cgtgcatgat attaaatagc ttggcagcaa caggactagg atgagtagca gcacgttcct 19551tatatgtagc tttcgacatg atttatcttc gtttcctgca ggtttttgtt ctgtgcagtt 19611gggttaagaa tactgggcaa tttcatgttt cttcaacact acatatgcgt atatatacca 19671atctaagtct gtgctccttc cttcgttctt ccttctgttc ggagattacc gaatcaaaaa 19731aatttcaagg aaaccgaaat caaaaaaaag aataaaaaaa aaatgatgaa ttgaaaagct 19791tatcgat 19798210112111771212PRT213人工序列220223人工序列的描述pd.deltaNS3NS5.pj40011Met Ala Ala Tyr Ala Ala Gln Gly Tyr Lys Val Leu Val Leu Asn Pro1 5 10 15Ser Val Ala Ala Thr Leu Gly Phe Gly Ala Tyr Met Ser Lys Ala His20 25 30Gly Ile Asp Pro Asn Ile Arg Thr Gly Val Arg Thr Ile Thr Thr Gly35 40 45Ser Pro Ile Thr Tyr Ser Thr Tyr Gly Lys Phe Leu Ala Asp Gly Gly50 55 60Cys Ser Gly Gly Ala Tyr Asp Ile Ile Ile Cys Asp Glu Cys His Ser65 70 75 80Thr Asp Ala Thr Ser Ile Leu Gly Ile Gly Thr Val Leu Asp Gln Ala85 90 95Glu Thr Ala Gly Ala Arg Leu Val Val Leu Ala Thr Ala Thr Pro Pro100 105 110Gly Ser Val Thr Val Pro His Pro Asn Ile Glu Glu Val Ala Leu Ser115 120 125Thr Thr Gly Glu Ile Pro Phe Tyr Gly Lys Ala Ile Pro Leu Glu Val130 135 140Ile Lys Gly Gly Arg His Leu Ile Phe Cys His Ser Lys Lys Lys Cys145 150 155 160Asp Glu Leu Ala Ala Lys Leu Val Ala Leu Gly Ile Asn Ala Val Ala165 170 175Tyr Tyr Arg Gly Leu Asp Val Ser Val Ile Pro Thr Ser Gly Asp Val180 185 190Val Val Val Ala Thr Asp Ala Leu Met Thr Gly Tyr Thr Gly Asp Phe195 200 205Asp Ser Val Ile Asp Cys Asn Thr Cys Val Thr Gln Thr Val Asp Phe210 215 220Ser Leu Asp Pro Thr Phe Thr Ile Glu Thr Ile Thr Leu Pro Gln Asp225 230 235 240Ala Val Ser Arg Thr Gln Arg Arg Gly Arg Thr Gly Arg Gly Lys Pro245 250 255Gly Ile Tyr Arg Phe Val Ala Pro Gly Glu Arg Pro Ser Gly Met Phe260 265 270Asp Ser Ser Val Leu Cys Glu Cys Tyr Asp Ala Gly Cys Ala Trp Tyr275 280 285Glu Leu Thr Pro Ala Glu Thr Thr Val Arg Leu Arg Ala Tyr Met Asn290 295 300Thr Pro Gly Leu Pro Val Cys Gln Asp His Leu Glu Phe Trp Glu Gly305 310 315 320Val Phe Thr Gly Leu Thr His Ile Asp Ala His Phe Leu Ser Gln Thr325 330 335Lys Gln Ser Gly Glu Asn Leu Pro Tyr Leu Val Ala Tyr Gln Ala Thr340 345 350Val Cys Ala Arg Ala Gln Ala Pro Pro Pro Ser Trp Asp Gln Met Trp355 360 365Lys Cys Leu Ile Arg Leu Lys Pro Thr Leu His Gly Pro Thr Pro Leu370 375 380Leu Tyr Arg Leu Gly Ala Val Gln Asn Glu Ile Thr Leu Thr His Pro385 390 395 400Val Thr Lys Tyr Ile Met Thr Cys Met Ser Ala Asp Leu Glu Val Val405 410 415Thr Ser Thr Trp Val Leu Val Gly Gly Val Leu Ala Ala Leu Ala Ala420 425 430Tyr Cys Leu Ser Thr Gly Cys Val Val Ile Val Gly Arg Val Val Leu435 440 445Ser Gly Lys Pro Ala Ile Ile Pro Asp Arg Glu Val Leu Tyr Arg Glu450 455 460Phe Asp Glu Met Glu Glu Cys Ser Gln His Leu Pro Tyr Ile Glu Gln465 470 475 480Gly Met Met Leu Ala Glu Gln Phe Lys Gln Lys Ala Leu Gly Leu Leu485 490 495Gln Thr Ala Ser Arg Gln Ala Glu Val Ile Ala Pro Ala Val Gln Thr500 505 510Asn Trp Gln Lys Leu Glu Thr Phe Trp Ala Lys His Met Trp Asn Phe515 520 525Ile Ser Gly Ile Gln Tyr Leu Ala Gly Leu Ser Thr Leu Pro Gly Asn530 535 540Pro Ala Ile Ala Ser Leu Met Ala Phe Thr Ala Ala Val Thr Ser Pro545 550 555 560Leu Thr Thr Ser Gln Thr Leu Leu Phe Asn Ile Leu Gly Gly Trp Val565 570 575Ala Ala Gln Leu Ala Ala Pro Gly Ala Ala Thr Ala Phe Val Gly Ala580 585 590Gly Leu Ala Gly Ala Ala Ile Gly Ser Val Gly Leu Gly Lys Val Leu595 600 605Ile Asp Ile Leu Ala Gly Tyr Gly Ala Gly Val Ala Gly Ala Leu Val610 615 620Ala Phe Lys Ile Met Ser Gly Glu Val Pro Ser Thr Glu Asp Leu Val625 630 635 640Asn Leu Leu Pro Ala Ile Leu Ser Pro Gly Ala Leu Val Val Gly Val645 650 655Val Cys Ala Ala Ile Leu Arg Arg His Val Gly Pro Gly Glu Gly Ala660 665 670Val Gln Trp Met Asn Arg Leu Ile Ala Phe Ala Ser Arg Gly Asn His675 680 685Val Ser Pro Thr His Tyr Val Pro Glu Ser Asp Ala Ala Ala Arg Val690 695 700Thr Ala Ile Leu Ser Ser Leu Thr Val Thr Gln Leu Leu Arg Arg Leu705 710 715 720His Gln Trp Ile Ser Ser Glu Cys Thr Thr Pro Cys Ser Gly Ser Trp725 730 735Leu Arg Asp Ile Trp Asp Trp Ile Cys Glu Val Leu Ser Asp Phe Lys740 745 750Thr Trp Leu Lys Ala Lys Leu Met Pro Gln Leu Pro Gly Ile Pro Phe755 760 765Val Ser Cys Gln Arg Gly Tyr Lys Gly Val Trp Arg Gly Asp Gly Ile770 775 780Met His Thr Arg Cys His Cys Gly Ala Glu Ile Thr Gly His Val Lys785 790 795 800Asn Gly Thr Met Arg Ile Val Gly Pro Arg Thr Cys Arg Asn Met Trp805 810 815Ser Gly Thr Phe Pro Ile Asn Ala Tyr Thr Thr Gly Pro Cys Thr Pro820 825 830Leu Pro Ala Pro Asn Tyr Thr Phe Ala Leu Trp Arg Val Ser Ala Glu835 840 845Glu Tyr Val Glu Ile Arg Gln Val Gly Asp Phe His Tyr Val Thr Gly850 855 860Met Thr Thr Asp Asn Leu Lys Cys Pro Cys Gln Val Pro Ser Pro Glu865 870 875 880Phe Phe Thr Glu Leu Asp Gly Val Arg Leu His Arg Phe Ala Pro Pro885 890 895Cys Lys Pro Leu Leu Arg Glu Glu Val Ser Phe Arg Val Gly Leu His900 905 910Glu Tyr Pro Val Gly Ser Gln Leu Pro Cys Glu Pro Glu Pro Asp Val915 920 925Ala Val Leu Thr Ser Met Leu Thr Asp Pro Ser His Ile Thr Ala Glu930 935 940Ala Ala Gly Arg Arg Leu Ala Arg Gly Ser Pro Pro Ser Val Ala Ser945 950 955 960Ser Ser Ala Ser Gln Leu Ser Ala Pro Ser Leu Lys Ala Thr Cys Thr965 970 975Ala Asn His Asp Ser Pro Asp Ala Glu Leu Ile Glu Ala Asn Leu Leu980 985 990Trp Arg Gln Glu Met Gly Gly Asn Ile Thr Arg Val Glu Ser Glu Asn99510001005Lys Val Val Ile Leu Asp Ser Phe Asp Pro Leu Val Ala Glu Glu Asp101010151020Glu Arg Glu Ile Ser Val Pro Ala Glu Ile Leu Arg Lys Ser Arg Arg025103010351040Phe Ala Gln Ala Leu Pro Val Trp Ala Arg Pro Asp Tyr Asn Pro Pro104510501055Leu Val Glu Thr Trp Lys Lys Pro Asp Tyr Glu Pro Pro Val Val His106010651070Gly Cys Pro Leu Pro Pro Pro Lys Ser Pro Pro Val Pro Pro Pro Arg107510801085Lys Lys Arg Thr Val Val Leu Thr Glu Ser Thr Leu Ser Thr Ala Leu109010951100Ala Glu Leu Ala Thr Arg Ser Phe Gly Ser Ser Ser Thr Ser Gly Ile105 lll01115 1120Thr Gly Asp Asn Thr Thr Thr Ser Ser Glu Pro Ala Pro Ser Gly Cys112511301135Pro Pro Asp Ser Asp Ala Glu Ser Tyr Ser Ser Met Pro Pro Leu Glu114011451150Gly Glu Pro Gly Asp Pro Asp Leu Ser Asp Gly Ser Trp Ser Thr Val115511601165Ser Ser Glu Ala Asn Ala Glu Asp Val Val Cys Cys Ser Met Ser Tyr117011751180Ser Trp Thr Gly Ala Leu Val Thr Pro Cys Ala Ala Glu Glu Gln Lys185119011951200Leu Pro Ile Asn Ala Leu Ser Asn Ser Leu Leu Arg His His Asn Leu120512101215Val Tyr Ser Thr Thr Ser Arg Ser Ala Cys Gln Arg Gln Lys Lys Val122012251230Thr Phe Asp Arg Leu Gln Val Leu Asp Ser His Tyr Gln Asp Val Leu123512401245Lys Glu Val Lys Ala Ala Ala Ser Lys Val Lys Ala Asn Leu Leu Ser1250 1255 1260Val Glu Glu Ala Cys Ser Leu Thr Pro Pro His Ser Ala Lys Ser Lys265127012751280Phe Gly Tyr Gly Ala Lys Asp Val Arg Cys His Ala Arg Lys Ala Val128512901295Thr His Ile Asn Ser Val Trp Lys Asp Leu Leu Glu Asp Asn Val Thr130013051310Pro Ile Asp Thr Thr Ile Met Ala Lys Asn Glu Val Phe Cys Val Gln131513201325Pro Glu Lys Gly Gly Arg Lys Pro Ala Arg Leu Ile Val Phe Pro Asp133013351340Leu Gly Val Arg Val Cys Glu Lys Met Ala Leu Tyr Asp Val Val Thr345135013551360Lys Leu Pro Leu Ala Val Met Gly Ser Ser Tyr Gly Phe Gln Tyr Ser136513701375Pro Gly Gln Arg Val Glu Phe Leu Val Gln Ala Trp Lys Ser Lys Lys138013851390Thr Pro Met Gly Phe Ser Tyr Asp Thr Arg Cys Phe Asp Ser Thr Val139514001405Thr Glu Ser Asp Ile Arg Thr Glu Glu Ala Ile Tyr Gln Cys Cys Asp141014151420Leu Asp Pro Gln Ala Arg Val Ala Ile Lys Ser Leu Thr Glu Arg Leu425143014351440Tyr Val Gly Gly Pro Leu Thr Asn Ser Arg Gly Glu Asn Cys Gly Tyr144514501455Arg Arg Cys Arg Ala Ser Gly Val Leu Thr Thr Ser Cys Gly Asn Thr146014651470Leu Thr Cys Tyr Ile Lys Ala Arg Ala Ala Cys Arg Ala Ala Gly Leu147514801485Gln Asp Cys Thr Met Leu Val Cys Gly Asp Asp Leu Val Val Ile Cys149014951500Glu Ser Ala Gly Val Gln Glu Asp Ala Ala Ser Leu Arg Ala Phe Thr505151015151520Glu Ala Met Thr Arg Tyr Ser Ala Pro Pro Gly Asp Pro Pro Gln Pro152515301535Glu Tyr Asp Leu Glu Leu Ile Thr Ser Cys Ser Ser Asn Val Ser Val154015451550Ala His Asp Gly Ala Gly Lys Arg Val Tyr Tyr Leu Thr Arg Asp Pro155515601565Thr Thr Pro Leu Ala Arg Ala Ala Trp Glu Thr Ala Arg His Thr Pro157015751580Val Asn Ser Trp Leu Gly Asn Ile Ile Met Phe Ala Pro Thr Leu Trp585159015951600Ala Arg Met Ile Leu Met Thr His Phe Phe Ser Val Leu Ile Ala Arg160516101615Asp Gln Leu Glu Gln Ala Leu Asp Cys Glu Ile Tyr Gly Ala Cys Tyr162016251630Ser Ile Glu Pro Leu Asp Leu Pro Pro Ile Ile Gln Arg Leu His Gly163516401645Leu Ser Ala Phe Ser Leu His Ser Tyr Ser Pro Gly Glu lle Asn Arg165016551660Val Ala Ala Cys Leu Arg Lys Leu Gly Val Pro Pro Leu Arg Ala Trp665167016751680Arg His Arg Ala Arg Ser Val Arg Ala Arg Leu Leu Ala Arg Gly Gly168516901695Arg Ala Ala Ile Cys Gly Lys Tyr Leu Phe Asn Trp Ala Val Arg Thr170017051710Lys Leu Lys Leu Thr Pro Ile Ala Ala Ala Gly Gln Leu Asp Leu Ser171517201725Gly Trp Phe Thr Ala Gly Tyr Ser Gly Gly Asp Ile Tyr His Ser Val173017351740Ser His Ala Arg Pro Arg Trp Ile Trp Phe Cys Leu Leu Leu Leu Ala745175017551760Ala Gly Val Gly Ile Tyr Leu Leu Pro Asn Arg1765 17702101221120220212DNA213人工序列220223人工序列的描述pd.delta.NS3NS5.pj.core121220221CDS222(12679)..(18354)40012atcgatccta ccccttgcgc taaagaagta tatgtgccta ctaacgcttg tctttgtctc 60tgtcactaaa cactggatta ttactcccag atacttattt tggactaatt taaatgattt 120cggatcaacg ttcttaatat cgctgaatct tccacaattg atgaaagtag ctaggaagag 180gaattggtat aaagtttttg tttttgtaaa tctcgaagta tactcaaacg aatttagtat 240tttctcagtg atctcccaga tgctttcacc ctcacttaga agtgctttaa gcattttttt 300actgtggcta tttcccttat ctgcttcttc cgatgattcg aactgtaatt gcaaactact 360tacaatatca gtgatatcag attgatgttt ttgtccatag taaggaataa ttgtaaattc 420ccaagcagga atcaatttct ttaatgaggc ttccagaatt gttgcttttt gcgtcttgta 480tttaaactgg agtgatttat tgacaatatc gaaactcagc gaattgctta tgatagtatt 540atagctcatg aatgtggctc tcttgattgc tgttccgtta tgtgtaatca tccaacataa 600ataggttagt tcagcagcac ataatgctat tttctcacct gaaggtcttt caaacctttc 660cacaaactga cgaacaagca ccttaggtgg tgttttacat aatatatcaa attgtggcat 720gcttagcgcc gatcttgtgt gcaattgata tctagtttca actactctat ttatcttgta 780tcttgcagta ttcaaacacg ctaactcgaa aaactaactt taattgtcct gtttgtctcg 840cgttctttcg aaaaatgcac cggccgcgca ttatttgtac tgcgaaaata attggtactg 900cggtatcttc atttcatatt ttaaaaatgc acctttgctg cttttcctta atttttagac 960ggcccgcagg ttcgttttgc ggtactatct tgtgataaaa agttgttttg acatgtgatc 1020tgcacagatt ttataatgta ataagcaaga atacattatc aaacgaacaa tactggtaaa 1080agaaaaccaa aatggacgac attgaaacag ccaagaatct gacggtaaaa gcacgtacag 1140cttatagcgt ctgggatgta tgtcggctgt ttattgaaat gattgctcct gatgtagata 1200ttgatataga gagtaaacgt aagtctgatg agctactctt tccaggatat gtcataaggc 1260ccatggaatc tctcacaacc ggtaggccgt atggtcttga ttctagcgca gaagattcca 1320gcgtatcttc tgactccagt gctgaggtaa ttttgcctgc tgcgaagatg gttaaggaaa 1380ggtttgattc gattggaaat ggtatgctct cttcacaaga agcaagtcag gctgccatag 1440atttgatgct acagaataac aagctgttag acaatagaaa gcaactatac aaatctattg 1500ctataataat aggaagattg cccgagaaag acaagaagag agctaccgaa atgctcatga 1560gaaaaatgga ttgtacacag ttattagtcc caccagctcc aacggaagaa gatgttatga 1620agctcgtaag cgtcgttacc caattgctta ctttagttcc accagatcgt caagctgctt 1680taataggtga tttattcatc ccggaatctc taaaggatat attcaatagt ttcaatgaac 1740tggcggcaga gaatcgttta cagcaaaaaa agagtgagtt ggaaggaagg actgaagtga 1800accatgctaa tacaaatgaa gaagttccct ccaggcgaac aagaagtaga gacacaaatg 1860caagaggagc atataaatta caaaacacca tcactgaggg ccctaaagcg gttcccacga 1920aaaaaaggag agtagcaacg agggtaaggg gcagaaaatc acgtaatact tctagggtat 1980gatccaatat caaaggaaat gatagcattg aaggatgaga ctaatccaat tgaggagtgg 2040cagcatatag aacagctaaa gggtagtgct gaaggaagca tacgataccc cgcatggaat 2100gggataatat cacaggaggt actagactac ctttcatcct acataaatag acgcatataa 2160gtacgcattt aagcataaac acgcactatg ccgttcttct catgtatata tatatacagg 2220caacacgcag atataggtgc gacgtgaaca gtgagctgta tgtgcgcagc tcgcgttgca 2280ttttcggaag cgctcgtttt cggaaacgct ttgaagttcc tattccgaag ttcctattct 2340ctagaaagta taggaacttc agagcgcttt tgaaaaccaa aagcgctctg aagacgcact 2400ttcaaaaaac caaaaacgca ccggactgta acgagctact aaaatattgc gaataccgct 2460tccacaaaca ttgctcaaaa gtatctcttt gctatatatc tctgtgctat atccctatat 2520aacctaccca tccacctttc gctccttgaa cttgcatcta aactcgacct ctacatcaac 2580aggcttccaa tgctcttcaa attttactgt caagtagacc catacggctg taatatgctg 2640ctcttcataa tgtaagctta tctttatcga atcgtgtgaa aaactactac cgcgataaac 2700ctttacggtt ccctgagatt gaattagttc ctttagtata tgatacaaga cacttttgaa 2760ctttgtacga cgaattttga ggttcgccat cctctggcta tttccaatta tcctgtcggc 2820tattatctcc gcctcagttt gatcttccgc ttcagactgc catttttcac ataatgaatc 2880tatttcaccc cacaatcctt catccgcctc cgcatcttgt tccgttaaac tattgacttc 2940atgttgtaca ttgtttagtt cacgagaagg gtcctcttca ggcggtagct cctgatctcc 3000tatatgacct ttatcctgtt ctctttccac aaacttagaa atgtattcat gaattatgga 3060gcacctaata acattcttca aggcggagaa gtttgggcca gatgcccaat atgcttgaca 3120tgaaaacgtg agaatgaatt tagtattatt gtgatattct gaggcaattt tattataatc 3180tcgaagataa gagaagaatg cagtgacctt tgtattgaca aatggagatt ccatgtatct 3240aaaaaatacg cctttaggcc ttctgatacc ctttcccctg cggtttagcg tgccttttac 3300attaatatct aaaccctctc cgatggtggc ctttaactga ctaataaatg caaccgatat 3360aaactgtgat aattctgggt gatttatgat tcgatcgaca attgtattgt acactagtgc 3420aggatcaggc caatccagtt ctttttcaat taccggtgtg tcgtctgtat tcagtacatg 3480tccaacaaat gcaaatgcta acgttttgta tttcttataa ttgtcaggaa ctggaaaagt 3540cccccttgtc gtctcgatta cacacctact ttcatcgtac accataggtt ggaagtgctg 3600cataatacat tgcttaatac aagcaagcag tctctcgcca ttcatatttc agttattttc 3660cattacagct gatgtcattg tatatcagcg ctgtaaaaat ctatctgtta cagaaggttt 3720tcgcggtttt tataaacaaa actttcgtta cgaaatcgag caatcacccc agctgcgtat 3780ttggaaattc gggaaaaagt agagcaacgc gagttgcatt ttttacacca taatgcatga 3840ttaacttcga gaagggatta aggctaattt cactagtatg tttcaaaaac ctcaatctgt 3900ccattgaatg ccttataaaa cagctataga ttgcatagaa gagttagcta ctcaatgctt 3960tttgtcaaag cttactgatg atgatgtgtc tactttcagg cgggtctgta gtaaggagaa 4020tgacattata aagctggcac ttagaattcc acggactata gactatacta gtatactccg 4080tctactgtac gatacacttc cgctcaggtc cttgtccttt aacgaggcct taccactctt 4140ttgttactct attgatccag ctcagcaaag gcagtgtgat ctaagattct atcttcgcga 4200tgtagtaaaa ctagctagac cgagaaagag actagaaatg caaaaggcac ttctacaatg 4260gctgccatca ttattatccg atgtgacgct gcattttttt tttttttttt tttttttttt 4320tttttttttt tttttttttt ttttttggta caaatatcat aaaaaaagag aatcttttta 4380agcaaggatt ttcttaactt cttcggcgac agcatcaccg acttcggtgg tactgttgga 4440accacctaaa tcaccagttc tgatacctgc atccaaaacc tttttaactg catcttcaat 4500ggctttacct tcttcaggca agttcaatga caatttcaac atcattgcag cagacaagat 4560agtggcgata gggttgacct tattctttgg caaatctgga gcggaaccat ggcatggttc 4620gtacaaacca aatgcggtgt tcttgtctgg caaagaggcc aaggacgcag atggcaacaa 4680acccaaggag cctgggataa cggaggcttc atcggagatg atatcaccaa acatgttgct 4740ggtgattata ataccattta ggtgggttgg gttcttaact aggatcatgg cggcagaatc 4800aatcaattga tgttgaactt tcaatgtagg gaattcgttc ttgatggttt cctccacagt 4860ttttctccat aatcttgaag aggccaaaac attagcttta tccaaggacc aaataggcaa 4920tggtggctca tgttgtaggg ccatgaaagc ggccattctt gtgattcttt gcacttctgg 4980aacggtgtat tgttcactat cccaagcgac accatcacca tcgtcttcct ttctcttacc 5040aaagtaaata cctcccacta attctctaac aacaacgaag tcagtacctt tagcaaattg 5100tggcttgatt ggagataagt ctaaaagaga gtcggatgca aagttacatg gtcttaagtt 5160ggcgtacaat tgaagttctt tacggatttt tagtaaacct tgttcaggtc taacactacc 5220ggtaccccat ttaggaccac ccacagcacc taacaaaacg gcatcagcct tcttggaggc 5280ttccagcgcc tcatctggaa gtggaacacc tgtagcatcg atagcagcac caccaattaa 5340atgattttcg aaatcgaact tgacattgga acgaacatca gaaatagctt taagaacctt 5400aatggcttcg gctgtgattt cttgaccaac gtggtcacct ggcaaaacga cgatcttctt 5460aggggcagac attacaatgg tatatccttg aaatatatat aaaaaaaaaa aaaaaaaaaa 5520aaaaaaaaaa atgcagcttc tcaatgatat tcgaatacgc tttgaggaga tacagcctaa 5580tatccgacaa actgttttac agatttacga tcgtacttgt tacccatcat tgaattttga 5640acatccgaac ctgggagttt tccctgaaac agatagtata tttgaacctg tataataata 5700tatagtctag cgctttacgg aagacaatgt atgtatttcg gttcctggag aaactattgc 5760atctattgca taggtaatct tgcacgtcgc atccccggtt cattttctgc gtttccatct 5820tgcacttcaa tagcatatct ttgttaacga agcatctgtg cttcattttg tagaacaaaa 5880atgcaacgcg agagcgctaa tttttcaaac aaagaatctg agctgcattt ttacagaaca 5940gaaatgcaac gcgaaagcgc tattttacca acgaagaatc tgtgcttcat ttttgtaaaa 6000caaaaatgca acgcgagagc gctaattttt caaacaaaga atctgagctg catttttaca 6060gaacagaaat gcaacgcgag agcgctattt taccaacaaa gaatctatac ttcttttttg 6120ttctacaaaa atgcatcccg agagcgctat ttttctaaca aagcatctta gattactttt 6180tttctccttt gtgcgctcta taatgcagtc tcttgataac tttttgcact gtaggtccgt 6240taaggttaga agaaggctac tttggtgtct attttctctt ccataaaaaa agcctgactc 6300cacttcccgc gtttactgat tactagcgaa gctgcgggtg cattttttca agataaaggc 6360atccccgatt atattctata ccgatgtgga ttgcgcatac tttgtgaaca gaaagtgata 6420gcgttgatga ttcttcattg gtcagaaaat tatgaacggt ttcttctatt ttgtctctat 6480atactacgta taggaaatgt ttacattttc gtattgtttt cgattcactc tatgaatagt 6540tcttactaca atttttttgt ctaaagagta atactagaga taaacataaa aaatgtagag 6600gtcgagttta gatgcaagtt caaggagcga aaggtggatg ggtaggttat atagggatat 6660agcacagaga tatatagcaa agagatactt ttgagcaatg tttgtggaag cggtattcgc 6720aatattttag tagctcgtta cagtccggtg cgtttttggt tttttgaaag tgcgtcttca 6780gagcgctttt ggttttcaaa agcgctctga agttcctata ctttctagag aataggaact 6840tcggaatagg aacttcaaag cgtttccgaa aacgagcgct tccgaaaatg caacgcgagc 6900tgcgcacata cagctcactg ttcacgtcgc acctatatct gcgtgttgcc tgtatatata 6960tatacatgag aagaacggca tagtgcgtgt ttatgcttaa atgcgtactt atatgcgtct 7020atttatgtag gatgaaaggt agtctagtac ctcctgtgat attatcccat tccatgcggg 7080gtatcgtatg cttccttcag cactaccctt tagctgttct atatgctgcc actcctcaat 7140tggattagtc tcatccttca atgctatcat ttcctttgat attggatcat atgcatagta 7200ccgagaaact agtgcgaagt agtgatcagg tattgctgtt atctgatgag tatacgttgt 7260cctggccacg gcagaagcac gcttatcgct ccaatttccc acaacattag tcaactccgt 7320taggcccttc attgaaagaa atgaggtcat caaatgtctt ccaatgtgag attttgggcc 7380attttttata gcaaagattg aataaggcgc atttttcttc aaagctttat tgtacgatct 7440gactaagtta tcttttaata attggtattc ctgtttattg cttgaagaat tgccggtcct 7500atttactcgt tttaggactg gttcagaatt cctcaaaaat tcatccaaat atacaagtgg 7560atcgatgata agctgtcaaa catgagaatt cttgaagacg aaagggcctc gtgatacgcc 7620tatttttata ggttaatgtc atgataataa tggtttctta gacgtcaggt ggcacttttc 7680ggggaaatgt gcgcggaacc cctatttgtt tatttttcta aatacattca aatatgtatc 7740cgctcatgag acaataaccc tgataaatgc ttcaataata ttgaaaaagg aagagtatga 7800gtattcaaca tttccgtgtc gcccttattc ccttttttgc ggcattttgc cttcctgttt 7860ttgctcaccc agaaacgctg gtgaaagtaa aagatgctga agatcagttg ggtgcacgag 7920tgggttacat cgaactggat ctcaacagcg gtaagatcct tgagagtttt cgccccgaag 7980aacgttttcc aatgatgagc acttttaaag ttctgctatg tggcgcggta ttatcccgtg 8040ttgacgccgg gcaagagcaa ctcggtcgcc gcatacacta ttctcagaat gacttggttg 8100agtactcacc agtcacagaa aagcatctta cggatggcat gacagtaaga gaattatgca 8160gtgctgccat aaccatgagt gataacactg cggccaactt acttctgaca acgatcggag 8220gaccgaagga gctaaccgct tttttgcaca acatggggga tcatgtaact cgccttgatc 8280gttgggaacc ggagctgaat gaagccatac caaacgacga gcgtgacacc acgatgcctg 8340cagcaatggc aacaacgttg cgcaaactat taactggcga actacttact ctagcttccc 8400ggcaacaatt aatagactgg atggaggcgg ataaagttgc aggaccactt ctgcgctcgg 8460cccttccggc tggctggttt attgctgata aatctggagc cggtgagcgt gggtctcgcg 8520gtatcattgc agcactgggg ccagatggta agccctcccg tatcgtagtt atctacacga 8580cggggagtca ggcaactatg gatgaacgaa atagacagat cgctgagata ggtgcctcac 8640tgattaagca ttggtaactg tcagaccaag tttactcata tatactttag attgatttaa 8700aacttcattt ttaatttaaa aggatctagg tgaagatcct ttttgataat ctcatgacca 8760aaatccctta acgtgagttt tcgttccact gagcgtcaga ccccgtagaa aagatcaaag 8820gatcttcttg agatcctttt tttctgcgcg taatctgctg cttgcaaaca aaaaaaccac 8880cgctaccagc ggtggtttgt ttgccggatc aagagctacc aactcttttt ccgaaggtaa 8940ctggcttcag cagagcgcag ataccaaata ctgtccttct agtgtagccg tagttaggcc 9000accacttcaa gaactctgta gcaccgccta catacctcgc tctgctaatc ctgttaccag 9060tggctgctgc cagtggcgat aagtcgtgtc ttaccgggtt ggactcaaga cgatagttac 9120cggataaggc gcagcggtcg ggctgaacgg ggggttcgtg cacacagccc agcttggagc 9180gaacgaccta caccgaactg agatacctac agcgtgagct atgagaaagc gccacgcttc 9240ccgaagggag aaaggcggac aggtatccgg taagcggcag ggtcggaaca ggagagcgca 9300cgagggagct tccaggggga aacgcctggt atctttatag tcctgtcggg tttcgccacc 9360tctgacttga gcgtcgattt ttgtgatgct cgtcaggggg gcggagccta tggaaaaacg 9420ccagcaacgc ggccttttta cggttcctgg ccttttgctg gccttttgct cacatgttct 9480ttcctgcgtt atcccctgat tctgtggata accgtattac cgcctttgag tgagctgata 9540ccgctcgccg cagccgaacg accgagcgca gcgagtcagt gagcgaggaa gcggaagagc 9600gcctgatgcg gtattttctc cttacgcatc tgtgcggtat ttcacaccgc atatggtgca 9660ctctcagtac aatctgctct gatgccgcat agttaagcca gtatacactc cgctatcgct 9720acgtgactgg gtcatggctg cgccccgaca cccgccaaca cccgctgacg cgccctgacg 9780ggcttgtctg ctcccggcat ccgcttacag acaagctgtg accgtctccg ggagctgcat 9840gtgtcagagg ttttcaccgt catcaccgaa acgcgcgagg cagctgcggt aaagctcatc 9900agcgtggtcg tgaagcgatt cacagatgtc tgcctgttca tccgcgtcca gctcgttgag 9960tttctccaga agcgttaatg tctggcttct gataaagcgg gccatgttaa gggcggtttt 10020ttcctgtttg gtcactgatg cctccgtgta agggggattt ctgttcatgg gggtaatgat 10080accgatgaaa cgagagagga tgctcacgat acgggttact gatgatgaac atgcccggtt 10140actggaacgt tgtgagggta aacaactggc ggtatggatg cggcgggacc agagaaaaat 10200cactcagggt caatgccagc gcttcgttaa tacagatgta ggtgttccac agggtagcca 10260gcagcatcct gcgatgcaga tccggaacat aatggtgcag ggcgctgact tccgcgtttc 10320cagactttac gaaacacgga aaccgaagac cattcatgtt gttgctcagg tcgcagacgt 10380tttgcagcag cagtcgcttc acgttcgctc gcgtatcggt gattcattct gctaaccagt 10440aaggcaaccc cgccagccta gccgggtcct caacgacagg agcacgatca tgcgcacccg 10500tggccaggac ccaacgctgc ccgagatgcg ccgcgtgcgg ctgctggaga tggcggacgc 10560gatggatatg ttctgccaag ggttggtttg cgcattcaca gttctccgca agaattgatt 10620ggctccaatt cttggagtgg tgaatccgtt agcgaggtgc cgccggcttc cattcaggtc 10680gaggtggccc ggctccatgc accgcgacgc aacgcgggga ggcagacaag gtatagggcg 10740gcgcctacaa tccatgccaa cccgttccat gtgctcgccg aggcggcata aatcgccgtg 10800acgatcagcg gtccaatgat cgaagttagg ctggtaagag ccgcgagcga tccttgaagc 10860tgtccctgat ggtcgtcatc tacctgcctg gacagcatgg cctgcaacgc gggcatcccg 10920atgccgccgg aagcgagaag aatcataatg gggaaggcca tccagcctcg cgtcgcgaac 10980gccagcaaga cgtagcccag cgcgtcggcc gccatgccgg cgataatggc ctgcttctcg 11040ccgaaacgtt tggtggcggg accagtgacg aaggcttgag cgagggcgtg caagattccg 11100aataccgcaa gcgacaggcc gatcatcgtc gcgctccagc gaaagcggtc ctcgccgaaa 11160atgacccaga gcgctgccgg cacctgtcct acgagttgca tgataaagaa gacagtcata 11220agtgcggcga cgatagtcat gccccgcgcc caccggaagg agctgactgg gttgaaggct 11280ctcaagggca tcggtcgagg atccttcaat atgcgcacat acgctgttat gttcaaggtc 11340ccttcgttta agaacgaaag cggtcttcct tttgagggat gtttcaagtt gttcaaatct 11400atcaaatttg caaatcccca gtctgtatct agagcgttga atcggtgatg cgatttgtta 11460attaaattga tggtgtcacc attaccaggt ctagatatac caatggcaaa ctgagcacaa 11520caataccagt ccggatcaac tggcaccatc tctcccgtag tctcatctaa tttttcttcc 11580ggatgaggtt ccagatatac cgcaacacct ttattatggt ttccctgagg gaataataga 11640atgtcccatt cgaaatcacc aattctaaac ctgggcgaat tgtatttcgg gtttgttaac 11700tcgttccagt caggaatgtt ccacgtgaag ctatcttcca gcaaagtctc cacttcttca 11760tcaaattgtg gagaatactc ccaatgctct tatctatggg acttccggga aacacagtac 11820cgatacttcc caattcgtct tcagagctca ttgtttgttt gaagagacta atcaaagaat 11880cgttttctca aaaaaattaa tatcttaact gatagtttga tcaaaggggc aaaacgtagg 11940ggcaaacaaa cggaaaaatc gtttctcaaa ttttctgatg ccaagaactc taaccagtct 12000tatctaaaaa ttgccttatg atccgtctct ccggttacag cctgtgtaac tgattaatcc 12060tgcctttcta atcaccattc taatgtttta attaagggat tttgtcttca ttaacggctt 12120tcgctcataa aaatgttatg acgttttgcc cgcaggcggg aaaccatcca cttcacgaga 12180ctgatctcct ctgccggaac accgggcatc tccaacttat aagttggaga aataagagaa 12240tttcagattg agagaatgaa aaaaaaaaac ccttagttca taggtccatt ctcttagcgc 12300aactacagag aacaggggca caaacaggca aaaaacgggc acaacctcaa tggagtgatg 12360caacctgcct ggagtaaatg atgacacaag gcaattgacc cacgcatgta tctatctcat 12420tttcttacac cttctattac cttctgctct ctctgatttg gaaaaagctg aaaaaaaagg 12480ttgaaaccag ttccctgaaa ttattcccct acttgactaa taagtatata aagacggtag 12540gtattgattg taattctgta aatctatttc ttaaacttct taaattctac ttttatagtt 12600agtctttttt ttagttttaa aacaccaaga acttagtttc gaataaacac acataaacaa 12660acaagcttac aaaacaaa atg gct gca tat gca gct cag ggc tat aag gtg 12711Met Ala Ala Tyr Ala Ala Gln Gly Tyr Lys Val1 5 10cta gta ctc aac ccc tct gtt gct gca aca ctg ggc ttt ggt gct tac 12759Leu Val Leu Asn Pro Ser Val Ala Ala Thr Leu Gly Phe Gly Ala Tyr15 20 25atg tcc aag gct cat ggg atc gat cct aac atc agg acc ggg gtg aga 12807Met Ser Lys Ala His Gly Ile Asp Pro Asn Ile Arg Thr Gly Val Arg30 35 40aca att acc act ggc agc ccc atc acg tac tcc acc tac ggc aag ttc 12855Thr Ile Thr Thr Gly Ser Pro Ile Thr Tyr Ser Thr Tyr Gly Lys Phe45 50 55ctt gcc gac ggc ggg tgc tcg ggg ggc gct tat gac ata ata att tgt 12903Leu Ala Asp Gly Gly Cys Ser Gly Gly Ala Tyr Asp Ile Ile Ile Cys60 65 70 75gac gag tgc cac tcc acg gat gcc aca tcc atc ttg ggc att ggc act 12951Asp Glu Cys His Ser Thr Asp Ala Thr Ser Ile Leu Gly Ile Gly Thr80 85 90gtc ctt gac caa gca gag act gcg ggg gcg aga ctg gtt gtg ctc gcc 12999Val Leu Asp Gln Ala Glu Thr Ala Gly Ala Arg Leu Val Val Leu Ala95 100 105acc gcc acc cct ccg ggc tcc gtc act gtg ccc cat ccc aac atc gag 13047Thr Ala Thr Pro Pro Gly Ser Val Thr Val Pro His Pro Asn Ile Glu110 115 120gag gtt gct ctg tcc acc acc gga gag atc cct ttt tac ggc aag gct 13095Glu Val Ala Leu Ser Thr Thr Gly Glu Ile Pro Phe Tyr Gly Lys Ala125 130 135atc ccc ctc gaa gta atc aag ggg ggg aga cat ctc atc ttc tgt cat 13143Ile Pro Leu Glu Val Ile Lys Gly Gly Arg His Leu Ile Phe Cys His140 145 150 155tca aag aag aag tgc gac gaa ctc gcc gca aag ctg gtc gca ttg ggc 13191Ser Lys Lys Lys Cys Asp Glu Leu Ala Ala Lys Leu Val Ala Leu Gly160165 170atc aat gcc gtg gcc tac tac cgc ggt ctt gac gtg tcc gtc atc ccg 13239Ile Asn Ala Val Ala Tyr Tyr Arg Gly Leu Asp Val Ser Val Ile Pro175 180 185acc agc ggc gat gtt gtc gtc gtg gca acc gat gcc ctc atg acc ggc 13287Thr Ser Gly Asp Val Val Val Val Ala Thr Asp Ala Leu Met Thr Gly190 195 200tat acc ggc gac ttc gac tcg gtg ata gac tgc aat acg tgt gtc acc 13335Tyr Thr Gly Asp Phe Asp Ser Val Ile Asp Cys Asn Thr Cys Val Thr205 210 215cag aca gtc gat ttc agc ctt gac cct acc ttc acc att gag aca atc 13383Gln Thr Val Asp Phe Ser Leu Asp Pro Thr Phe Thr Ile Glu Thr Ile220 225 230 235acg ctc ccc caa gat gct gtc tcc cgc act caa cgt cgg ggc agg act 13431Thr Leu Pro Gln Asp Ala Val Ser Arg Thr Gln Arg Arg Gly Arg Thr240 245 250ggc agg ggg aag cca ggc atc tac aga ttt gtg gca ccg ggg gag cgc 13479Gly Arg Gly Lys Pro Gly Ile Tyr Arg Phe Val Ala Pro Gly Glu Arg255 260 265ccc tcc ggc atg ttc gac tcg tcc gtc ctc tgt gag tgc tat gac gca 13527Pro Ser Gly Met Phe Asp Ser Ser Val Leu Cys Glu Cys Tyr Asp Ala270 275 280ggc tgt gct tgg tat gag ctc acg ccc gcc gag act aca gtt agg cta 13575Gly Cys Ala Trp Tyr Glu Leu Thr Pro Ala Glu Thr Thr Val Arg Leu285 290 295cga gcg tac atg aac acc ccg ggg ctt ccc gtg tgc cag gac cat ctt 13623Arg Ala Tyr Met Asn Thr Pro Gly Leu Pro Val Cys Gln Asp His Leu300 305 310 315gaa ttt tgg gag ggc gtc ttt aca ggc ctc act cat ata gat gcc cac 13671Glu Phe Trp Glu Gly Val Phe Thr Gly Leu Thr His Ile Asp Ala His320 325 330ttt cta tcc cag aca aag cag agt ggg gag aac ctt cct tac ctg gta 13719Phe Leu Ser Gln Thr Lys Gln Ser Gly Glu Asn Leu Pro Tyr Leu Val335 340 345gcg tac caa gcc acc gtg tgc gct agg gct caa gcc cct ccc cca tcg 13767Ala Tyr Gln Ala Thr Val Cys Ala Arg Ala Gln Ala Pro Pro Pro Ser350 355 360tgg gac cag atg tgg aag tgt ttg att cgc ctc aag ccc acc ctc cat 13815Trp Asp Gln Met Trp Lys Cys Leu Ile Arg Leu Lys Pro Thr Leu His365 370 375ggg cca aca ccc ctg cta tac aga ctg ggc gct gtt cag aat gaa atc 13863Gly Pro Thr Pro Leu Leu Tyr Arg Leu Gly Ala Val Gln Asn Glu Ile380 385 390 395acc ctg acg cac cca gtc acc aaa tac atc atg aca tgc atg tcg gcc 13911Thr Leu Thr His Pro Val Thr Lys Tyr Ile Met Thr Cys Met Ser Ala400 405 410gac ctg gag gtc gtc acg agc acc tgg gtg ctc gtt ggc ggc gtc ctg 13959Asp Leu Glu Val Val Thr Ser Thr Trp Val Leu Val Gly Gly Val Leu415 420 425gct gct ttg gcc gcg tat tgc ctg tca aca ggc tgc gtg gtc ata gtg 14007Ala Ala Leu Ala Ala Tyr Cys Leu Ser Thr Gly Cys Val Val Ile Val430 435 440ggc agg gtc gtc ttg tcc ggg aag ccg gca atc ata cct gac agg gaa 14055Gly Arg Val Val Leu Ser Gly Lys Pro Ala Ile Ile Pro Asp Arg Glu445 450 455gtc ctc tac cga gag ttc gat gag atg gaa gag tgc tct cag cac tta 14103Val Leu Tyr Arg Glu Phe Asp Glu Met Glu Glu Cys Ser Gln His Leu460 465 470 475ccg tac atc gag caa ggg atg atg ctc gcc gag cag ttc aag cag aag 14151Pro Tyr Ile Glu Gln Gly Met Met Leu Ala Glu Gln Phe Lys Gln Lys480 485 490gcc ctc ggc ctc ctg cag acc gcg tcc cgt cag gca gag gtt atc gcc 14199Ala Leu Gly Leu Leu Gln Thr Ala Ser Arg Gln Ala Glu Val Ile Ala495 500 505cct gct gtc cag acc aac tgg caa aaa ctc gag acc ttc tgg gcg aag 14247Pro Ala Val Gln Thr Asn Trp Gln Lys Leu Glu Thr Phe Trp Ala Lys510 515 520cat atg tgg aac ttc atc agt ggg ata caa tac ttg gcg ggc ttg tca 14295His Met Trp Asn Phe Ile Ser Gly Ile Gln Tyr Leu Ala Gly Leu Ser525 530 535acg ctg cct ggt aac ccc gcc att gct tca ttg atg gct ttt aca gct 14343Thr Leu Pro Gly Asn Pro Ala Ile Ala Ser Leu Met Ala Phe Thr Ala540 545 550 555gct gtc acc agc cca cta acc act agc caa acc ctc ctc ttc aac ata 14391Ala Val Thr Ser Pro Leu Thr Thr Ser Gln Thr Leu Leu Phe Asn Ile560 565 570ttg ggg ggg tgg gtg gct gcc cag ctc gcc gcc ccc ggt gcc gct act 14439Leu Gly Gly Trp Val Ala Ala Gln Leu Ala Ala Pro Gly Ala Ala Thr575 580 585gcc ttt gtg ggc gct ggc tta gct ggc gcc gcc atc ggc agt gtt gga 14487Ala Phe Val Gly Ala Gly Leu Ala Gly Ala Ala Ile Gly Ser Val Gly590 595 600ctg ggg aag gtc ctc ata gac atc ctt gca ggg tat ggc gcg ggc gtg 14535Leu Gly Lys Val Leu Ile Asp Ile Leu Ala Gly Tyr Gly Ala Gly Val605 610 615gcg gga gct ctt gtg gca ttc aag atc atg agc ggt gag gtc ccc tcc 14583Ala Gly Ala Leu Val Ala Phe Lys Ile Met Ser Gly Glu Val Pro Ser620 625 630 635acg gag gac ctg gtc aat cta ctg ccc gcc atc ctc tcg ccc gga gcc 14631Thr Glu Asp Leu Val Asn Leu Leu Pro Ala Ile Leu Ser Pro Gly Ala640 645 650ctc gta gtc ggc gtg gtc tgt gca gca ata ctg cgc cgg cac gtt ggc 14679Leu Val Val Gly Val Val Cys Ala Ala Ile Leu Arg Arg His Val Gly655 660 665ccg ggc gag ggg gca gtg cag tgg atg aac cgg ctg ata gcc ttc gcc 14727Pro Gly Glu Gly Ala Val Gln Trp Met Asn Arg Leu Ile Ala Phe Ala670 675 680tcc cgg ggg aac cat gtt tcc ccc acg cac tac gtg ccg gag agc gat 14775Ser Arg Gly Asn His Val Ser Pro Thr His Tyr Val Pro Glu Ser Asp685 690 695gca gct gcc cgc gtc act gcc ata ctc agc agc ctc act gta acc cag 14823Ala Ala Ala Arg Val Thr Ala Ile Leu Ser Ser Leu Thr Val Thr Gln700 705 710 715ctc ctg agg cga ctg cac cag tgg ata agc tcg gag tgt acc act cca 14871Leu Leu Arg Arg Leu His Gln Trp Ile Ser Ser Glu Cys Thr Thr Pro720 725 730tgc tcc ggt tcc tgg cta agg gac atc tgg gac tgg ata tgc gag gtg 14919Cys Ser Gly Ser Trp Leu Arg Asp Ile Trp Asp Trp Ile Cys Glu Val735 740 745ttg agc gac ttt aag acc tgg cta aaa gct aag ctc atg cca cag ctg 14967Leu Ser Asp Phe Lys Thr Trp Leu Lys Ala Lys Leu Met Pro Gln Leu750 755 760cct ggg atc ccc ttt gtg tcc tgc cag cgc ggg tat aag ggg gtc tgg 15015Pro Gly Ile Pro Phe Val Ser Cys Gln Arg Gly Tyr Lys Gly Val Trp765 770 775cga ggg gac ggc atc atg cac act cgc tgc cac tgt gga gct gag atc 15063Arg Gly Asp Gly Ile Met His Thr Arg Cys His Cys Gly Ala Glu Ile780 785 790 795act gga cat gtc aaa aac ggg acg atg agg atc gtc ggt cct agg acc 15111Thr Gly His Val Lys Asn Gly Thr Met Arg Ile Val Gly Pro Arg Thr800 805 810tgc agg aac atg tgg agt ggg acc ttc ccc att aat gcc tac acc acg 15159Cys Arg Asn Met Trp Ser Gly Thr Phe Pro Ile Asn Ala Tyr Thr Thr815 820 825ggc ccc tgt acc ccc ctt cct gcg ccg aac tac acg ttc gcg cta tgg 15207Gly Pro Cys Thr Pro Leu Pro Ala Pro Asn Tyr Thr Phe Ala Leu Trp830 835 840agg gtg tct gca gag gaa tac gtg gag ata agg cag gtg ggg gac ttc 15255Arg Val Ser Ala Glu Glu Tyr Val Glu Ile Arg Gln Val Gly Asp Phe845 850 855cac tac gtg acg ggt atg act act gac aat ctt aaa tgc ccg tgc cag 15303His Tyr Val Thr Gly Met Thr Thr Asp Asn Leu Lys Cys Pro Cys Gln860 865 870 875gtc cca tcg ccc gaa ttt ttc aca gaa ttg gac ggg gtg cgc cta cat 15351Val Pro Ser Pro Glu Phe Phe Thr Glu Leu Asp Gly Val Arg Leu His880 885 890agg ttt gcg ccc ccc tgc aag ccc ttg ctg cgg gag gag gta tca ttc 15399Arg Phe Ala Pro Pro Cys Lys Pro Leu Leu Arg Glu Glu Val Ser Phe895 900 905aga gta gga ctc cac gaa tac ccg gta ggg tcg caa tta cct tgc gag 15447Arg Val Gly Leu His Glu Tyr Pro Val Gly Ser Gln Leu Pro Cys Glu910 915 920ccc gaa ccg gac gtg gcc gtg ttg acg tcc atg ctc act gat ccc tcc 15495Pro Glu Pro Asp Val Ala Val Leu Thr Ser Met Leu Thr Asp Pro Ser925 930 935cat ata aca gca gag gcg gcc ggg cga agg ttg gcg agg gga tca ccc 15543His Ile Thr Ala Glu Ala Ala Gly Arg Arg Leu Ala Arg Gly Ser Pro940 945 950 955ccc tct gtg gcc agc tcc tcg gct agc cag cta tcc gct cca tct ctc 15591Pro Ser Val Ala Ser Ser Ser Ala Ser Gln Leu Ser Ala Pro Ser Leu960 965 970aag gca act tgc acc gct aac cat gac tcc cct gat gct gag ctc ata 15639Lys Ala Thr Cys Thr Ala Asn His Asp Ser Pro Asp Ala Glu Leu Ile975 980 985gag gcc aac ctc cta tgg agg cag gag atg ggc ggc aac atc acc agg 15687Glu Ala Asn Leu Leu Trp Arg Gln Glu Met Gly Gly Asn Ile Thr Arg990 9951000gtt gag tca gaa aac aaa gtg gtg att ctg gac tcc ttc gat ccg ctt 15735Val Glu Ser Glu Asn Lys Val Val Ile Leu Asp Ser Phe Asp Pro Leu100510101015gtg gcg gag gag gac gag cgg gag atc tcc gta ccc gca gaa atc ctg 15783Val Ala Glu Glu Asp Glu Arg Glu Ile Ser Val Pro Ala Glu Ile Leu1020 102510301035cgg aag tct cgg aga ttc gcc cag gcc ctg ccc gtt tgg gcg cgg ccg 15831Arg Lys Ser Arg Arg Phe Ala Gln Ala Leu Pro Val Trp Ala Arg Pro104010451050gac tat aac ccc ccg cta gtg gag acg tgg aaa aag ccc gac tac gaa 15879Asp Tyr Asn Pro Pro Leu Val Glu Thr Trp Lys Lys Pro Asp Tyr Glu105510601065cca cct gtg gtc cat ggc tgc ccg ctt cca cct cca aag tcc cct cct 15927Pro Pro Val Val His Gly Cys Pro Leu Pro Pro Pro Lys Ser Pro Pro107010751080gtg cct ccg cct cgg aag aag cgg acg gtg gtc ctc act gaa tca acc 15975Val Pro Pro Pro Arg Lys Lys Arg Thr Val Val Leu Thr Glu Ser Thr108510901095cta tct act gcc ttg gcc gag ctc gcc acc aga agc ttt ggc agc tcc 16023Leu Ser Thr Ala Leu Ala Glu Leu Ala Thr Arg Ser Phe Gly Ser Ser1100 110511101115tca act tcc ggc att acg ggc gac aat acg aca aca tcc tct gag ccc 16071Ser Thr Ser Gly Ile Thr Gly Asp Asn Thr Thr Thr Ser Ser Glu Pro112011251130gcc cct tct ggc tgc ccc ccc gac tcc gac gct gag tcc tat tcc tcc 16119Ala Pro Ser Gly Cys Pro Pro Asp Ser Asp Ala Glu Ser Tyr Ser Ser113511401145atg ccc ccc ctg gag ggg gag cct ggg gat ccg gat ctt agc gac ggg 16167Met Pro Pro Leu Glu Gly Glu Pro Gly Asp Pro Asp Leu Ser Asp Gly115011551160tca tgg tca acg gtc agt agt gag gcc aac gcg gag gat gtc gtg tgc 16215Ser Trp Ser Thr Val Ser Ser Glu Ala Asn Ala Glu Asp Val Val Cys116511701175tgc tca atg tct tac tct tgg aca ggc gca ctc gtc acc ccg tgc gcc 16263Cys Ser Met Ser Tyr Ser Trp Thr Gly Ala Leu Val Thr Pro Cys Ala1180 118511901195gcg gaa gaa cag aaa ctg ccc atc aat gca cta agc aac tcg ttg cta 16311Ala Glu Glu Gln Lys Leu Pro Ile Asn Ala Leu Ser Asn Ser Leu Leu120012051210cgt cac cac aat ttg gtg tat tcc acc acc tca cgc agt gct tgc caa 16359Arg His His Asn Leu Val Tyr Ser Thr Thr Ser Arg Ser Ala Cys Gln121512201225agg cag aag aaa gtc aca ttt gac aga ctg caa gtt ctg gac agc cat 16407Arg Gln Lys Lys Val Thr Phe Asp Arg Leu Gln Val Leu Asp Ser His123012351240tac cag gac gta ctc aag gag gtt aaa gca gcg gcg tca aaa gtg aag 16455Tyr Gln Asp Val Leu Lys Glu Val Lys Ala Ala Ala Ser Lys Val Lys124512501255gct aac ttg cta tcc gta gag gaa gct tgc agc ctg acg ccc cca cac 16503Ala Asn Leu Leu Ser Val Glu Glu Ala Cys Ser Leu Thr Pro Pro His1260 126512701275tca gcc aaa tcc aag ttt ggt tat ggg gca aaa gac gtc cgt tgc cat 16551Ser Ala Lys Ser Lys Phe Gly Tyr Gly Ala Lys Asp Val Arg Cys His128012851290gcc aga aag gcc gta acc cac atc aac tcc gtg tgg aaa gac ctt ctg 16599Ala Arg Lys Ala Val Thr His Ile Asn Ser Val Trp Lys Asp Leu Leu129513001305gaa gac aat gta aca cca ata gac act acc atc atg gct aag aac gag 16647Glu Asp Asn Val Thr Pro Ile Asp Thr Thr Ile Met Ala Lys Asn Glu131013151320gtt ttc tgc gtt cag cct gag aag ggg ggt cgt aag cca gct cgt ctc 16695Val Phe Cys Val Gln Pro Glu Lys Gly Gly Arg Lys Pro Ala Arg Leu132513301335atc gtg ttc ccc gat ctg ggc gtg cgc gtg tgc gaa aag atg gct ttg 16743Ile Val Phe Pro Asp Leu Gly Val Arg Val Cys Glu Lys Met Ala Leu1340 134513501355tac gac gtg gtt aca aag ctc ccc ttg gcc gtg atg gga agc tcc tac 16791Tyr Asp Val Val Thr Lys Leu Pro Leu Ala Val Met Gly Ser Ser Tyr136013651370gga ttc caa tac tca cca gga cag cgg gtt gaa ttc ctc gtg caa gcg 16839Gly Phe Gln Tyr Ser Pro Gly Gln Arg Val Glu Phe Leu Val Gln Ala137513801385tgg aag tcc aag aaa acc cca atg ggg ttc tcg tat gat acc cgc tgc 16887Trp Lys Ser Lys Lys Thr Pro Met Gly Phe Ser Tyr Asp Thr Arg Cys139013951400ttt gac tcc aca gtc act gag agc gac atc cgt acg gag gag gca atc 16935Phe Asp Ser Thr Val Thr Glu Ser Asp Ile Arg Thr Glu Glu Ala Ile140514101415tac caa tgt tgt gac ctc gac ccc caa gcc cgc gtg gcc atc aag tcc 16983Tyr Gln Cys Cys Asp Leu Asp Pro Gln Ala Arg Val Ala Ile Lys Ser1420 142514301435ctc acc gag agg ctt tat gtt ggg ggc cct ctt acc aat tca agg ggg 17031Leu Thr Glu Arg Leu Tyr Val Gly Gly Pro Leu Thr Asn Ser Arg Gly144014451450gag aac tgc ggc tat cgc agg tgc cgc gcg agc ggc gta ctg aca act 17079Glu Asn Cys Gly Tyr Arg Arg Cys Arg Ala Ser Gly Val Leu Thr Thr145514601465agc tgt ggt aac acc ctc act tgc tac atc aag gcc cgg gca gcc tgt 17127Ser Cys Gly Asn Thr Leu Thr Cys Tyr Ile Lys Ala Arg Ala Ala Cys147014751480cga gcc gca ggg ctc cag gac tgc acc atg ctc gtg tgt ggc gac gac 17175Arg Ala Ala Gly Leu Gln Asp Cys Thr Met Leu Val Cys Gly Asp Asp148514901495tta gtc gtt atc tgt gaa agc gcg ggg gtc cag gag gac gcg gcg agc 17223Leu Val Val Ile Cys Glu Ser Ala Gly Val Gln Glu Asp Ala Ala Ser1500 150515101515ctg aga gcc ttc acg gag gct atg acc agg tac tcc gcc ccc cct ggg 17271Leu Arg Ala Phe Thr Glu Ala Met Thr Arg Tyr Ser Ala Pro Pro Gly152015251530gac ccc cca caa cca gaa tac gac ttg gag ctc ata aca tca tgc tcc 17319Asp Pro Pro Gln Pro Glu Tyr Asp Leu Glu Leu Ile Thr Ser Cys Ser153515401545tcc aac gtg tca gtc gcc cac gac ggc gct gga aag agg gtc tac tac 17367Ser Asn Val Ser Val Ala His Asp Gly Ala Gly Lys Arg Val Tyr Tyr155015551560ctc acc cgt gac cct aca acc ccc ctc gcg aga gct gcg tgg gag aca 17415Leu Thr Arg Asp Pro Thr Thr Pro Leu Ala Arg Ala Ala Trp Glu Thr156515701575gca aga cac act cca gtc aat tcc tgg cta ggc aac ata atc atg ttt 17463Ala Arg His Thr Pro Val Asn Ser Trp Leu Gly Asn Ile Ile Met Phe1580 158515901595gcc ccc aca ctg tgg gcg agg atg ata ctg atg acc cat ttc ttt agc 17511Ala Pro Thr Leu Trp Ala Arg Met Ile Leu Met Thr His Phe Phe Ser160016051610gtc ctt ata gcc agg gac cag ctt gaa cag gcc ctc gat tgc gag atc 17559Val Leu Ile Ala Arg Asp Gln Leu Glu Gln Ala Leu Asp Cys Glu Ile161516201625tac ggg gcc tgc tac tcc ata gaa cca ctg gat cta cct cca atc att 17607Tyr Gly Ala Cys Tyr Ser Ile Glu Pro Leu Asp Leu Pro Pro Ile Ile163016351640caa aga ctc cat ggc ctc agc gca ttt tca ctc cac agt tac tct cca 17655Gln Arg Leu His Gly Leu Ser Ala Phe Ser Leu His Ser Tyr Ser Pro164516501655ggt gaa atc aat agg gtg gcc gca tgc ctc aga aaa ctt ggg gta ccg 17703Gly Glu Ile Asn Arg Val Ala Ala Cys Leu Arg Lys Leu Gly Val Pro1660 166516701675ccc ttg cga gct tgg aga cac cgg gcc cgg agc gtc cgc gct agg ctt 17751Pro Leu Arg Ala Trp Arg His Arg Ala Arg Ser Val Arg Ala Arg Leu168016851690ctg gcc aga gga ggc agg gct gcc ata tgt ggc aag tac ctc ttc aac 17799Leu Ala Arg Gly Gly Arg Ala Ala Ile Cys Gly Lys Tyr Leu Phe Asn169517001705tgg gca gta aga aca aag ctc aaa ctc act cca ata gcg gcc gct ggc 17847Trp Ala Val Arg Thr Lys Leu Lys Leu Thr Pro Ile Ala Ala Ala Gly171017151720cag ctg gac ttg tcc ggc tgg ttc acg gct ggc tac agc ggg gga gac 17895Gln Leu Asp Leu Ser Gly Trp Phe Thr Ala Gly Tyr Ser Gly Gly Asp172517301735att tat cac agc gtg tct cat gcc cgg ccc cgc tgg atc tgg ttt tgc 17943Ile Tyr His Ser Val Ser His Ala Arg Pro Arg Trp Ile Trp Phe Cys1740 174517501755cta ctc ctg ctt gct gca ggg gta ggc atc tac ctc ctc ccc aac cga 17991Leu Leu Leu Leu Ala Ala Gly Val Gly Ile Tyr Leu Leu Pro Asn Arg176017651770atg agc acg aat cct aaa cct caa aga aag acc aaa cgt aac acc aac 18039Met Ser Thr Asn Pro Lys Pro Gln Arg Lys Thr Lys Arg Asn Thr Asn177517801785cgg cgg ccg cag gac gtc aag ttc ccg ggt ggc ggt cag atc gtt ggt 18087Arg Arg Pro Gln Asp Val Lys Phe Pro Gly Gly Gly Gln Ile Val Gly179017951800gga gtt tac ttg ttg ccg cgc agg ggc cct aga ttg ggt gtg cgc gcg 18135Gly Val Tyr Leu Leu Pro Arg Arg Gly Pro Arg Leu Gly Val Arg Ala180518101815acg aga aag act tcc gag cgg tcg caa cct cga ggt aga cgt cag cct 18183Thr Arg Lys Thr Ser Glu Arg Ser Gln Pro Arg Gly Arg Arg Gln Pro1820 182518301835atc ccc aag gct cgt cgg ccc gag ggc agg acc tgg gct cag ccc ggg 18231Ile Pro Lys Ala Arg Arg Pro Glu Gly Arg Thr Trp Ala Gln Pro Gly184018451850tac cct tgg ccc ctc tat ggc aat gag ggc tgc ggg tgg gcg gga tgg 18279Tyr Pro Trp Pro Leu Tyr Gly Asn Glu Gly Cys Gly Trp Ala Gly Trp185518601865ctc ctg tct ccc cgt ggc tct cgg cct agc tgg ggc ccc aca gac ccc 18327Leu Leu Ser Pro Arg Gly Ser Arg Pro Ser Trp Gly Pro Thr Asp Pro187018751880cgg cgt agg tcg cgc aat ttg ggt aag taatagtcga ctttgttccc 18374Arg Arg Arg Ser Arg Asn Leu Gly Lys18851890actgtacttt tagctcgtac aaaatacaat atacttttca tttctccgta aacaacatgt 18434tttcccatgt aatatccttt tctatttttc gttccgttac caactttaca catactttat 18494atagctattc acttctatac actaaaaaac taagacaatt ttaattttgc tgcctgccat 18554atttcaattt gttataaatt cctataattt atcctattag tagctaaaaa aagatgaatg 18614tgaatcgaat cctaagagaa ttggatctga tccacaggac gggtgtggtc gccatgatcg 18674cgtagtcgat agtggctcca agtagcgaag cgagcaggac tgggcggcgg ccaaagcggt 18734cggacagtgc tccgagaacg ggtgcgcata gaaattgcat caacgcatat agcgctagca 18794gcacgccata gtgactggcg atgctgtcgg aatggacgat atcccgcaag aggcccggca 18854gtaccggcat aaccaagcct atgcctacag catccagggt gacggtgccg aggatgacga 18914tgagcgcatt gttagatttc atacacggtg cctgactgcg ttagcaattt aactgtgata 18974aactaccgca ttaaagcttt ttctttccaa tttttttttt ttcgtcatta taaaaatcat 19034tacgaccgag attcccgggt aataactgat ataattaaat tgaagctcta atttgtgagt 19094ttagtataca tgcatttact tataatacag ttttttagtt ttgctggccg catcttctca 19154aatatgcttc ccagcctgct tttctgtaac gttcaccctc taccttagca tcccttccct 19214ttgcaaatag tcctcttcca acaataataa tgtcagatcc tgtagagacc acatcatcca 19274cggttctata ctgttgaccc aatgcgtctc ccttgtcatc taaacccaca ccgggtgtca 19334taatcaacca atcgtaacct tcatctcttc cacccatgtc tctttgagca ataaagccga 19394taacaaaatc tttgtcgctc ttcgcaatgt caacagtacc cttagtatat tctccagtag 19454atagggagcc cttgcatgac aattctgcta acatcaaaag gcctctaggt tcctttgtta 19514cttcttctgc cgcctgcttc aaaccgctaa caatacctgg gcccaccaca ccgtgtgcat 19574tcgtaatgtc tgcccattct gctattctgt atacacccgc agagtactgc aatttgactg 19634tattaccaat gtcagcaaat tttctgtctt cgaagagtaa aaaattgtac ttggcggata 19694atgcctttag cggcttaact gtgccctcca tggaaaaatc agtcaagata tccacatgtg 19754tttttagtaa acaaattttg ggacctaatg cttcaactaa ctccagtaat tccttggtgg 19814tacgaacatc caatgaagca cacaagtttg tttgcttttc gtgcatgata ttaaatagct 19874tggcagcaac aggactagga tgagtagcag cacgttcctt atatgtagct ttcgacatga 19934tttatcttcg tttcctgcag gtttttgttc tgtgcagttg ggttaagaat actgggcaat 19994ttcatgtttc ttcaacacta catatgcgta tatataccaa tctaagtctg tgctccttcc 20054ttcgttcttc cttctgttcg gagattaccg aatcaaaaaa atttcaagga aaccgaaatc 20114aaaaaaaaga ataaaaaaaa aatgatgaat tgaaaagctt atcgat20160210132111892212PRT213人工序列220223人工序列的描述pd.delta.NS3NS5.pj.core12140013Met Ala Ala Tyr Ala Ala Gln Gly Tyr Lys Val Leu Val Leu Asn Pro1 5 10 15Ser Val Ala Ala Thr Leu Gly Phe Gly Ala Tyr Met Ser Lys Ala His20 25 30Gly Ile Asp Pro Asn Ile Arg Thr Gly Val Arg Thr Ile Thr Thr Gly35 40 45Ser Pro Ile Thr Tyr Ser Thr Tyr Gly Lys Phe Leu Ala Asp Gly Gly50 55 60Cys Ser Gly Gly Ala Tyr Asp Ile Ile Ile Cys Asp Glu Cys His Ser65 70 75 80Thr Asp Ala Thr Ser Ile Leu Gly Ile Gly Thr Val Leu Asp Gln Ala85 90 95Glu Thr Ala Gly Ala Arg Leu Val Val Leu Ala Thr Ala Thr Pro Pro100 105 110Gly Ser Val Thr Val Pro His Pro Asn Ile Glu Glu Val Ala Leu Ser115 120 125Thr Thr Gly Glu Ile Pro Phe Tyr Gly Lys Ala Ile Pro Leu Glu Val130 135 140Ile Lys Gly Gly Arg His Leu Ile Phe Cys His Ser Lys Lys Lys Cys145 150 155 160Asp Glu Leu Ala Ala Lys Leu Val Ala Leu Gly Ile Asn Ala Val Ala165 170 175Tyr Tyr Arg Gly Leu Asp Val Ser Val Ile Pro Thr Ser Gly Asp Val180 185 190Val Val Val Ala Thr Asp Ala Leu Met Thr Gly Tyr Thr Gly Asp Phe195 200 205Asp Ser Val Ile Asp Cys Asn Thr Cys Val Thr Gln Thr Val Asp Phe210 215 220Ser Leu Asp Pro Thr Phe Thr Ile Glu Thr Ile Thr Leu Pro Gln Asp225 230 235 240Ala Val Ser Arg Thr Gln Arg Arg Gly Arg Thr Gly Arg Gly Lys Pro245 250 255Gly Ile Tyr Arg Phe Val Ala Pro Gly Glu Arg Pro Ser Gly Met Phe260 265 270Asp Ser Ser Val Leu Cys Glu Cys Tyr Asp Ala Gly Cys Ala Trp Tyr275 280 285Glu Leu Thr Pro Ala Glu Thr Thr Val Arg Leu Arg Ala Tyr Met Asn290 295 300Thr Pro Gly Leu Pro Val Cys Gln Asp His Leu Glu Phe Trp Glu Gly305 310 315 320Val Phe Thr Gly Leu Thr His Ile Asp Ala His Phe Leu Ser Gln Thr325 330 335Lys Gln Ser Gly Glu Asn Leu Pro Tyr Leu Val Ala Tyr Gln Ala Thr340 345 350Val Cys Ala Arg Ala Gln Ala Pro Pro Pro Ser Trp Asp Gln Met Trp355 360 365Lys Cys Leu Ile Arg Leu Lys Pro Thr Leu His Gly Pro Thr Pro Leu370 375 380Leu Tyr Arg Leu Gly Ala Val Gln Asn Glu Ile Thr Leu Thr His Pro385 390 395 400Val Thr Lys Tyr Ile Met Thr Cys Met Ser Ala Asp Leu Glu Val Val405 410 415Thr Ser Thr Trp Val Leu Val Gly Gly Val Leu Ala Ala Leu Ala Ala420 425 430Tyr Cys Leu Ser Thr Gly Cys Val Val Ile Val Gly Arg Val Val Leu435 440 445Ser Gly Lys Pro Ala Ile Ile Pro Asp Arg Glu Val Leu Tyr Arg Glu450 455 460Phe Asp Glu Met Glu Glu Cys Ser Gln His Leu Pro Tyr Ile Glu Gln465 470 475 480Gly Met Met Leu Ala Glu Gln Phe Lys Gln Lys Ala Leu Gly Leu Leu485 490 495Gln Thr Ala Ser Arg Gln Ala Glu Val Ile Ala Pro Ala Val Gln Thr500 505 510Asn Trp Gln Lys Leu Glu Thr Phe Trp Ala Lys His Met Trp Asn Phe515 520 525Ile Ser Gly Ile Gln Tyr Leu Ala Gly Leu Ser Thr Leu Pro Gly Asn530 535 540Pro Ala Ile Ala Ser Leu Met Ala Phe Thr Ala Ala Val Thr Ser Pro545 550 555 560Leu Thr Thr Ser Gln Thr Leu Leu Phe Asn Ile Leu Gly Gly Trp Val565 570 575Ala Ala Gln Leu Ala Ala Pro Gly Ala Ala Thr Ala Phe Val Gly Ala
580 585 590Gly Leu Ala Gly Ala Ala Ile Gly Ser Val Gly Leu Gly Lys Val Leu595 600 605Ile Asp Ile Leu Ala Gly Tyr Gly Ala Gly Val Ala Gly Ala Leu Val610 615 620Ala Phe Lys Ile Met Ser Gly Glu Val Pro Ser Thr Glu Asp Leu Val625 630 635 640Asn Leu Leu Pro Ala Ile Leu Ser Pro Gly Ala Leu Val Val Gly Val645 650 655Val Cys Ala Ala Ile Leu Arg Arg His Val Gly Pro Gly Glu Gly Ala660 665 670Val Gln Trp Met Asn Arg Leu Ile Ala Phe Ala Ser Arg Gly Asn His675 680 685Val Ser Pro Thr His Tyr Val Pro Glu Ser Asp Ala Ala Ala Arg Val690 695 700Thr Ala Ile Leu Ser Ser Leu Thr Val Thr Gln Leu Leu Arg Arg Leu705 710 715 720His Gln Trp Ile Ser Ser Glu Cys Thr Thr Pro Cys Ser Gly Ser Trp725 730 735Leu Arg Asp Ile Trp Asp Trp Ile Cys Glu Val Leu Ser Asp Phe Lys740 745 750Thr Trp Leu Lys Ala Lys Leu Met Pro Gln Leu Pro Gly Ile Pro Phe755 760 765Val Ser Cys Gln Arg Gly Tyr Lys Gly Val Trp Arg Gly Asp Gly Ile770 775 780Met His Thr Arg Cys His Cys Gly Ala Glu Ile Thr Gly His Val Lys785 790 795 800Asn Gly Thr Met Arg Ile Val Gly Pro Arg Thr Cys Arg Asn Met Trp805 810 815Ser Gly Thr Phe Pro Ile Asn Ala Tyr Thr Thr Gly Pro Cys Thr Pro820 825 830Leu Pro Ala Pro Asn Tyr Thr Phe Ala Leu Trp Arg Val Ser Ala Glu835 840 845Glu Tyr Val Glu Ile Arg Gln Val Gly Asp Phe His Tyr Val Thr Gly850 855 860Met Thr Thr Asp Asn Leu Lys Cys Pro Cys Gln Val Pro Ser Pro Glu865 870 875 880Phe Phe Thr Glu Leu Asp Gly Val Arg Leu His Arg Phe Ala Pro Pro885 890 895Cys Lys Pro Leu Leu Arg Glu Glu Val Ser Phe Arg Val Gly Leu His
900 905 910Glu Tyr Pro Val Gly Ser Gln Leu Pro Cys Glu Pro Glu Pro Asp Val915 920 925Ala Val Leu Thr Ser Met Leu Thr Asp Pro Ser His Ile Thr Ala Glu930 935 940Ala Ala Gly Arg Arg Leu Ala Arg Gly Ser Pro Pro Ser Val Ala Ser945 950 955 960Ser Ser Ala Ser Gln Leu Ser Ala Pro Ser Leu Lys Ala Thr Cys Thr965 970 975Ala Asn His Asp Ser Pro Asp Ala Glu Leu Ile Glu Ala Asn Leu Leu980 985 990Trp Arg Gln Glu Met Gly Gly Asn Ile Thr Arg Val Glu Ser Glu Asn99510001005Lys Val Val Ile Leu Asp Ser Phe Asp Pro Leu Val Ala Glu Glu Asp101010151020Glu Arg Glu Ile Ser Val Pro Ala Glu Ile Leu Arg Lys Ser Arg Arg025103010351040Phe Ala Gln Ala Leu Pro Val Trp Ala Arg Pro Asp Tyr Asn Pro Pro104510501055Leu Val Glu Thr Trp Lys Lys Pro Asp Tyr Glu Pro Pro Val Val His106010651070Gly Cys Pro Leu Pro Pro Pro Lys Ser Pro Pro Val Pro Pro Pro Arg107510801085Lys Lys Arg Thr Val Val Leu Thr Glu Ser Thr Leu Ser Thr Ala Leu109010951100Ala Glu Leu Ala Thr Arg Ser Phe Gly Ser Ser Ser Thr Ser Gly Ile105111011151120Thr Gly Asp Asn Thr Thr Thr Ser Ser Glu Pro Ala Pro Ser Gly Cys112511301135Pro Pro Asp Ser Asp Ala Glu Ser Tyr Ser Ser Met Pro Pro Leu Glu114011451150Gly Glu Pro Gly Asp Pro Asp Leu Ser Asp Gly Ser Trp Ser Thr Val115511601165Ser Ser Glu Ala Asn Ala Glu Asp Val Val Cys Cys Ser Met Ser Tyr117011751180Ser Trp Thr Gly Ala Leu Val Thr Pro Cys Ala Ala Glu Glu Gln Lys185119011951200Leu Pro Ile Asn Ala Leu Ser Asn Ser Leu Leu Arg His His Asn Leu120512101215Val Tyr Ser Thr Thr Ser Arg Ser Ala Cys Gln Arg Gln Lys Lys Val
122012251230Thr Phe Asp Arg Leu Gln Val Leu Asp Ser His Tyr Gln Asp Val Leu123512401245Lys Glu Val Lys Ala Ala Ala Ser Lys Val Lys Ala Asn Leu Leu Ser125012551260Val Glu Glu Ala Cys Ser Leu Thr Pro Pro His Ser Ala Lys Ser Lys265127012751280Phe Gly Tyr Gly Ala Lys Asp Val Arg Cys His Ala Arg Lys Ala Val128512901295Thr His Ile Asn Ser Val Trp Lys Asp Leu Leu Glu Asp Asn Val Thr130013051310Pro Ile Asp Thr Thr Ile Met Ala Lys Asn Glu Val Phe Cys Val Gln131513201325Pro Glu Lys Gly Gly Arg Lys Pro Ala Arg Leu Ile Val Phe Pro Asp133013351340Leu Gly Val Arg Val Cys Glu Lys Met Ala Leu Tyr Asp Val Val Thr345135013551360Lys Leu Pro Leu Ala Val Met Gly Ser Ser Tyr Gly Phe Gln Tyr Ser136513701375Pro Gly Gln Arg Val Glu Phe Leu Val Gln Ala Trp Lys Ser Lys Lys138013851390Thr Pro Met Gly Phe Ser Tyr Asp Thr Arg Cys Phe Asp Ser Thr Val139514001405Thr Glu Ser Asp Ile Arg Thr Glu Glu Ala Ile Tyr Gln Cys Cys Asp141014151420Leu Asp Pro Gln Ala Arg Val Ala Ile Lys Ser Leu Thr Glu Arg Leu425143014351440Tyr Val Gly Gly Pro Leu Thr Asn Ser Arg Gly Glu Asn Cys Gly Tyr144514501455Arg Arg Cys Arg Ala Ser Gly Val Leu Thr Thr Ser Cys Gly Asn Thr146014651470Leu Thr Cys Tyr Ile Lys Ala Arg Ala Ala Cys Arg Ala Ala Gly Leu147514801485Gln Asp Cys Thr Met Leu Val Cys Gly Asp Asp Leu Val Val Ile Cys149014951500Glu Ser Ala Gly Val Gln Glu Asp Ala Ala Ser Leu Arg Ala Phe Thr505151015151520Glu Ala Met Thr Arg Tyr Ser Ala Pro Pro Gly Asp Pro Pro Gln Pro152515301535Glu Tyr Asp Leu Glu Leu Ile Thr Ser Cys Ser Ser Asn Val Ser Val
154015451550Ala His Asp Gly Ala Gly Lys Arg Val Tyr Tyr Leu Thr Arg Asp Pro155515601565Thr Thr Pro Leu Ala Arg Ala Ala Trp Glu Thr Ala Arg His Thr Pro157015751580Val Asn Ser Trp Leu Gly Asn Ile Ile Met Phe Ala Pro Thr Leu Trp585159015951600Ala Arg Met Ile Leu Met Thr His Phe Phe Ser Val Leu Ile Ala Arg160516101615Asp Gln Leu Glu Gln Ala Leu Asp Cys Glu Ile Tyr Gly Ala Cys Tyr162016251630Ser Ile Glu Pro Leu Asp Leu Pro Pro Ile Ile Gln Arg Leu His Gly163516401645Leu Ser Ala Phe Ser Leu His Ser Tyr Ser Pro Gly Glu Ile Asn Arg165016551660Val Ala Ala Cys Leu Arg Lys Leu Gly Val Pro Pro Leu Arg Ala Trp665167016751680Arg His Arg Ala Arg Ser Val Arg Ala Arg Leu Leu Ala Arg Gly Gly168516901695Arg Ala Ala Ile Cys Gly Lys Tyr Leu Phe Asn Trp Ala Val Arg Thr170017051710Lys Leu Lys Leu Thr Pro Ile Ala Ala Ala Gly Gln Leu Asp Leu Ser171517201725Gly Trp Phe Thr Ala Gly Tyr Ser Gly Gly Asp Ile Tyr His Ser Val173017351740Ser His Ala Arg Pro Arg Trp Ile Trp Phe Cys Leu Leu Leu Leu Ala745175017551760Ala Gly Val Gly Ile Tyr Leu Leu Pro Asn Arg Met Ser Thr Asn Pro176517701775Lys Pro Gln Arg Lys Thr Lys Arg Asn Thr Asn Arg Arg Pro Gln Asp178017851790Val Lys Phe Pro Gly Gly Gly Gln Ile Val Gly Gly Val Tyr Leu Leu179518001805Pro Arg Arg Gly Pro Arg Leu Gly Val Arg Ala Thr Arg Lys Thr Ser181018151820Glu Arg Ser Gln Pro Arg Gly Arg Arg Gln Pro Ile Pro Lys Ala Arg825183018351840Arg Pro Glu Gly Arg Thr Trp Ala Gln Pro Gly Tyr Pro Trp Pro Leu184518501855Tyr Gly Asn Glu Gly Cys Gly Trp Ala Gly Trp Leu Leu Ser Pro Arg
186018651870Gly Ser Arg Pro Ser Trp Gly Pro Thr Asp Pro Arg Arg Arg Ser Arg187518801885Asn Leu Gly Lys18902101421120316212DNA213人工序列220223人工序列的描述pd.delta.NS3NS5.pj.core173220221CDS222(12679)..(18510)40014atcgatccta ccccttgcgc taaagaagta tatgtgccta ctaacgcttg tctttgtctc 60tgtcactaaa cactggatta ttactcccag atacttattt tggactaatt taaatgattt 120cggatcaacg ttcttaatat cgctgaatct tccacaattg atgaaagtag ctaggaagag 180gaattggtat aaagtttttg tttttgtaaa tctcgaagta tactcaaacg aatttagtat 240tttctcagtg atctcccaga tgctttcacc ctcacttaga agtgctttaa gcattttttt 300actgtggcta tttcccttat ctgcttcttc cgatgattcg aactgtaatt gcaaactact 360tacaatatca gtgatatcag attgatgttt ttgtccatag taaggaataa ttgtaaattc 420ccaagcagga atcaatttct ttaatgaggc ttccagaatt gttgcttttt gcgtcttgta 480tttaaactgg agtgatttat tgacaatatc gaaactcagc gaattgctta tgatagtatt 540atagctcatg aatgtggctc tcttgattgc tgttccgtta tgtgtaatca tccaacataa 600ataggttagt tcagcagcac ataatgctat tttctcacct gaaggtcttt caaacctttc 660cacaaactga cgaacaagca ccttaggtgg tgttttacat aatatatcaa attgtggcat 720gcttagcgcc gatcttgtgt gcaattgata tctagtttca actactctat ttatcttgta 780tcttgcagta ttcaaacacg ctaactcgaa aaactaactt taattgtcct gtttgtctcg 840cgttctttcg aaaaatgcac cggccgcgca ttatttgtac tgcgaaaata attggtactg 900cggtatcttc atttcatatt ttaaaaatgc acctttgctg cttttcctta atttttagac 960ggcccgcagg ttcgttttgc ggtactatct tgtgataaaa agttgttttg acatgtgatc 1020tgcacagatt ttataatgta ataagcaaga atacattatc aaacgaacaa tactggtaaa 1080agaaaaccaa aatggacgac attgaaacag ccaagaatct gacggtaaaa gcacgtacag 1140cttatagcgt ctgggatgta tgtcggctgt ttattgaaat gattgctcct gatgtagata 1200ttgatataga gagtaaacgt aagtctgatg agctactctt tccaggatat gtcataaggc 1260ccatggaatc tctcacaacc ggtaggccgt atggtcttga ttctagcgca gaagattcca 1320gcgtatcttc tgactccagt gctgaggtaa ttttgcctgc tgcgaagatg gttaaggaaa 1380ggtttgattc gattggaaat ggtatgctct cttcacaaga agcaagtcag gctgccatag 1440atttgatgct acagaataac aagctgttag acaatagaaa gcaactatac aaatctattg 1500ctataataat aggaagattg cccgagaaag acaagaagag agctaccgaa atgctcatga 1560gaaaaatgga ttgtacacag ttattagtcc caccagctcc aacggaagaa gatgttatga 1620agctcgtaag cgtcgttacc caattgctta ctttagttcc accagatcgt caagctgctt 1680taataggtga tttattcatc ccggaatctc taaaggatat attcaatagt ttcaatgaac 1740tggcggcaga gaatcgttta cagcaaaaaa agagtgagtt ggaaggaagg actgaagtga 1800accatgctaa tacaaatgaa gaagttccct ccaggcgaac aagaagtaga gacacaaatg 1860caagaggagc atataaatta caaaacacca tcactgaggg ccctaaagcg gttcccacga 1920aaaaaaggag agtagcaacg agggtaaggg gcagaaaatc acgtaatact tctagggtat 1980gatccaatat caaaggaaat gatagcattg aaggatgaga ctaatccaat tgaggagtgg 2040cagcatatag aacagctaaa gggtagtgct gaaggaagca tacgataccc cgcatggaat 2100gggataatat cacaggaggt actagactac ctttcatcct acataaatag acgcatataa 2160gtacgcattt aagcataaac acgcactatg ccgttcttct catgtatata tatatacagg 2220caacacgcag atataggtgc gacgtgaaca gtgagctgta tgtgcgcagc tcgcgttgca 2280ttttcggaag cgctcgtttt cggaaacgct ttgaagttcc tattccgaag ttcctattct 2340ctagaaagta taggaacttc agagcgcttt tgaaaaccaa aagcgctctg aagacgcact 2400ttcaaaaaac caaaaacgca ccggactgta acgagctact aaaatattgc gaataccgct 2460tccacaaaca ttgctcaaaa gtatctcttt gctatatatc tctgtgctat atccctatat 2520aacctaccca tccacctttc gctccttgaa cttgcatcta aactcgacct ctacatcaac 2580aggcttccaa tgctcttcaa attttactgt caagtagacc catacggctg taatatgctg 2640ctcttcataa tgtaagctta tctttatcga atcgtgtgaa aaactactac cgcgataaac 2700ctttacggtt ccctgagatt gaattagttc ctttagtata tgatacaaga cacttttgaa 2760ctttgtacga cgaattttga ggttcgccat cctctggcta tttccaatta tcctgtcggc 2820tattatctcc gcctcagttt gatcttccgc ttcagactgc catttttcac ataatgaatc 2880tatttcaccc cacaatcctt catccgcctc cgcatcttgt tccgttaaac tattgacttc 2940atgttgtaca ttgtttagtt cacgagaagg gtcctcttca ggcggtagct cctgatctcc 3000tatatgacct ttatcctgtt ctctttccac aaacttagaa atgtattcat gaattatgga 3060gcacctaata acattcttca aggcggagaa gtttgggcca gatgcccaat atgcttgaca 3120tgaaaacgtg agaatgaatt tagtattatt gtgatattct gaggcaattt tattataatc 3180tcgaagataa gagaagaatg cagtgacctt tgtattgaca aatggagatt ccatgtatct 3240aaaaaatacg cctttaggcc ttctgatacc ctttcccctg cggtttagcg tgccttttac 3300attaatatct aaaccctctc cgatggtggc ctttaactga ctaataaatg caaccgatat 3360aaactgtgat aattctgggt gatttatgat tcgatcgaca attgtattgt acactagtgc 3420aggatcaggc caatccagtt ctttttcaat taccggtgtg tcgtctgtat tcagtacatg 3480tccaacaaat gcaaatgcta acgttttgta tttcttataa ttgtcaggaa ctggaaaagt 3540cccccttgtc gtctcgatta cacacctact ttcatcgtac accataggtt ggaagtgctg 3600cataatacat tgcttaatac aagcaagcag tctctcgcca ttcatatttc agttattttc 3660cattacagct gatgtcattg tatatcagcg ctgtaaaaat ctatctgtta cagaaggttt 3720tcgcggtttt tataaacaaa actttcgtta cgaaatcgag caatcacccc agctgcgtat 3780ttggaaattc gggaaaaagt agagcaacgc gagttgcatt ttttacacca taatgcatga 3840ttaacttcga gaagggatta aggctaattt cactagtatg tttcaaaaac ctcaatctgt 3900ccattgaatg ccttataaaa cagctataga ttgcatagaa gagttagcta ctcaatgctt 3960tttgtcaaag cttactgatg atgatgtgtc tactttcagg cgggtctgta gtaaggagaa 4020tgacattata aagctggcac ttagaattcc acggactata gactatacta gtatactccg 4080tctactgtac gatacacttc cgctcaggtc cttgtccttt aacgaggcct taccactctt 4140ttgttactct attgatccag ctcagcaaag gcagtgtgat ctaagattct atcttcgcga 4200tgtagtaaaa ctagctagac cgagaaagag actagaaatg caaaaggcac ttctacaatg 4260gctgccatca ttattatccg atgtgacgct gcattttttt tttttttttt tttttttttt 4320tttttttttt tttttttttt ttttttggta caaatatcat aaaaaaagag aatcttttta 4380agcaaggatt ttcttaactt cttcggcgac agcatcaccg acttcggtgg tactgttgga 4440accacctaaa tcaccagttc tgatacctgc atccaaaacc tttttaactg catcttcaat 4500ggctttacct tcttcaggca agttcaatga caatttcaac atcattgcag cagacaagat 4560agtggcgata gggttgacct tattctttgg caaatctgga gcggaaccat ggcatggttc 4620gtacaaacca aatgcggtgt tcttgtctgg caaagaggcc aaggacgcag atggcaacaa 4680acccaaggag cctgggataa cggaggcttc atcggagatg atatcaccaa acatgttgct 4740ggtgattata ataccattta ggtgggttgg gttcttaact aggatcatgg cggcagaatc 4800aatcaattga tgttgaactt tcaatgtagg gaattcgttc ttgatggttt cctccacagt 4860ttttctccat aatcttgaag aggccaaaac attagcttta tccaaggacc aaataggcaa 4920tggtggctca tgttgtaggg ccatgaaagc ggccattctt gtgattcttt gcacttctgg 4980aacggtgtat tgttcactat cccaagcgac accatcacca tcgtcttcct ttctcttacc 5040aaagtaaata cctcccacta attctctaac aacaacgaag tcagtacctt tagcaaattg 5100tggcttgatt ggagataagt ctaaaagaga gtcggatgca aagttacatg gtcttaagtt 5160ggcgtacaat tgaagttctt tacggatttt tagtaaacct tgttcaggtc taacactacc 5220ggtaccccat ttaggaccac ccacagcacc taacaaaacg gcatcagcct tcttggaggc 5280ttccagcgcc tcatctggaa gtggaacacc tgtagcatcg atagcagcac caccaattaa 5340atgattttcg aaatcgaact tgacattgga acgaacatca gaaatagctt taagaacctt 5400aatggcttcg gctgtgattt cttgaccaac gtggtcacct ggcaaaacga cgatcttctt 5460aggggcagac attacaatgg tatatccttg aaatatatat aaaaaaaaaa aaaaaaaaaa 5520aaaaaaaaaa atgcagcttc tcaatgatat tcgaatacgc tttgaggaga tacagcctaa 5580tatccgacaa actgttttac agatttacga tcgtacttgt tacccatcat tgaattttga 5640acatccgaac ctgggagttt tccctgaaac agatagtata tttgaacctg tataataata 5700tatagtctag cgctttacgg aagacaatgt atgtatttcg gttcctggag aaactattgc 5760atctattgca taggtaatct tgcacgtcgc atccccggtt cattttctgc gtttccatct 5820tgcacttcaa tagcatatct ttgttaacga agcatctgtg cttcattttg tagaacaaaa 5880atgcaacgcg agagcgctaa tttttcaaac aaagaatctg agctgcattt ttacagaaca 5940gaaatgcaac gcgaaagcgc tattttacca acgaagaatc tgtgcttcat ttttgtaaaa 6000caaaaatgca acgcgagagc gctaattttt caaacaaaga atctgagctg catttttaca 6060gaacagaaat gcaacgcgag agcgctattt taccaacaaa gaatctatac ttcttttttg 6120ttctacaaaa atgcatcccg agagcgctat ttttctaaca aagcatctta gattactttt 6180tttctccttt gtgcgctcta taatgcagtc tcttgataac tttttgcact gtaggtccgt 6240taaggttaga agaaggctac tttggtgtct attttctctt ccataaaaaa agcctgactc 6300cacttcccgc gtttactgat tactagcgaa gctgcgggtg cattttttca agataaaggc 6360atccccgatt atattctata ccgatgtgga ttgcgcatac tttgtgaaca gaaagtgata 6420gcgttgatga ttcttcattg gtcagaaaat tatgaacggt ttcttctatt ttgtctctat 6480atactacgta taggaaatgt ttacattttc gtattgtttt cgattcactc tatgaatagt 6540tcttactaca atttttttgt ctaaagagta atactagaga taaacataaa aaatgtagag 6600gtcgagttta gatgcaagtt caaggagcga aaggtggatg ggtaggttat atagggatat 6660agcacagaga tatatagcaa agagatactt ttgagcaatg tttgtggaag cggtattcgc 6720aatattttag tagctcgtta cagtccggtg cgtttttggt tttttgaaag tgcgtcttca 6780gagcgctttt ggttttcaaa agcgctctga agttcctata ctttctagag aataggaact 6840tcggaatagg aacttcaaag cgtttccgaa aacgagcgct tccgaaaatg caacgcgagc 6900tgcgcacata cagctcactg ttcacgtcgc acctatatct gcgtgttgcc tgtatatata 6960tatacatgag aagaacggca tagtgcgtgt ttatgcttaa atgcgtactt atatgcgtct 7020atttatgtag gatgaaaggt agtctagtac ctcctgtgat attatcccat tccatgcggg 7080gtatcgtatg cttccttcag cactaccctt tagctgttct atatgctgcc actcctcaat 7140tggattagtc tcatccttca atgctatcat ttcctttgat attggatcat atgcatagta 7200ccgagaaact agtgcgaagt agtgatcagg tattgctgtt atctgatgag tatacgttgt 7260cctggccacg gcagaagcac gcttatcgct ccaatttccc acaacattag tcaactccgt 7320taggcccttc attgaaagaa atgaggtcat caaatgtctt ccaatgtgag attttgggcc 7380attttttata gcaaagattg aataaggcgc atttttcttc aaagctttat tgtacgatct 7440gactaagtta tcttttaata attggtattc ctgtttattg cttgaagaat tgccggtcct 7500atttactcgt tttaggactg gttcagaatt cctcaaaaat tcatccaaat atacaagtgg 7560atcgatgata agctgtcaaa catgagaatt cttgaagacg aaagggcctc gtgatacgcc 7620tatttttata ggttaatgtc atgataataa tggtttctta gacgtcaggt ggcacttttc 7680ggggaaatgt gcgcggaacc cctatttgtt tatttttcta aatacattca aatatgtatc 7740cgctcatgag acaataaccc tgataaatgc ttcaataata ttgaaaaagg aagagtatga 7800gtattcaaca tttccgtgtc gcccttattc ccttttttgc ggcattttgc cttcctgttt 7860ttgctcaccc agaaacgctg gtgaaagtaa aagatgctga agatcagttg ggtgcacgag 7920tgggttacat cgaactggat ctcaacagcg gtaagatcct tgagagtttt cgccccgaag 7980aacgttttcc aatgatgagc acttttaaag ttctgctatg tggcgcggta ttatcccgtg 8040ttgacgccgg gcaagagcaa ctcggtcgcc gcatacacta ttctcagaat gacttggttg 8100agtactcacc agtcacagaa aagcatctta cggatggcat gacagtaaga gaattatgca 8160gtgctgccat aaccatgagt gataacactg cggccaactt acttctgaca acgatcggag 8220gaccgaagga gctaaccgct tttttgcaca acatggggga tcatgtaact cgccttgatc 8280gttgggaacc ggagctgaat gaagccatac caaacgacga gcgtgacacc acgatgcctg 8340cagcaatggc aacaacgttg cgcaaactat taactggcga actacttact ctagcttccc 8400ggcaacaatt aatagactgg atggaggcgg ataaagttgc aggaccactt ctgcgctcgg 8460cccttccggc tggctggttt attgctgata aatctggagc cggtgagcgt gggtctcgcg 8520gtatcattgc agcactgggg ccagatggta agccctcccg tatcgtagtt atctacacga 8580cggggagtca ggcaactatg gatgaacgaa atagacagat cgctgagata ggtgcctcac 8640tgattaagca ttggtaactg tcagaccaag tttactcata tatactttag attgatttaa 8700aacttcattt ttaatttaaa aggatctagg tgaagatcct ttttgataat ctcatgacca 8760aaatccctta acgtgagttt tcgttccact gagcgtcaga ccccgtagaa aagatcaaag 8820gatcttcttg agatcctttt tttctgcgcg taatctgctg cttgcaaaca aaaaaaccac 8880cgctaccagc ggtggtttgt ttgccggatc aagagctacc aactcttttt ccgaaggtaa 8940ctggcttcag cagagcgcag ataccaaata ctgtccttct agtgtagccg tagttaggcc 9000accacttcaa gaactctgta gcaccgccta catacctcgc tctgctaatc ctgttaccag 9060tggctgctgc cagtggcgat aagtcgtgtc ttaccgggtt ggactcaaga cgatagttac 9120cggataaggc gcagcggtcg ggctgaacgg ggggttcgtg cacacagccc agcttggagc 9180gaacgaccta caccgaactg agatacctac agcgtgagct atgagaaagc gccacgcttc 9240ccgaagggag aaaggcggac aggtatccgg taagcggcag ggtcggaaca ggagagcgca 9300cgagggagct tccaggggga aacgcctggt atctttatag tcctgtcggg tttcgccacc 9360tctgacttga gcgtcgattt ttgtgatgct cgtcaggggg gcggagccta tggaaaaacg 9420ccagcaacgc ggccttttta cggttcctgg ccttttgctg gccttttgct cacatgttct 9480ttcctgcgtt atcccctgat tctgtggata accgtattac cgcctttgag tgagctgata 9540ccgctcgccg cagccgaacg accgagcgca gcgagtcagt gagcgaggaa gcggaagagc 9600gcctgatgcg gtattttctc cttacgcatc tgtgcggtat ttcacaccgc atatggtgca 9660ctctcagtac aatctgctct gatgccgcat agttaagcca gtatacactc cgctatcgct 9720acgtgactgg gtcatggctg cgccccgaca cccgccaaca cccgctgacg cgccctgacg 9780ggcttgtctg ctcccggcat ccgcttacag acaagctgtg accgtctccg ggagctgcat 9840gtgtcagagg ttttcaccgt catcaccgaa acgcgcgagg cagctgcggt aaagctcatc 9900agcgtggtcg tgaagcgatt cacagatgtc tgcctgttca tccgcgtcca gctcgttgag 9960tttctccaga agcgttaatg tctggcttct gataaagcgg gccatgttaa gggcggtttt 10020ttcctgtttg gtcactgatg cctccgtgta agggggattt ctgttcatgg gggtaatgat 10080accgatgaaa cgagagagga tgctcacgat acgggttact gatgatgaac atgcccggtt 10140actggaacgt tgtgagggta aacaactggc ggtatggatg cggcgggacc agagaaaaat 10200cactcagggt caatgccagc gcttcgttaa tacagatgta ggtgttccac agggtagcca 10260gcagcatcct gcgatgcaga tccggaacat aatggtgcag ggcgctgact tccgcgtttc 10320cagactttac gaaacacgga aaccgaagac cattcatgtt gttgctcagg tcgcagacgt 10380tttgcagcag cagtcgcttc acgttcgctc gcgtatcggt gattcattct gctaaccagt 10440aaggcaaccc cgccagccta gccgggtcct caacgacagg agcacgatca tgcgcacccg 10500tggccaggac ccaacgctgc ccgagatgcg ccgcgtgcgg ctgctggaga tggcggacgc 10560gatggatatg ttctgccaag ggttggtttg cgcattcaca gttctccgca agaattgatt 10620ggctccaatt cttggagtgg tgaatccgtt agcgaggtgc cgccggcttc cattcaggtc 10680gaggtggccc ggctccatgc accgcgacgc aacgcgggga ggcagacaag gtatagggcg 10740gcgcctacaa tccatgccaa cccgttccat gtgctcgccg aggcggcata aatcgccgtg 10800acgatcagcg gtccaatgat cgaagttagg ctggtaagag ccgcgagcga tccttgaagc 10860tgtccctgat ggtcgtcatc tacctgcctg gacagcatgg cctgcaacgc gggcatcccg 10920atgccgccgg aagcgagaag aatcataatg gggaaggcca tccagcctcg cgtcgcgaac 10980gccagcaaga cgtagcccag cgcgtcggcc gccatgccgg cgataatggc ctgcttctcg 11040ccgaaacgtt tggtggcggg accagtgacg aaggcttgag cgagggcgtg caagattccg 11100aataccgcaa gcgacaggcc gatcatcgtc gcgctccagc gaaagcggtc ctcgccgaaa 11160atgacccaga gcgctgccgg cacctgtcct acgagttgca tgataaagaa gacagtcata 11220agtgcggcga cgatagtcat gccccgcgcc caccggaagg agctgactgg gttgaaggct 11280ctcaagggca tcggtcgagg atccttcaat atgcgcacat acgctgttat gttcaaggtc 11340ccttcgttta agaacgaaag cggtcttcct tttgagggat gtttcaagtt gttcaaatct 11400atcaaatttg caaatcccca gtctgtatct agagcgttga atcggtgatg cgatttgtta 11460attaaattga tggtgtcacc attaccaggt ctagatatac caatggcaaa ctgagcacaa 11520caataccagt ccggatcaac tggcaccatc tctcccgtag tctcatctaa tttttcttcc 11580ggatgaggtt ccagatatac cgcaacacct ttattatggt ttccctgagg gaataataga 11640atgtcccatt cgaaatcacc aattctaaac ctgggcgaat tgtatttcgg gtttgttaac 11700tcgttccagt caggaatgtt ccacgtgaag ctatcttcca gcaaagtctc cacttcttca 11760tcaaattgtg gagaatactc ccaatgctct tatctatggg acttccggga aacacagtac 11820cgatacttcc caattcgtct tcagagctca ttgtttgttt gaagagacta atcaaagaat 11880cgttttctca aaaaaattaa tatcttaact gatagtttga tcaaaggggc aaaacgtagg 11940ggcaaacaaa cggaaaaatc gtttctcaaa ttttctgatg ccaagaactc taaccagtct 12000tatctaaaaa ttgccttatg atccgtctct ccggttacag cctgtgtaac tgattaatcc 12060tgcctttcta atcaccattc taatgtttta attaagggat tttgtcttca ttaacggctt 12120tcgctcataa aaatgttatg acgttttgcc cgcaggcggg aaaccatcca cttcacgaga 12180ctgatctcct ctgccggaac accgggcatc tccaacttat aagttggaga aataagagaa 12240tttcagattg agagaatgaa aaaaaaaaac ccttagttca taggtccatt ctcttagcgc 12300aactacagag aacaggggca caaacaggca aaaaacgggc acaacctcaa tggagtgatg 12360caacctgcct ggagtaaatg atgacacaag gcaattgacc cacgcatgta tctatctcat 12420tttcttacac cttctattac cttctgctct ctctgatttg gaaaaagctg aaaaaaaagg 12480ttgaaaccag ttccctgaaa ttattcccct acttgactaa taagtatata aagacggtag 12540gtattgattg taattctgta aatctatttc ttaaacttct taaattctac ttttatagtt 12600agtctttttt ttagttttaa aacaccaaga acttagtttc gaataaacac acataaacaa 12660acaagcttac aaaacaaa atg gct gca tat gca gct cag ggc tat aag gtg 12711Met Ala Ala Tyr Ala Ala Gln Gly Tyr Lys Val1 5 10cta gta ctc aac ccc tct gtt gct gca aca ctg ggc ttt ggt gct tac 12759Leu Val Leu Asn Pro Ser Val Ala Ala Thr Leu Gly Phe Gly Ala Tyr15 20 25atg tcc aag gct cat ggg atc gat cct aac atc agg acc ggg gtg aga 12807Met Ser Lys Ala His Gly Ile Asp Pro Asn Ile Arg Thr Gly Val Arg30 35 40aca att acc act ggc agc ccc atc acg tac tcc acc tac ggc aag ttc 12855Thr Ile Thr Thr Gly Ser Pro Ile Thr Tyr Ser Thr Tyr GIy Lys Phe45 50 55ctt gcc gac ggc ggg tgc tcg ggg ggc gct tat gac ata ata att tgt 12903Leu Ala Asp Gly Gly Cys Ser Gly Gly Ala Tyr Asp Ile Ile Ile Cys60 65 70 75gac gag tgc cac tcc acg gat gcc aca tcc atc ttg ggc att ggc act 12951Asp Glu Cys His Ser Thr Asp Ala Thr Ser Ile Leu Gly Ile Gly Thr80 85 90gtc ctt gac caa gca gag act gcg ggg gcg aga ctg gtt gtg ctc gcc 12999Val Leu Asp Gln Ala Glu Thr Ala Gly Ala Arg Leu Val Val Leu Ala95 100 105acc gcc acc cct ccg ggc tcc gtc act gtg ccc cat ccc aac atc gag 13047Thr Ala Thr Pro Pro Gly Ser Val Thr Val Pro His Pro Asn Ile Glu110 115 120gag gtt gct ctg tcc acc acc gga gag atc cct ttt tac ggc aag gct 13095Glu Val Ala Leu Ser Thr Thr Gly Glu Ile Pro Phe Tyr Gly Lys Ala125 130 135atc ccc ctc gaa gta atc aag ggg ggg aga cat ctc atc ttc tgt cat 13143Ile Pro Leu Glu Val Ile Lys Gly Gly Arg His Leu Ile Phe Cys His140 145 150 155tca aag aag aag tgc gac gaa ctc gcc gca aag ctg gtc gca ttg ggc 13191Ser Lys Lys Lys Cys Asp Glu Leu Ala Ala Lys Leu Val Ala Leu Gly160 165 170atc aat gcc gtg gcc tac tac cgc ggt ctt gac gtg tcc gtc atc ccg 13239Ile Asn Ala Val Ala Tyr Tyr Arg Gly Leu Asp Val Ser Val Ile Pro175 180 185acc agc ggc gat gtt gtc gtc gtg gca acc gat gcc ctc atg acc ggc 13287Thr Ser Gly Asp Val Val Val Val Ala Thr Asp Ala Leu Met Thr Gly190 195 200tat acc ggc gac ttc gac tcg gtg ata gac tgc aat acg tgt gtc acc 13335Tyr Thr Gly Asp Phe Asp Ser Val Ile Asp Cys Asn Thr Cys Val Thr205 210 215cag aca gtc gat ttc agc ctt gac cct acc ttc acc att gag aca atc 13383Gln Thr Val Asp Phe Ser Leu Asp Pro Thr Phe Thr Ile Glu Thr Ile220 225 230 235acg ctc ccc caa gat gct gtc tcc cgc act caa cgt cgg ggc agg act 13431Thr Leu Pro Gln Asp Ala Val Ser Arg Thr Gln Arg Arg Gly Arg Thr240 245 250ggc agg ggg aag cca ggc atc tac aga ttt gtg gca ccg ggg gag cgc 13479Gly Arg Gly Lys Pro Gly Ile Tyr Arg Phe Val Ala Pro Gly Glu Arg255 260 265ccc tcc ggc atg ttc gac tcg tcc gtc ctc tgt gag tgc tat gac gca 13527Pro Ser Gly Met Phe Asp Ser Ser Val Leu Cys Glu Cys Tyr Asp Ala270 275 280ggc tgt gct tgg tat gag ctc acg ccc gcc gag act aca gtt agg cta 13575Gly Cys Ala Trp Tyr Glu Leu Thr Pro Ala Glu Thr Thr Val Arg Leu285 290 295cga gcg tac atg aac acc ccg ggg ctt ccc gtg tgc cag gac cat ctt 13623Arg Ala Tyr Met Asn Thr Pro Gly Leu Pro Val Cys Gln Asp His Leu300 305 310 315gaa ttt tgg gag ggc gtc ttt aca ggc ctc act cat ata gat gcc cac 13671Glu Phe Trp Glu Gly Val Phe Thr Gly Leu Thr His Ile Asp Ala His320 325 330ttt cta tcc cag aca aag cag agt ggg gag aac ctt cct tac ctg gta 13719Phe Leu Ser Gln Thr Lys Gln Ser Gly Glu Asn Leu Pro Tyr Leu Val335 340 345gcg tac caa gcc acc gtg tgc gct agg gct caa gcc cct ccc cca tcg 13767Ala Tyr Gln Ala Thr Val Cys Ala Arg Ala Gln Ala Pro Pro Pro Ser350 355 360tgg gac cag atg tgg aag tgt ttg att cgc ctc aag ccc acc ctc cat 13815Trp Asp Gln Met Trp Lys Cys Leu Ile Arg Leu Lys Pro Thr Leu His365 370 375ggg cca aca ccc ctg cta tac aga ctg ggc gct gtt cag aat gaa atc 13863Gly Pro Thr Pro Leu Leu Tyr Arg Leu Gly Ala Val Gln Asn Glu Ile380 385 390 395acc ctg acg cac cca gtc acc aaa tac atc atg aca tgc atg tcg gcc 13911Thr Leu Thr His Pro Val Thr Lys Tyr Ile Met Thr Cys Met Ser Ala400 405 410gac ctg gag gtc gtc acg agc acc tgg gtg ctc gtt ggc ggc gtc ctg 13959Asp Leu Glu Val Val Thr Ser Thr Trp Val Leu Val Gly Gly Val Leu415 420 425gct gct ttg gcc gcg tat tgc ctg tca aca ggc tgc gtg gtc ata gtg 14007Ala Ala Leu Ala Ala Tyr Cys Leu Ser Thr Gly Cys Val Val Ile Val430 435 440ggc agg gtc gtc ttg tcc ggg aag ccg gca atc ata cct gac agg gaa 14055Gly Arg Val Val Leu Ser Gly Lys Pro Ala Ile Ile Pro Asp Arg Glu445 450 455gtc ctc tac cga gag ttc gat gag atg gaa gag tgc tct cag cac tta 14103Val Leu Tyr Arg Glu Phe Asp Glu Met Glu Glu Cys Ser Gln His Leu460 465 470 475ccg tac atc gag caa ggg atg atg ctc gcc gag cag ttc aag cag aag 14151Pro Tyr Ile Glu Gln Gly Met Met Leu Ala Glu Gln Phe Lys Gln Lys480 485 490gcc ctc ggc ctc ctg cag acc gcg tcc cgt cag gca gag gtt atc gcc 14199Ala Leu Gly Leu Leu Gln Thr Ala Ser Arg Gln Ala Glu Val Ile Ala495 500 505cct gct gtc cag acc aac tgg caa aaa ctc gag acc ttc tgg gcg aag 14247Pro Ala Val Gln Thr Asn Trp Gln Lys Leu Glu Thr Phe Trp Ala Lys510 515 520cat atg tgg aac ttc atc agt ggg ata caa tac ttg gcg ggc ttg tca 14295His Met Trp Asn Phe Ile Ser Gly Ile Gln Tyr Leu Ala Gly Leu Ser525 530 535acg ctg cct ggt aac ccc gcc att gct tca ttg atg gct ttt aca gct 14343Thr Leu Pro Gly Asn Pro Ala Ile Ala Ser Leu Met Ala Phe Thr Ala540 545 550 555gct gtc acc agc cca cta acc act agc caa acc ctc ctc ttc aac ata 14391Ala Val Thr Ser Pro Leu Thr Thr Ser Gln Thr Leu Leu Phe Asn Ile560 565 570ttg ggg ggg tgg gtg gct gcc cag ctc gcc gcc ccc ggt gcc gct act 14439Leu Gly Gly Trp Val Ala Ala Gln Leu Ala Ala Pro Gly Ala Ala Thr575 580 585gcc ttt gtg ggc gct ggc tta gct ggc gcc gcc atc ggc agt gtt gga 14487Ala Phe Val Gly Ala Gly Leu Ala Gly Ala Ala Ile Gly Ser Val Gly590 595 600ctg ggg aag gtc ctc ata gac atc ctt gca ggg tat ggc gcg ggc gtg 14535Leu Gly Lys Val Leu Ile Asp Ile Leu Ala Gly Tyr Gly Ala Gly Val605 610 615gcg gga gct ctt gtg gca ttc aag atc atg agc ggt gag gtc ccc tcc 14583Ala Gly Ala Leu Val Ala Phe Lys Ile Met Ser Gly Glu Val Pro Ser620 625 630 635acg gag gac ctg gtc aat cta ctg ccc gcc atc ctc tcg ccc gga gcc 14631Thr Glu Asp Leu Val Asn Leu Leu Pro Ala Ile Leu Ser Pro Gly Ala640 645 650ctc gta gtc ggc gtg gtc tgt gca gca ata ctg cgc cgg cac gtt ggc 14679Leu Val Val Gly Val Val Cys Ala Ala Ile Leu Arg Arg His Val Gly655 660 665ccg ggc gag ggg gca gtg cag tgg atg aac cgg ctg ata gcc ttc gcc 14727Pro Gly Glu Gly Ala Val Gln Trp Met Asn Arg Leu Ile Ala Phe Ala670 675 680tcc cgg ggg aac cat gtt tcc ccc acg cac tac gtg ccg gag agc gat 14775Ser Arg Gly Asn His Val Ser Pro Thr His Tyr Val Pro Glu Ser Asp685 690 695gca gct gcc cgc gtc act gcc ata ctc agc agc ctc act gta acc cag 14823Ala Ala Ala Arg Val Thr Ala Ile Leu Ser Ser Leu Thr Val Thr Gln700 705 710 715ctc ctg agg cga ctg cac cag tgg ata agc tcg gag tgt acc act cca 14871Leu Leu Arg Arg Leu His Gln Trp Ile Ser Ser Glu Cys Thr Thr Pro720 725 730tgc tcc ggt tcc tgg cta agg gac atc tgg gac tgg ata tgc gag gtg 14919Cys Ser Gly Ser Trp Leu Arg Asp Ile Trp Asp Trp Ile Cys Glu Val735 740 745ttg agc gac ttt aag acc tgg cta aaa gct aag ctc atg cca cag ctg 14967Leu Ser Asp Phe Lys Thr Trp Leu Lys Ala Lys Leu Met Pro Gln Leu750 755 760cct ggg atc ccc ttt gtg tcc tgc cag cgc ggg tat aag ggg gtc tgg 15015Pro Gly Ile Pro Phe Val Ser Cys Gln Arg Gly Tyr Lys Gly Val Trp765 770 775cga ggg gac ggc atc atg cac act cgc tgc cac tgt gga gct gag atc 15063Arg Gly Asp Gly Ile Met His Thr Arg Cys His Cys Gly Ala Glu Ile780 785 790 795act gga cat gtc aaa aac ggg acg atg agg atc gtc ggt cct agg acc 15111Thr Gly His Val Lys Asn Gly Thr Met Arg Ile Val Gly Pro Arg Thr800 805 810tgc agg aac atg tgg agt ggg acc ttc ccc att aat gcc tac acc acg 15159Cys Arg Asn Met Trp Ser Gly Thr Phe Pro Ile Asn Ala Tyr Thr Thr815 820 825ggc ccc tgt acc ccc ctt cct gcg ccg aac tac acg ttc gcg cta tgg 15207Gly Pro Cys Thr Pro Leu Pro Ala Pro Asn Tyr Thr Phe Ala Leu Trp830 835 840agg gtg tct gca gag gaa tac gtg gag ata agg cag gtg ggg gac ttc 15255Arg Val Ser Ala Glu Glu Tyr Val Glu Ile Arg Gln Val Gly Asp Phe845 850 855cac tac gtg acg ggt atg act act gac aat ctt aaa tgc ccg tgc cag 15303His Tyr Val Thr Gly Met Thr Thr Asp Asn Leu Lys Cys Pro Cys Gln860 865 870 875gtc cca tcg ccc gaa ttt ttc aca gaa ttg gac ggg gtg cgc cta cat 15351Val Pro Ser Pro Glu Phe Phe Thr Glu Leu Asp Gly Val Arg Leu His880 885 890agg ttt gcg ccc ccc tgc aag ccc ttg ctg cgg gag gag gta tca ttc 15399Arg Phe Ala Pro Pro Cys Lys Pro Leu Leu Arg Glu Glu Val Ser Phe895 900 905aga gta gga ctc cac gaa tac ccg gta ggg tcg caa tta cct tgc gag 15447Arg Val Gly Leu His Glu Tyr Pro Val Gly Ser Gln Leu Pro Cys Glu910 915 920ccc gaa ccg gac gtg gcc gtg ttg acg tcc atg ctc act gat ccc tcc 15495Pro Glu Pro Asp Val Ala Val Leu Thr Ser Met Leu Thr Asp Pro Ser925 930 935cat ata aca gca gag gcg gcc ggg cga agg ttg gcg agg gga tca ccc 15543His Ile Thr Ala Glu Ala Ala Gly Arg Arg Leu Ala Arg Gly Ser Pro940 945 950 955ccc tct gtg gcc agc tcc tcg gct agc cag cta tcc gct cca tct ctc 15591Pro Ser Val Ala Ser Ser Ser Ala Ser Gln Leu Ser Ala Pro Ser Leu960 965 970aag gca act tgc acc gct aac cat gac tcc cct gat gct gag ctc ata 15639Lys Ala Thr Cys Thr Ala Asn His Asp Ser Pro Asp Ala Glu Leu Ile975 980 985gag gcc aac ctc cta tgg agg cag gag atg ggc ggc aac atc acc agg 15687Glu Ala Asn Leu Leu Trp Arg Gln Glu Met Gly Gly Asn Ile Thr Arg990 9951000gtt gag tca gaa aac aaa gtg gtg att ctg gac tcc ttc gat ccg ctt 15735Val Glu Ser Glu Asn Lys Val Val Ile Leu Asp Ser Phe Asp Pro Leu100510101015gtg gcg gag gag gac gag cgg gag atc tcc gta ccc gca gaa atc ctg 15783Val Ala Glu Glu Asp Glu Arg Glu Ile Ser Val Pro Ala Glu Ile Leu1020 102510301035cgg aag tct cgg aga ttc gcc cag gcc ctg ccc gtt tgg gcg cgg ccg 15831Arg Lys Ser Arg Arg Phe Ala Gln Ala Leu Pro Val Trp Ala Arg Pro104010451050gac tat aac ccc ccg cta gtg gag acg tgg aaa aag ccc gac tac gaa 15879Asp Tyr Asn Pro Pro Leu Val Glu Thr Trp Lys Lys Pro Asp Tyr Glu105510601065cca cct gtg gtc cat ggc tgc ccg ctt cca cct cca aag tcc cct cct 15927Pro Pro Val Val His Gly Cys Pro Leu Pro Pro Pro Lys Ser Pro Pro107010751080gtg cct ccg cct cgg aag aag cgg acg gtg gtc ctc act gaa tca acc 15975Val Pro Pro Pro Arg Lys Lys Arg Thr Val Val Leu Thr Glu Ser Thr108510901095cta tct act gcc ttg gcc gag ctc gcc acc aga agc ttt ggc agc tcc 16023Leu Ser Thr Ala Leu Ala Glu Leu Ala Thr Arg Ser Phe Gly Ser Ser1100 110511101115tca act tcc ggc att acg ggc gac aat acg aca aca tcc tct gag ccc 16071Ser Thr Ser Gly Ile Thr Gly Asp Asn Thr Thr Thr Ser Ser Glu Pro112011251130gcc cct tct ggc tgc ccc ccc gac tcc gac gct gag tcc tat tcc tcc 16119Ala Pro Ser Gly Cys Pro Pro Asp Ser Asp Ala Glu Ser Tyr Ser Ser11351140 1145atg ccc ccc ctg gag ggg gag cct ggg gat ccg gat ctt agc gac ggg 16167Met Pro Pro Leu Glu Gly Glu Pro Gly Asp Pro Asp Leu Ser Asp Gly1150 11551160tca tgg tca acg gtc agt agt gag gcc aac gcg gag gat gtc gtg tgc 16215Ser Trp Ser Thr Val Ser Ser Glu Ala Asn Ala Glu Asp Val Val Cys116511701175tgc tca atg tct tac tct tgg aca ggc gca ctc gtc acc ccg tgc gcc 16263Cys Ser Met Ser Tyr Ser Trp Thr Gly Ala Leu Val Thr Pro Cys Ala1180 1185 1190 1195gcg gaa gaa cag aaa ctg ccc atc aat gca cta agc aac tcg ttg cta 16311Ala Glu Glu Gln Lys Leu Pro Ile Asn Ala Leu Ser Asn Ser Leu Leu120012051210cgt cac cac aat ttg gtg tat tcc acc acc tca cgc agt gct tgc caa 16359Arg His His Asn Leu Val Tyr Ser Thr Thr Ser Arg Ser Ala Cys Gln121512201225agg cag aag aaa gtc aca ttt gac aga ctg caa gtt ctg gac agc cat 16407Arg Gln Lys Lys Val Thr Phe Asp Arg Leu Gln Val Leu Asp Ser His123012351240tac cag gac gta ctc aag gag gtt aaa gca gcg gcg tca aaa gtg aag 16455Tyr Gln Asp Val Leu Lys Glu Val Lys Ala Ala Ala Ser Lys Val Lys124512501255gct aac ttg cta tcc gta gag gaa gct tgc agc ctg acg ccc cca cac 16503Ala Asn Leu Leu Ser Val Glu Glu Ala Cys Ser Leu Thr Pro Pro His1260 126512701275tca gcc aaa tcc aag ttt ggt tat ggg gca aaa gac gtc cgt tgc cat 16551Ser Ala Lys Ser Lys Phe Gly Tyr Gly Ala Lys Asp Val Arg Cys His128012851290gcc aga aag gcc gta acc cac atc aac tcc gtg tgg aaa gac ctt ctg 16599Ala Arg Lys Ala Val Thr His Ile Asn Ser Val Trp Lys Asp Leu Leu129513001305gaa gac aat gta aca cca ata gac act acc atc atg gct aag aac gag 16647Glu Asp Asn Val Thr Pro Ile Asp Thr Thr Ile Met Ala Lys Asn Glu131013151320gtt ttc tgc gtt cag cct gag aag ggg ggt cgt aag cca gct cgt ctc 16695Val Phe Cys Val Gln Pro Glu Lys Gly Gly Arg Lys Pro Ala Arg Leu132513301335atc gtg ttc ccc gat ctg ggc gtg cgc gtg tgc gaa aag atg gct ttg 16743Ile Val Phe Pro Asp Leu Gly Val Arg Val Cys Glu Lys Met Ala Leu1340 134513501355tac gac gtg gtt aca aag ctc ccc ttg gcc gtg atg gga agc tcc tac 16791Tyr Asp Val Val Thr Lys Leu Pro Leu Ala Val Met Gly Ser Ser Tyr
136013651370gga ttc caa tac tca cca gga cag cgg gtt gaa ttc ctc gtg caa gcg 16839Gly Phe Gln Tyr Ser Pro Gly Gln Arg Val Glu Phe Leu Val Gln Ala137513801385tgg aag tcc aag aaa acc cea atg ggg ttc tcg tat gat acc cgc tgc 16887Trp Lys Ser Lys Lys Thr Pro Met Gly Phe Ser Tyr Asp Thr Arg Cys139013951400ttt gac tcc aca gtc act gag agc gac atc cgt acg gag gag gca atc 16935Phe Asp Ser Thr Val Thr Glu Ser Asp Ile Arg Thr Glu Glu Ala Ile140514101415tac caa tgt tgt gac ctc gac ccc caa gcc cgc gtg gcc ate aag tcc 16983Tyr Gln Cys Cys Asp Leu Asp Pro Gln Ala Arg Val Ala Ile Lys Ser1420 142514301435ctc acc gag agg ctt tat gtt ggg ggc cct ctt acc aat tca agg ggg 17031Leu Thr Glu Arg Leu Tyr Val Gly Gly Pro Leu Thr Asn Ser Arg Gly144014451450gag aac tgc ggc tat cgc agg tgc cgc gcg agc ggc gta ctg aca act 17079Glu Asn Cys Gly Tyr Arg Arg Cys Arg Ala Ser Gly Val Leu Thr Thr145514601465agc tgt ggt aac acc ctc act tgc tac atc aag gcc cgg gca gcc tgt 17127Ser Cys Gly Asn Thr Leu Thr Cys Tyr Ile Lys Ala Arg Ala Ala Cys147014751480cga gcc gca ggg ctc cag gac tgc acc atg ctc gtg tgt ggc gac gac 17175Arg Ala Ala Gly Leu Gln Asp Cys Thr Met Leu Val Cys Gly Asp Asp148514901495tta gtc gtt atc tgt gaa agc gcg ggg gtc cag gag gac gcg gcg agc 17223Leu Val Val Ile Cys Glu Ser Ala Gly Val Gln Glu Asp Ala Ala Ser1500 150515101515ctg aga gcc ttc acg gag gct atg acc agg tac tcc gcc ccc cct ggg 17271Leu Arg Ala Phe Thr Glu Ala Met Thr Arg Tyr Ser Ala Pro Pro Gly152015251530gac ccc cca caa cca gaa tac gac ttg gag ctc ata aca tca tgc tcc 17319Asp Pro Pro Gln Pro Glu Tyr Asp Leu Glu Leu Ile Thr Ser Cys Ser153515401545tcc aac gtg tca gtc gcc cac gac ggc gct gga aag agg gtc tac tac 17367Ser Asn Val Ser Val Ala His Asp Gly Ala Gly Lys Arg Val Tyr Tyr155015551560ctc acc cgt gac cct aca acc ccc ctc gcg aga gct gcg tgg gag aca 17415Leu Thr Arg Asp Pro Thr Thr Pro Leu Ala Arg Ala Ala Trp Glu Thr156515701575gca aga cac act cca gtc aat tcc tgg cta ggc aac ata atc atg ttt 17463Ala Arg His Thr Pro Val Asn Ser Trp Leu Gly Asn Ile Ile Met Phe1580 158515901595gcc ccc aca ctg tgg gcg agg atg ata ctg atg acc cat ttc ttt agc 17511Ala Pro Thr Leu Trp Ala Arg Met Ile Leu Met Thr His Phe Phe Ser160016051610gtc ctt ata gcc agg gac cag ctt gaa cag gcc ctc gat tgc gag atc 17559Val Leu Ile Ala Arg Asp Gln Leu Glu Gln Ala Leu Asp Cys Glu Ile161516201625tac ggg gcc tgc tac tcc ata gaa cca ctg gat cta cct cca atc att 17607Tyr Gly Ala Cys Tyr Ser Ile Glu Pro Leu Asp Leu Pro Pro Ile Ile163016351640caa aga ctc cat ggc ctc agc gca ttt tca ctc cac agt tac tct cca 17655Gln Arg Leu His Gly Leu Ser Ala Phe Ser Leu His Ser Tyr Ser Pro164516501655ggt gaa atc aat agg gtg gcc gca tgc ctc aga aaa ctt ggg gta ccg 17703Gly Glu Ile Asn Arg Val Ala Ala Cys Leu Arg Lys Leu Gly Val Pro1660 166516701675ccc ttg cga gct tgg aga cac cgg gcc cgg agc gtc cgc gct agg ctt 17751Pro Leu Arg Ala Trp Arg His Arg Ala Arg Ser Val Arg Ala Arg Leu168016851690ctg gcc aga gga ggc agg gct gcc ata tgt ggc aag tac ctc ttc aac 17799Leu Ala Arg Gly Gly Arg Ala Ala Ile Cys Gly Lys Tyr Leu Phe Asn169517001705tgg gca gta aga aca aag ctc aaa ctc act cca ata gcg gcc gct ggc 17847Trp Ala Val Arg Thr Lys Leu Lys Leu Thr Pro Ile Ala Ala Ala Gly171017151720cag ctg gac ttg tcc ggc tgg ttc acg gct ggc tac agc ggg gga gac 17895Gln Leu Asp Leu Ser Gly Trp Phe Thr Ala Gly Tyr Ser Gly Gly Asp172517301735att tat cac agc gtg tct cat gcc cgg ccc cgc tgg atc tgg ttt tgc 17943Ile Tyr His Ser Val Ser His Ala Arg Pro Arg Trp Ile Trp Phe Cys1740 174517501755cta ctc ctg ctt gct gca ggg gta ggc atc tac ctc ctc ccc aac cga 17991Leu Leu Leu Leu Ala Ala Gly Val Gly Ile Tyr Leu Leu Pro Asn Arg176017651770atg agc acg aat cct aaa cct caa aga aag acc aaa cgt aac acc aac 18039Met Ser Thr Asn Pro Lys Pro Gln Arg Lys Thr Lys Arg Asn Thr Asn177517801785cgg cgg ccg cag gac gtc aag ttc ccg ggt ggc ggt cag atc gtt ggt 18087Arg Arg Pro Gln Asp Val Lys Phe Pro Gly Gly Gly Gln Ile Val Gly179017951800gga gtt tac ttg ttg ccg cgc agg ggc cct aga ttg ggt gtg cgc gcg 18135Gly Val Tyr Leu Leu Pro Arg Arg Gly Pro Arg Leu Gly Val Arg Ala180518101815acg aga aag act tcc gag cgg tcg caa cct cga ggt aga cgt cag cct 18183Thr Arg Lys Thr Ser Glu Arg Ser Gln Pro Arg Gly Arg Arg Gln Pro1820 182518301835atc ccc aag gct cgt cgg ccc gag ggc agg acc tgg gct cag ccc ggg 18231Ile Pro Lys Ala Arg Arg Pro Glu Gly Arg Thr Trp Ala Gln Pro Gly184018451850tac cct tgg ccc ctc tat ggc aat gag ggc tgc ggg tgg gcg gga tgg 18279Tyr Pro Trp Pro Leu Tyr Gly Asn Glu Gly Cys Gly Trp Ala Gly Trp185518601865ctc ctg tct ccc cgt ggc tct cgg cct agc tgg ggc ccc aca gac ccc 18327Leu Leu Ser Pro Arg Gly Ser Arg Pro Ser Trp Gly Pro Thr Asp Pro187018751880cgg cgt agg tcg cgc aat ttg ggt aag gtc atc gat acc ctt acg tgc 18375Arg Arg Arg Ser Arg Asn Leu Gly Lys Val Ile Asp Thr Leu Thr Cys188518901895ggc ttc gcc gac ctc atg ggg tac ata ccg ctc gtc ggc gcc cct ctt 18423Gly Phe Ala Asp Leu Met Gly Tyr Ile Pro Leu Val Gly Ala Pro Leu1900 190519101915gga ggc gct gcc agg gcc ctg gcg cat ggc gtc cgg gtt ctg gaa gac 18471Gly Gly Ala Ala Arg Ala Leu Ala His Gly Val Arg Val Leu Glu Asp192019251930ggc gtg aac tat gca aca ggg aac ctt cct ggt tgc tct taatagtcga18520Gly Val Asn Tyr Ala Thr Gly Asn Leu Pro Gly Cys Ser19351940ctttgttccc actgtacttt tagctcgtac aaaatacaat atacttttca tttctccgta 18580aacaacatgt tttcccatgt aatatccttt tctatttttc gttccgttac caactttaca 18640catactttat atagctattc acttctatac actaaaaaac taagacaatt ttaattttgc 18700tgcctgccatatttcaattt gttataaatt cctataattt atcctattag tagctaaaaa 18760aagatgaatg tgaatcgaat cctaagagaa ttggatctga tccacaggac gggtgtggtc 18820gccatgatcg cgtagtcgat agtggctcca agtagcgaag cgagcaggac tgggcggcgg 18880ccaaagcggt cggacagtgc tccgagaacg ggtgcgcata gaaattgcat caacgcatat 18940agcgctagca gcacgccata gtgactggcg atgctgtcgg aatggacgat atcccgcaag 19000aggcccggca gtaccggcat aaccaagcct atgcctacag catccagggt gacggtgccg 19060aggatgacga tgagcgcatt gttagatttc atacacggtg cctgactgcg ttagcaattt 19120aactgtgata aactaccgca ttaaagcttt ttctttccaa tttttttttt ttcgtcatta 19180taaaaatcat tacgaccgag attcccgggt aataactgat ataattaaat tgaagctcta 19240atttgtgagt ttagtataca tgcatttact tataatacag ttttttagtt ttgctggccg 19300catcttctca aatatgcttc ccagcctgct tttctgtaac gttcaccctc taccttagca 19360tcccttccct ttgcaaatag tcctcttcca acaataataa tgtcagatcc tgtagagacc 19420acatcatcca cggttctata ctgttgaccc aatgcgtctc ccttgtcatc taaacccaca 19480ccgggtgtca taatcaacca atcgtaacct tcatctcttc cacccatgtc tctttgagca 19540ataaagccga taacaaaatc tttgtcgctc ttcgcaatgt caacagtacc cttagtatat 19600tctccagtag atagggagcc cttgcatgac aattctgcta acatcaaaag gcctctaggt 19660tcctttgtta cttcttctgc cgcctgcttc aaaccgctaa caatacctgg gcccaccaca 19720ccgtgtgcat tcgtaatgtc tgcccattct gctattctgt atacacccgc agagtactgc 19780aatttgactg tattaccaat gtcagcaaat tttctgtctt cgaagagtaa aaaattgtac 19840ttggcggata atgcctttag cggcttaact gtgccctcca tggaaaaatc agtcaagata 19900tccacatgtg tttttagtaa acaaattttg ggacctaatg cttcaactaa ctccagtaat 19960tccttggtgg tacgaacatc caatgaagca cacaagtttg tttgcttttc gtgcatgata 20020ttaaatagct tggcagcaac aggactagga tgagtagcag cacgttcctt atatgtagct 20080ttcgacatga tttatcttcg tttcctgcag gtttttgttc tgtgcagttg ggttaagaat 20140actgggcaat ttcatgtttc ttcaacacta catatgcgta tatataccaa tctaagtctg 20200tgctccttcc ttcgttcttc cttctgttcg gagattaccg aatcaaaaaa atttcaagga 20260aaccgaaatc aaaaaaaaga ataaaaaaaa aatgatgaat tgaaaagctt atcgat 20316210152111944212PRT213人工序列220223人工序列的描述pd.delta.NS3NS5.pj.core17340015Met Ala Ala Tyr Ala Ala Gln Gly Tyr Lys Val Leu Val Leu Asn Pro1 5 10 15Ser Val Ala Ala Thr Leu Gly Phe Gly Ala Tyr Met Ser Lys Ala His20 25 30Gly Ile Asp Pro Asn Ile Arg Thr Gly Val Arg Thr Ile Thr Thr Gly35 40 45Ser Pro Ile Thr Tyr Ser Thr Tyr Gly Lys Phe Leu Ala Asp Gly Gly50 55 60Cys Ser Gly Gly Ala Tyr Asp Ile Ile Ile Cys Asp Glu Cys His Ser65 70 75 80Thr Asp Ala Thr Ser Ile Leu Gly Ile Gly Thr Val Leu Asp Gln Ala85 90 95Glu Thr Ala Gly Ala Arg Leu Val Val Leu Ala Thr Ala Thr Pro Pro100 105 110Gly Ser Val Thr Val Pro His Pro Asn Ile Glu Glu Val Ala Leu Ser115 120 125Thr Thr Gly Glu Ile Pro Phe Tyr Gly Lys Ala Ile Pro Leu Glu Val130 135 140Ile Lys Gly Gly Arg His Leu Ile Phe Cys His Ser Lys Lys Lys Cys145 150 155 160Asp Glu Leu Ala Ala Lys Leu Val Ala Leu Gly Ile Asn Ala Val Ala165 170 175Tyr Tyr Arg Gly Leu Asp Val Ser Val Ile Pro Thr Ser Gly Asp Val180 185 190Val Val Val Ala Thr Asp Ala Leu Met Thr Gly Tyr Thr Gly Asp Phe195 200 205Asp Ser Val Ile Asp Cys Asn Thr Cys Val Thr Gln Thr Val Asp Phe210 215 220Ser Leu Asp Pro Thr Phe Thr Ile Glu Thr Ile Thr Leu Pro Gln Asp225 230 235 240Ala Val Ser Arg Thr Gln Arg Arg Gly Arg Thr Gly Arg Gly Lys Pro245 250 255Gly Ile Tyr Arg Phe Val Ala Pro Gly Glu Arg Pro Ser Gly Met Phe260 265 270Asp Ser Ser Val Leu Cys Clu Cys Tyr Asp Ala Gly Cys Ala Trp Tyr275 280 285Glu Leu Thr Pro Ala Glu Thr Thr Val Arg Leu Arg Ala Tyr Met Asn290 295 300Thr Pro Gly Leu Pro Val Cys Gln Asp His Leu Glu Phe Trp Glu Gly305 310 315 320Val Phe Thr Gly Leu Thr His Ile Asp Ala His Phe Leu Ser Gln Thr325 330 335Lys Gln Ser Gly Glu Asn Leu Pro Tyr Leu Val Ala Tyr Gln Ala Thr340 345 350Val Cys Ala Arg Ala Gln Ala Pro Pro Pro Ser Trp Asp Gln Met Trp355 360 365Lys Cys Leu Ile Arg Leu Lys Pro Thr Leu His Gly Pro Thr Pro Leu370 375 380Leu Tyr Arg Leu Gly Ala Val Gln Asn Glu Ile Thr Leu Thr His Pro385 390 395 400Val Thr Lys Tyr Ile Met Thr Cys Met Ser Ala Asp Leu Glu Val Val405 410 415Thr Ser Thr Trp Val Leu Val Gly Gly Val Leu Ala Ala Leu Ala Ala420 425 430Tyr Cys Leu Ser Thr Gly Cys Val Val Ile Val Gly Arg Val Val Leu435 440 445Ser Gly Lys Pro Ala Ile Ile Pro Asp Arg Glu Val Leu Tyr Arg Glu450 455 460Phe Asp Glu Met Glu Glu Cys Ser Gln His Leu Pro Tyr Ile Glu Gln465 470 475 480Gly Met Met Leu Ala Glu Gln Phe Lys Gln Lys Ala Leu Gly Leu Leu485 490 495Gln Thr Ala Ser Arg Gln Ala Glu Val Ile Ala Pro Ala Val Gln Thr500 505 510Asn Trp Gln Lys Leu Glu Thr Phe Trp Ala Lys His Met Trp Asn Phe515 520 525Ile Ser Gly Ile Gln Tyr Leu Ala Gly Leu Ser Thr Leu Pro Gly Asn530 535 540Pro Ala Ile Ala Ser Leu Met Ala Phe Thr Ala Ala Val Thr Ser Pro545 550 555 560Leu Thr Thr Ser Gln Thr Leu Leu Phe Asn Ile Leu Gly Gly Trp Val565 570 575Ala Ala Gln Leu Ala Ala Pro Gly Ala Ala Thr Ala Phe Val Gly Ala580 585 590Gly Leu Ala Gly Ala Ala Ile Gly Ser Val Gly Leu Gly Lys Val Leu595 600 605Ile Asp Ile Leu Ala Gly Tyr Gly Ala Gly Val Ala Gly Ala Leu Val610 615 620Ala Phe Lys Ile Met Ser Gly Glu Val Pro Ser Thr Glu Asp Leu Val625 630 635 640Asn Leu Leu Pro Ala Ile Leu Ser Pro Gly Ala Leu Val Val Gly Val645 650 655Val Cys Ala Ala Ile Leu Arg Arg His Val Gly Pro Gly Glu Gly Ala660 665 670Val Gln Trp Met Asn Arg Leu Ile Ala Phe Ala Ser Arg Gly Asn His675 680 685Val Ser Pro Thr His Tyr Val Pro Glu Ser Asp Ala Ala Ala Arg Val690 695 700Thr Ala Ile Leu Ser Ser Leu Thr Val Thr Gln Leu Leu Arg Arg Leu705 710 715 720His Gln Trp Ile Ser Ser Glu Cys Thr Thr Pro Cys Ser Gly Ser Trp725 730 735Leu Arg Asp Ile Trp Asp Trp Ile Cys Glu Val Leu Ser Asp Phe Lys740 745 750Thr Trp Leu Lys Ala Lys Leu Met Pro Gln Leu Pro Gly Ile Pro Phe755 760 765Val Ser Cys Gln Arg Gly Tyr Lys Gly Val Trp Arg Gly Asp Gly Ile770 775 780Met His Thr Arg Cys His Cys Gly Ala Glu Ile Thr Gly His Val Lys785 790 795 800Asn Gly Thr Met Arg Ile Val Gly Pro Arg Thr Cys Arg Asn Met Trp805 810 815Ser Gly Thr Phe Pro Ile Asn Ala Tyr Thr Thr Gly Pro Cys Thr Pro820 825 830Leu Pro Ala Pro Asn Tyr Thr Phe Ala Leu Trp Arg Val Ser Ala Glu835 840 845Glu Tyr Val Glu Ile Arg Gln Val Gly Asp Phe His Tyr Val Thr Gly850 855 860Met Thr Thr Asp Asn Leu Lys Cys Pro Cys Gln Val Pro Ser Pro Glu865 870 875 880Phe Phe Thr Glu Leu Asp Gly Val Arg Leu His Arg Phe Ala Pro Pro885 890 895Cys Lys Pro Leu Leu Arg Glu Glu Val Ser Phe Arg Val Gly Leu His900 905 910Glu Tyr Pro Val Gly Ser Gln Leu Pro Cys Glu Pro Glu Pro Asp Val915 920 925Ala Val Leu Thr Ser Met Leu Thr Asp Pro Ser His Ile Thr Ala Glu930 935 940Ala Ala Gly Arg Arg Leu Ala Arg Gly Ser Pro Pro Ser Val Ala Ser945 950 955 960Ser Ser Ala Ser Gln Leu Ser Ala Pro Ser Leu Lys Ala Thr Cys Thr965 970 975Ala Asn His Asp Ser Pro Asp Ala Glu Leu Ile Glu Ala Asn Leu Leu980 985 990Trp Arg Gln Glu Met Gly Gly Asn Ile Thr Arg Val Glu Ser Glu Asn99510001005Lys Val Val Ile Leu Asp Ser Phe Asp Pro Leu Val Ala Glu Glu ASp101010151020Glu Arg Glu Ile Ser Val Pro Ala Glu Ile Leu Arg Lys Ser Arg Arg025103010351040Phe Ala Gln Ala Leu Pro Val Trp Ala Arg Pro Asp Tyr Asn Pro Pro104510501055Leu Val Glu Thr Trp Lys Lys Pro Asp Tyr Glu Pro Pro Val Val His106010651070Gly Cys Pro Leu Pro Pro Pro Lys Ser Pro Pro Val Pro Pro Pro Arg107510801085Lys Lys Arg Thr Val Val Leu Thr Glu Ser Thr Leu Ser Thr Ala Leu109010951100Ala Glu Leu Ala Thr Arg Ser Phe Gly Ser Ser Ser Thr Ser Gly Ile105111011151120Thr Gly Asp Asn Thr Thr Thr Ser Ser Glu Pro Ala Pro Ser Gly Cys112511301135Pro Pro Asp Ser Asp Ala Glu Ser Tyr Ser Ser Met Pro Pro Leu Glu114011451150Gly Glu Pro Gly Asp Pro Asp Leu Ser Asp Gly Ser Trp Ser Thr Val115511601165Ser Ser Glu Ala Asn Ala Glu Asp Val Val Cys Cys Ser Met Ser Tyr117011751180Ser Trp Thr Gly Ala Leu Val Thr Pro Cys Ala Ala Glu Glu Gln Lys185119011951200Leu Pro Ile Asn Ala Leu Ser Asn Ser Leu Leu Arg His His Asn Leu120512101215Val Tyr Ser Thr Thr Ser Arg Ser Ala Cys Gln Arg Gln Lys Lys Val122012251230Thr Phe Asp Arg Leu Gln Val Leu Asp Ser His Tyr Gln Asp Val Leu123512401245Lys Glu Val Lys Ala Ala Ala Ser Lys Val Lys Ala Asn Leu Leu Ser125012551260Val Glu Glu Ala Cys Ser Leu Thr Pro Pro His Ser Ala Lys Ser Lys265127012751280Phe Gly Tyr Gly Ala Lys Asp Val Arg Cys His Ala Arg Lys Ala Val128512901295Thr His Ile Asn Ser Val Trp Lys Asp Leu Leu Glu Asp Asn Val Thr130013051310Pro Ile Asp Thr Thr Ile Met Ala Lys Asn Glu Val Phe Cys Val Gln131513201325Pro Glu Lys Gly Gly Arg Lys Pro Ala Arg Leu Ile Val Phe Pro Asp133013351340Leu Gly Val Arg Val Cys Glu Lys Met Ala Leu Tyr Asp Val Val Thr345135013551360Lys Leu Pro Leu Ala Val Met Gly Ser Ser Tyr Gly Phe Gln Tyr Ser136513701375Pro Gly Gln Arg Val Glu Phe Leu Val Gln Ala Trp Lys Ser Lys Lys138013851390Thr Pro Met Gly Phe Ser Tyr Asp Thr Arg Cys Phe Asp Ser Thr Val139514001405Thr Glu Ser Asp Ile Arg Thr Glu Glu Ala Ile Tyr Gln Cys Cys Asp141014151420Leu Asp Pro Gln Ala Arg Val Ala Ile Lys Ser Leu Thr Glu Arg Leu425143014351440Tyr Val Gly Gly Pro Leu Thr Asn Ser Arg Gly Glu Asn Cys Gly Tyr144514501455Arg Arg Cys Arg Ala Ser Gly Val Leu Thr Thr Ser Cys Gly Asn Thr146014651470Leu Thr Cys Tyr lle Lys Ala Arg Ala Ala Cys Arg Ala Ala Gly Leu147514801485Gln Asp Cys Thr Met Leu Val Cys Gly Asp Asp Leu Val Val Ile Cys149014951500Glu Ser Ala Gly Val Gln Glu Asp Ala Ala Ser Leu Arg Ala Phe Thr505151015151520Glu Ala Met Thr Arg Tyr Ser Ala Pro Pro Gly Asp Pro Pro Gln Pro152515301535Glu Tyr Asp Leu Glu Leu Ile Thr Ser Cys Ser Ser Asn Val Ser Val154015451550Ala His Asp Gly Ala Gly Lys Arg Val Tyr Tyr Leu Thr Arg Asp Pro155515601565Thr Thr Pro Leu Ala Arg Ala Ala Trp Glu Thr Ala Arg His Thr Pro157015751580ValAsn Ser Trp Leu Gly Asn Ile Ile Met Phe Ala Pro Thr Leu Trp585 159015951600Ala Arg Met Ile Leu Met Thr His Phe Phe Ser Val Leu Ile Ala Arg160516101615Asp Gln Leu Glu Gln Ala Leu Asp Cys Glu Ile Tyr Gly Ala Cys Tyr162016251630Ser Ile Glu Pro Leu Asp Leu Pro Pro Ile Ile Gln Arg Leu His Gly163516401645Leu Ser Ala Phe Ser Leu His Ser Tyr Ser Pro Gly Glu Ile Asn Arg165016551660Val Ala Ala Cys Leu Arg Lys Leu Gly Val Pro Pro Leu Arg Ala Trp665167016751680Arg His Arg Ala Arg Ser Val Arg Ala Arg Leu Leu Ala Arg Gly Gly168516901695Arg Ala Ala Ile Cys Gly Lys Tyr Leu Phe Asn Trp Ala Val Arg Thr170017051710Lys Leu Lys Leu Thr Pro Ile Ala Ala Ala Gly Gln Leu Asp Leu Ser171517201725Gly Trp Phe Thr Ala Gly Tyr Ser Gly Gly Asp Ile Tyr His Ser Val173017351740Ser His Ala Arg Pro Arg Trp Ile Trp Phe Cys Leu Leu Leu Leu Ala745175017551760Ala Gly Val Gly Ile Tyr Leu Leu Pro Asn Arg Met Ser Thr Asn Pro176517701775Lys Pro Gln Arg Lys Thr Lys Arg Asn Thr Asn Arg Arg Pro Gln Asp178017851790Val Lys Phe Pro Gly Gly Gly Gln Ile Val Gly Gly Val Tyr Leu Leu179518001805Pro Arg Arg Gly Pro Arg Leu Gly Val Arg Ala Thr Arg Lys Thr Ser181018151820Glu Arg Ser Gln Pro Arg Gly Arg Arg Gln Pro Ile Pro Lys Ala Arg825183018351840Arg Pro Glu Gly Arg Thr Trp Ala Gln Pro Gly Tyr Pro Trp Pro Leu184518501855Tyr Gly Asn Glu Gly Cys Gly Trp Ala Gly Trp Leu Leu Ser Pro Arg186018651870Gly Ser Arg Pro Ser Trp Gly Pro Thr Asp Pro Arg Arg Arg Ser Arg187518801885Asn Leu Gly Lys Val Ile Asp Thr Leu Thr Cys Gly Phe Ala Asp Leu189018951900Met Gly Tyr lle Pro Leu Val Gly Ala Pro Leu Gly Gly Ala Ala Arg905191019151920Ala Leu Ala His Gly Val Arg Val Leu Glu Asp Gly Val Asn Tyr Ala192519301935Thr Gly Asn Leu Pro Gly Cys Ser19402101621120217212DNA213人工序列220223人工序列的描述pd.delta.NS3NS5.pj.core140220221CDS222(12679)..(18411)40016atcgatccta ccccttgcgc taaagaagta tatgtgccta ctaacgcttg tctttgtctc 60tgtcactaaa cactggatta ttactcccag atacttattt tggactaatt taaatgattt 120cggatcaacg ttcttaatat cgctgaatct tccacaattg atgaaagtag ctaggaagag 180gaattggtat aaagtttttg tttttgtaaa tctcgaagta tactcaaacg aatttagtat 240tttctcagtg atctcccaga tgctttcacc ctcacttaga agtgctttaa gcattttttt 300actgtggcta tttcccttat ctgcttcttc cgatgattcg aactgtaatt gcaaactact 360tacaatatca gtgatatcag attgatgttt ttgtccatag taaggaataa ttgtaaattc 420ccaagcagga atcaatttct ttaatgaggc ttccagaatt gttgcttttt gcgtcttgta 480tttaaactgg agtgatttat tgacaatatc gaaactcagc gaattgctta tgatagtatt 540atagctcatg aatgtggctc tcttgattgc tgttccgtta tgtgtaatca tccaacataa 600ataggttagt tcagcagcac ataatgctat tttctcacct gaaggtcttt caaacctttc 660cacaaactga cgaacaagca ccttaggtgg tgttttacat aatatatcaa attgtggcat 720gcttagcgcc gatcttgtgt gcaattgata tctagtttca actactctat ttatcttgta 780tcttgcagta ttcaaacacg ctaactcgaa aaactaactt taattgtcct gtttgtctcg 840cgttctttcg aaaaatgcac cggccgcgca ttatttgtac tgcgaaaata attggtactg 900cggtatcttc atttcatatt ttaaaaatgc acctttgctg cttttcctta atttttagac 960ggcccgcagg ttcgttttgc ggtactatct tgtgataaaa agttgttttg acatgtgatc 1020tgcacagatt ttataatgta ataagcaaga atacattatc aaacgaacaa tactggtaaa 1080agaaaaccaa aatggacgac attgaaacag ccaagaatct gacggtaaaa gcacgtacag 1140cttatagcgt ctgggatgta tgtcggctgt ttattgaaat gattgctcct gatgtagata 1200ttgatataga gagtaaacgt aagtctgatg agctactctt tccaggatat gtcataaggc 1260ccatggaatc tctcacaacc ggtaggccgt atggtcttga ttctagcgca gaagattcca 1320gcgtatcttc tgactccagt gctgaggtaa ttttgcctgc tgcgaagatg gttaaggaaa 1380ggtttgattc gattggaaat ggtatgctct cttcacaaga agcaagtcag gctgccatag 1440atttgatgct acagaataac aagctgttag acaatagaaa gcaactatac aaatctattg 1500ctataataat aggaagattg cccgagaaag acaagaagag agctaccgaa atgctcatga 1560gaaaaatgga ttgtacacag ttattagtcc caccagctcc aacggaagaa gatgttatga 1620agctcgtaag cgtcgttacc caattgctta ctttagttcc accagatcgt caagctgctt 1680taataggtga tttattcatc ccggaatctc taaaggatat attcaatagt ttcaatgaac 1740tggcggcaga gaatcgttta cagcaaaaaa agagtgagtt ggaaggaagg actgaagtga 1800accatgctaa tacaaatgaa gaagttccct ccaggcgaac aagaagtaga gacacaaatg 1860caagaggagc atataaatta caaaacacca tcactgaggg ccctaaagcg gttcccacga 1920aaaaaaggag agtagcaacg agggtaaggg gcagaaaatc acgtaatact tctagggtat 1980gatccaatat caaaggaaat gatagcattg aaggatgaga ctaatccaat tgaggagtgg 2040cagcatatag aacagctaaa gggtagtgct gaaggaagca tacgataccc cgcatggaat 2100gggataatat cacaggaggt actagactac ctttcatcct acataaatag acgcatataa 2160gtacgcattt aagcataaac acgcactatg ccgttcttct catgtatata tatatacagg 2220caacacgcag atataggtgc gacgtgaaca gtgagctgta tgtgcgcagc tcgcgttgca 2280ttttcggaag cgctcgtttt cggaaacgct ttgaagttcc tattccgaag ttcctattct 2340ctagaaagta taggaacttc agagcgcttt tgaaaaccaa aagcgctctg aagacgcact 2400ttcaaaaaac caaaaacgca ccggactgta acgagctact aaaatattgc gaataccgct 2460tccacaaaca ttgctcaaaa gtatctcttt gctatatatc tctgtgctat atccctatat 2520aacctaccca tccacctttc gctccttgaa cttgcatcta aactcgacct ctacatcaac 2580aggcttccaa tgctcttcaa attttactgt caagtagacc catacggctg taatatgctg 2640ctcttcataa tgtaagctta tctttatcga atcgtgtgaa aaactactac cgcgataaac 2700ctttacggtt ccctgagatt gaattagttc ctttagtata tgatacaaga cacttttgaa 2760ctttgtacga cgaattttga ggttcgccat cctctggcta tttccaatta tcctgtcggc 2820tattatctcc gcctcagttt gatcttccgc ttcagactgc catttttcac ataatgaatc 2880tatttcaccc cacaatcctt catccgcctc cgcatcttgt tccgttaaac tattgacttc 2940atgttgtaca ttgtttagtt cacgagaagg gtcctcttca ggcggtagct cctgatctcc 3000tatatgacct ttatcctgtt ctctttccac aaacttagaa atgtattcat gaattatgga 3060gcacctaata acattcttca aggcggagaa gtttgggcca gatgcccaat atgcttgaca 3120tgaaaacgtg agaatgaatt tagtattatt gtgatattct gaggcaattt tattataatc 3180tcgaagataa gagaagaatg cagtgacctt tgtattgaca aatggagatt ccatgtatct 3240aaaaaatacg cctttaggcc ttctgatacc ctttcccctg cggtttagcg tgccttttac 3300attaatatct aaaccctctc cgatggtggc ctttaactga ctaataaatg caaccgatat 3360aaactgtgat aattctgggt gatttatgat tcgatcgaca attgtattgt acactagtgc 3420aggatcaggc caatccagtt ctttttcaat taccggtgtg tcgtctgtat tcagtacatg 3480tccaacaaat gcaaatgcta acgttttgta tttcttataa ttgtcaggaa ctggaaaagt 3540cccccttgtc gtctcgatta cacacctact ttcatcgtac accataggtt ggaagtgctg 3600cataatacat tgcttaatac aagcaagcag tctctcgcca ttcatatttc agttattttc 3660cattacagct gatgtcattg tatatcagcg ctgtaaaaat ctatctgtta cagaaggttt 3720tcgcggtttt tataaacaaa actttcgtta cgaaatcgag caatcacccc agctgcgtat 3780ttggaaattc gggaaaaagt agagcaacgc gagttgcatt ttttacacca taatgcatga 3840ttaacttcga gaagggatta aggctaattt cactagtatg tttcaaaaac ctcaatctgt 3900ccattgaatg ccttataaaa cagctataga ttgcatagaa gagttagcta ctcaatgctt 3960tttgtcaaag cttactgatg atgatgtgtc tactttcagg cgggtctgta gtaaggagaa 4020tgacattata aagctggcac ttagaattcc acggactata gactatacta gtatactccg 4080tctactgtac gatacacttc cgctcaggtc cttgtccttt aacgaggcct taccactctt 4140ttgttactct attgatccag ctcagcaaag gcagtgtgat ctaagattct atcttcgcga 4200tgtagtaaaa ctagctagac cgagaaagag actagaaatg caaaaggcac ttctacaatg 4260gctgccatca ttattatccg atgtgacgct gcattttttt tttttttttt tttttttttt 4320tttttttttt tttttttttt ttttttggta caaatatcat aaaaaaagag aatcttttta 4380agcaaggatt ttcttaactt cttcggcgac agcatcaccg acttcggtgg tactgttgga 4440accacctaaa tcaccagttc tgatacctgc atccaaaacc tttttaactg catcttcaat 4500ggctttacct tcttcaggca agttcaatga caatttcaac atcattgcag cagacaagat 4560agtggcgata gggttgacct tattctttgg caaatctgga gcggaaccat ggcatggttc 4620gtacaaacca aatgcggtgt tcttgtctgg caaagaggcc aaggacgcag atggcaacaa 4680acccaaggag cctgggataa cggaggcttc atcggagatg atatcaccaa acatgttgct 4740ggtgattata ataccattta ggtgggttgg gttcttaact aggatcatgg cggcagaatc 4800aatcaattga tgttgaactt tcaatgtagg gaattcgttc ttgatggttt cctccacagt 4860ttttctccat aatcttgaag aggccaaaac attagcttta tccaaggacc aaataggcaa 4920tggtggctca tgttgtaggg ccatgaaagc ggccattctt gtgattcttt gcacttctgg 4980aacggtgtat tgttcactat cccaagcgac accatcacca tcgtcttcct ttctcttacc 5040aaagtaaata cctcccacta attctctaac aacaacgaag tcagtacctt tagcaaattg 5100tggcttgatt ggagataagt ctaaaagaga gtcggatgca aagttacatg gtcttaagtt 5160ggcgtacaat tgaagttctt tacggatttt tagtaaacct tgttcaggtc taacactacc 5220ggtaccccat ttaggaccac ccacagcacc taacaaaacg gcatcagcct tcttggaggc 5280ttccagcgcc tcatctggaa gtggaacacc tgtagcatcg atagcagcac caccaattaa 5340atgattttcg aaatcgaact tgacattgga acgaacatca gaaatagctt taagaacctt 5400aatggcttcg gctgtgattt cttgaccaac gtggtcacct ggcaaaacga cgatcttctt 5460aggggcagac attacaatgg tatatccttg aaatatatat aaaaaaaaaa aaaaaaaaaa 5520aaaaaaaaaa atgcagcttc tcaatgatat tcgaatacgc tttgaggaga tacagcctaa 5580tatccgacaa actgttttac agatttacga tcgtacttgt tacccatcat tgaattttga 5640acatccgaac ctgggagttt tccctgaaac agatagtata tttgaacctg tataataata 5700tatagtctag cgctttacgg aagacaatgt atgtatttcg gttcctggag aaactattgc 5760atctattgca taggtaatct tgcacgtcgc atccccggtt cattttctgc gtttccatct 5820tgcacttcaa tagcatatct ttgttaacga agcatctgtg cttcattttg tagaacaaaa 5880atgcaacgcg agagcgctaa tttttcaaac aaagaatctg agctgcattt ttacagaaca 5940gaaatgcaac gcgaaagcgc tattttacca acgaagaatc tgtgcttcat ttttgtaaaa 6000caaaaatgca acgcgagagc gctaattttt caaacaaaga atctgagctg catttttaca 6060gaacagaaat gcaacgcgag agcgctattt taccaacaaa gaatctatac ttcttttttg 6120ttctacaaaa atgcatcccg agagcgctat ttttctaaca aagcatctta gattactttt 6180tttctccttt gtgcgctcta taatgcagtc tcttgataac tttttgcact gtaggtccgt 6240taaggttaga agaaggctac tttggtgtct attttctctt ccataaaaaa agcctgactc 6300cacttcccgc gtttactgat tactagcgaa gctgcgggtg cattttttca agataaaggc 6360atccccgatt atattctata ccgatgtgga ttgcgcatac tttgtgaaca gaaagtgata 6420gcgttgatga ttcttcattg gtcagaaaat tatgaacggt ttcttctatt ttgtctctat 6480atactacgta taggaaatgt ttacattttc gtattgtttt cgattcactc tatgaatagt 6540tcttactaca atttttttgt ctaaagagta atactagaga taaacataaa aaatgtagag 6600gtcgagttta gatgcaagtt caaggagcga aaggtggatg ggtaggttat atagggatat 6660agcacagaga tatatagcaa agagatactt ttgagcaatg tttgtggaag cggtattcgc 6720aatattttag tagctcgtta cagtccggtg cgtttttggt tttttgaaag tgcgtcttca 6780gagcgctttt ggttttcaaa agcgctctga agttcctata ctttctagag aataggaact 6840tcggaatagg aacttcaaag cgtttccgaa aacgagcgct tccgaaaatg caacgcgagc 6900tgcgcacata cagctcactg ttcacgtcgc acctatatct gcgtgttgcc tgtatatata 6960tatacatgag aagaacggca tagtgcgtgt ttatgcttaa atgcgtactt atatgcgtct 7020atttatgtag gatgaaaggt agtctagtac ctcctgtgat attatcccat tccatgcggg 7080gtatcgtatg cttccttcag cactaccctt tagctgttct atatgctgcc actcctcaat 7140tggattagtc tcatccttca atgctatcat ttcctttgat attggatcat atgcatagta 7200ccgagaaact agtgcgaagt agtgatcagg tattgctgtt atctgatgag tatacgttgt 7260cctggccacg gcagaagcac gcttatcgct ccaatttccc acaacattag tcaactccgt 7320taggcccttc attgaaagaa atgaggtcat caaatgtctt ccaatgtgag attttgggcc 7380attttttata gcaaagattg aataaggcgc atttttcttc aaagctttat tgtacgatct 7440gactaagtta tcttttaata attggtattc ctgtttattg cttgaagaat tgccggtcct 7500atttactcgt tttaggactg gttcagaatt cctcaaaaat tcatccaaat atacaagtgg 7560atcgatgata agctgtcaaa catgagaatt cttgaagacg aaagggcctc gtgatacgcc 7620tatttttata ggttaatgtc atgataataa tggtttctta gacgtcaggt ggcacttttc 7680ggggaaatgt gcgcggaacc cctatttgtt tatttttcta aatacattca aatatgtatc 7740cgctcatgag acaataaccc tgataaatgc ttcaataata ttgaaaaagg aagagtatga 7800gtattcaaca tttccgtgtc gcccttattc ccttttttgc ggcattttgc cttcctgttt 7860ttgctcaccc agaaacgctg gtgaaagtaa aagatgctga agatcagttg ggtgcacgag 7920tgggttacat cgaactggat ctcaacagcg gtaagatcct tgagagtttt cgccccgaag 7980aacgttttcc aatgatgagc acttttaaag ttctgctatg tggcgcggta ttatcccgtg 8040ttgacgccgg gcaagagcaa ctcggtcgcc gcatacacta ttctcagaat gacttggttg 8100agtactcacc agtcacagaa aagcatctta cggatggcat gacagtaaga gaattatgca 8160gtgctgccat aaccatgagt gataacactg cggccaactt acttctgaca acgatcggag 8220gaccgaagga gctaaccgct tttttgcaca acatggggga tcatgtaact cgccttgatc 8280gttgggaacc ggagctgaat gaagccatac caaacgacga gcgtgacacc acgatgcctg 8340cagcaatggc aacaacgttg cgcaaactat taactggcga actacttact ctagcttccc 8400ggcaacaatt aatagactgg atggaggcgg ataaagttgc aggaccactt ctgcgctcgg 8460cccttccggc tggctggttt attgctgata aatctggagc cggtgagcgt gggtctcgcg 8520gtatcattgc agcactgggg ccagatggta agccctcccg tatcgtagtt atctacacga 8580cggggagtca ggcaactatg gatgaacgaa atagacagat cgctgagata ggtgcctcac 8640tgattaagca ttggtaactg tcagaccaag tttactcata tatactttag attgatttaa 8700aacttcattt ttaatttaaa aggatctagg tgaagatcct ttttgataat ctcatgacca 8760aaatccctta acgtgagttt tcgttccact gagcgtcaga ccccgtagaa aagatcaaag 8820gatcttcttg agatcctttt tttctgcgcg taatctgctg cttgcaaaca aaaaaaccac 8880cgctaccagc ggtggtttgt ttgccggatc aagagctacc aactcttttt ccgaaggtaa 8940ctggcttcag cagagcgcag ataccaaata ctgtccttct agtgtagccg tagttaggcc 9000accacttcaa gaactctgta gcaccgccta catacctcgc tctgctaatc ctgttaccag 9060tggctgctgc cagtggcgat aagtcgtgtc ttaccgggtt ggactcaaga cgatagttac 9120cggataaggc gcagcggtcg ggctgaacgg ggggttcgtg cacacagccc agcttggagc 9180gaacgaccta caccgaactg agatacctac agcgtgagct atgagaaagc gccacgcttc 9240ccgaagggag aaaggcggac aggtatccgg taagcggcag ggtcggaaca ggagagcgca 9300cgagggagct tccaggggga aacgcctggt atctttatag tcctgtcggg tttcgccacc 9360tctgacttga gcgtcgattt ttgtgatgct cgtcaggggg gcggagccta tggaaaaacg 9420ccagcaacgc ggccttttta cggttcctgg ccttttgctg gccttttgct cacatgttct 9480ttcctgcgtt atcccctgat tctgtggata accgtattac cgcctttgag tgagctgata 9540ccgctcgccg cagccgaacg accgagcgca gcgagtcagt gagcgaggaa gcggaagagc 9600gcctgatgcg gtattttctc cttacgcatc tgtgcggtat ttcacaccgc atatggtgca 9660ctctcagtac aatctgctct gatgccgcat agttaagcca gtatacactc cgctatcgct 9720acgtgactgg gtcatggctg cgccccgaca cccgccaaca cccgctgacg cgccctgacg 9780ggcttgtctg ctcccggcat ccgcttacag acaagctgtg accgtctccg ggagctgcat 9840gtgtcagagg ttttcaccgt catcaccgaa acgcgcgagg cagctgcggt aaagctcatc 9900agcgtggtcg tgaagcgatt cacagatgtc tgcctgttca tccgcgtcca gctcgttgag 9960tttctccaga agcgttaatg tctggcttct gataaagcgg gccatgttaa gggcggtttt 10020ttcctgtttg gtcactgatg cctccgtgta agggggattt ctgttcatgg gggtaatgat 10080accgatgaaa cgagagagga tgctcacgat acgggttact gatgatgaac atgcccggtt 10140actggaacgt tgtgagggta aacaactggc ggtatggatg cggcgggacc agagaaaaat 10200cactcagggt caatgccagc gcttcgttaa tacagatgta ggtgttccac agggtagcca 10260gcagcatcct gcgatgcaga tccggaacat aatggtgcag ggcgctgact tccgcgtttc 10320cagactttac gaaacacgga aaccgaagac cattcatgtt gttgctcagg tcgcagacgt 10380tttgcagcag cagtcgcttc acgttcgctc gcgtatcggt gattcattct gctaaccagt 10440aaggcaaccc cgccagccta gccgggtcct caacgacagg agcacgatca tgcgcacccg 10500tggccaggac ccaacgctgc ccgagatgcg ccgcgtgcgg ctgctggaga tggcggacgc 10560gatggatatg ttctgccaag ggttggtttg cgcattcaca gttctccgca agaattgatt 10620ggctccaatt cttggagtgg tgaatccgtt agcgaggtgc cgccggcttc cattcaggtc 10680gaggtggccc ggctccatgc accgcgacgc aacgcgggga ggcagacaag gtatagggcg 10740gcgcctacaa tccatgccaa cccgttccat gtgctcgccg aggcggcata aatcgccgtg 10800acgatcagcg gtccaatgat cgaagttagg ctggtaagag ccgcgagcga tccttgaagc 10860tgtccctgat ggtcgtcatc tacctgcctg gacagcatgg cctgcaacgc gggcatcccg 10920atgccgccgg aagcgagaag aatcataatg gggaaggcca tccagcctcg cgtcgcgaac 10980gccagcaaga cgtagcccag cgcgtcggcc gccatgccgg cgataatggc ctgcttctcg 11040ccgaaacgtt tggtggcggg accagtgacg aaggcttgag cgagggcgtg caagattccg 11100aataccgcaa gcgacaggcc gatcatcgtc gcgctccagc gaaagcggtc ctcgccgaaa 11160atgacccaga gcgctgccgg cacctgtcct acgagttgca tgataaagaa gacagtcata 11220agtgcggcga cgatagtcat gccccgcgcc caccggaagg agctgactgg gttgaaggct 11280ctcaagggca tcggtcgagg atccttcaat atgcgcacat acgctgttat gttcaaggtc 11340ccttcgttta agaacgaaag cggtcttcct tttgagggat gtttcaagtt gttcaaatct 11400atcaaatttg caaatcccca gtctgtatct agagcgttga atcggtgatg cgatttgtta 11460attaaattga tggtgtcacc attaccaggt ctagatatac caatggcaaa ctgagcacaa 11520caataccagt ccggatcaac tggcaccatc tctcccgtag tctcatctaa tttttcttcc 11580ggatgaggtt ccagatatac cgcaacacct ttattatggt ttccctgagg gaataataga 11640atgtcccatt cgaaatcacc aattctaaac ctgggcgaat tgtatttcgg gtttgttaac 11700tcgttccagt caggaatgtt ccacgtgaag ctatcttcca gcaaagtctc cacttcttca 11760tcaaattgtg gagaatactc ccaatgctct tatctatggg acttccggga aacacagtac 11820cgatacttcc caattcgtct tcagagctca ttgtttgttt gaagagacta atcaaagaat 11880cgttttctca aaaaaattaa tatcttaact gatagtttga tcaaaggggc aaaacgtagg 11940ggcaaacaaa cggaaaaatc gtttctcaaa ttttctgatg ccaagaactc taaccagtct 12000tatctaaaaa ttgccttatg atccgtctct ccggttacag cctgtgtaac tgattaatcc 12060tgcctttcta atcaccattc taatgtttta attaagggat tttgtcttca ttaacggctt 12120tcgctcataa aaatgttatg acgttttgcc cgcaggcggg aaaccatcca cttcacgaga 12180ctgatctcct ctgccggaac accgggcatc tccaacttat aagttggaga aataagagaa 12240tttcagattg agagaatgaa aaaaaaaaac ccttagttca taggtccatt ctcttagcgc 12300aactacagag aacaggggca caaacaggca aaaaacgggc acaacctcaa tggagtgatg 12360caacctgcct ggagtaaatg atgacacaag gcaattgacc cacgcatgta tctatctcat 12420tttcttacac cttctattac cttctgctct ctctgatttg gaaaaagctg aaaaaaaagg 12480ttgaaaccag ttccctgaaa ttattcccct acttgactaa taagtatata aagacggtag 12540gtattgattg taattctgta aatctatttc ttaaacttct taaattctac ttttatagtt 12600agtctttttt ttagttttaa aacaccaaga acttagtttc gaataaacac acataaacaa 12660acaagcttac aaaacaaa atg gct gca tat gca gct cag ggc tat aag gtg 12711Met Ala Ala Tyr Ala Ala Gln Gly Tyr Lys Val1 5 10cta gta ctc aac ccc tct gtt gct gca aca ctg ggc ttt ggt gct tac 12759Leu Val Leu Asn Pro Ser Val Ala Ala Thr Leu Gly Phe Gly Ala Tyr15 20 25atg tcc aag gct cat ggg atc gat cct aac atc agg acc ggg gtg aga 12807Met Ser Lys Ala His Gly Ile Asp Pro Asn Ile Arg Thr Gly Val Arg30 35 40aca att acc act ggc agc ccc atc acg tac tcc acc tac ggc aag ttc 12855Thr Ile Thr Thr Gly Ser Pro Ile Thr Tyr Ser Thr Tyr Gly Lys Phe45 50 55ctt gcc gac ggc ggg tgc tcg ggg ggc gct tat gac ata ata att tgt 12903Leu Ala Asp Gly Gly Cys Ser Gly Gly Ala Tyr Asp Ile Ile Ile Cys60 65 70 75gac gag tgc cac tcc acg gat gcc aca tcc atc ttg ggc att ggc act 12951Asp Glu Cys His Ser Thr Asp Ala Thr Ser Ile Leu Gly Ile Gly Thr80 85 90gtc ctt gac caa gca gag act gcg ggg gcg aga ctg gtt gtg ctc gcc 12999Val Leu Asp Gln Ala Glu Thr Ala Gly Ala Arg Leu Val Val Leu Ala95 100 105acc gcc acc cct ccg ggc tcc gtc act gtg ccc cat ccc aac atc gag 13047Thr Ala Thr Pro Pro Gly Ser Val Thr Val Pro His Pro Asn Ile Glu110 115 120gag gtt gct ctg tcc acc acc gga gag atc cct ttt tac ggc aag gct 13095Glu Val Ala Leu Ser Thr Thr Gly Glu Ile Pro Phe Tyr Gly Lys Ala125 130 135atc ccc ctc gaa gta atc aag ggg ggg aga cat ctc atc ttc tgt cat 13143Ile Pro Leu Glu Val Ile Lys Gly Gly Arg His Leu Ile Phe Cys His140 145 150 155tca aag aag aag tgc gac gaa ctc gcc gca aag ctg gtc gca ttg ggc 13191Ser Lys Lys Lys Cys Asp Glu Leu Ala Ala Lys Leu Val Ala Leu Gly160 165 170atc aat gcc gtg gcc tac tac cgc ggt ctt gac gtg tcc gtc atc ccg 13239Ile Asn Ala Val Ala Tyr Tyr Arg Gly Leu Asp Val Ser Val Ile Pro175 180 185acc age ggc gat gtt gtc gtc gtg gca acc gat gcc ctc atg acc ggc 13287Thr Ser Gly Asp Val Val Val Val Ala Thr Asp Ala Leu Met Thr Gly190 195 200tat acc ggc gac ttc gac tcg gtg ata gac tgc aat acg tgt gtc acc 13335Tyr Thr Gly Asp Phe Asp Ser Val Ile Asp Cys Asn Thr Cys Val Thr205 210 215cag aca gtc gat ttc agc ctt gac cct acc ttc acc att gag aca atc 13383Gln Thr Val Asp Phe Ser Leu Asp Pro Thr Phe Thr Ile Glu Thr Ile220 225 230 235acg ctc ccc caa gat gct gtc tcc cgc act caa cgt cgg ggc agg act 13431Thr Leu Pro Gln Asp Ala Val Ser Arg Thr Gln Arg Arg Gly Arg Thr240 245 250ggc agg ggg aag cca ggc atc tac aga ttt gtg gca ccg ggg gag cgc 13479Gly Arg Gly Lys Pro Gly Ile Tyr Arg Phe Val Ala Pro Gly Glu Arg255 260 265ccc tcc ggc atg ttc gac tcg tcc gtc ctc tgt gag tgc tat gac gca 13527Pro Ser Gly Met Phe Asp Ser Ser Val Leu Cys Glu Cys Tyr Asp Ala
270 275 280ggc tgt gct tgg tat gag ctc acg ccc gcc gag act aca gtt agg cta 13575Gly Cys Ala Trp Tyr Glu Leu Thr Pro Ala Glu Thr Thr Val Arg Leu285 290 295cga gcg tac atg aac acc ccg ggg ctt ccc gtg tgc cag gac cat ctt 13623Arg Ala Tyr Met Asn Thr Pro Gly Leu Pro Val Cys Gln Asp His Leu300 305 310 315gaa ttt tgg gag ggc gtc ttt aca ggc ctc act cat ata gat gcc cac 13671Glu Phe Trp Glu Gly Val Phe Thr Gly Leu Thr His Ile Asp Ala His320 325 330ttt cta tcc cag aca aag cag agt ggg gag aac ctt cct tac ctg gta 13719Phe Leu Ser Gln Thr Lys Gln Ser Gly Glu Asn Leu Pro Tyr Leu Val335 340 345gcg tac caa gcc acc gtg tgc gct agg gct caa gcc cct ccc cca tcg 13767Ala Tyr Gln Ala Thr Val Cys Ala Arg Ala Gln Ala Pro Pro Pro Ser350 355 360tgg gac cag atg tgg aag tgt ttg att cgc ctc aag ccc acc ctc cat 13815Trp Asp Gln Met Trp Lys Cys Leu Ile Arg Leu Lys Pro Thr Leu His365 370 375ggg cca aca ccc ctg cta tac aga ctg ggc gct gtt cag aat gaa atc 13863Gly Pro Thr Pro Leu Leu Tyr Arg Leu Gly Ala Val Gln Asn Glu Ile380 385 390 395acc ctg acg cac cca gtc acc aaa tac atc atg aca tgc atg tcg gcc 13911Thr Leu Thr His Pro Val Thr Lys Tyr Ile Met Thr Cys Met Ser Ala400 405 410gac ctg gag gtc gtc acg agc acc tgg gtg ctc gtt ggc ggc gtc ctg 13959Asp Leu Glu Val Val Thr Ser Thr Trp Val Leu Val Gly Gly Val Leu415 420 425gct gct ttg gcc gcg tat tgc ctg tca aca ggc tgc gtg gtc ata gtg 14007Ala Ala Leu Ala Ala Tyr Cys Leu Ser Thr Gly Cys Val Val Ile Val430 435 440ggc agg gtc gtc ttg tcc ggg aag ccg gca atc ata cct gac agg gaa 14055Gly Arg Val Val Leu Ser Gly Lys Pro Ala Ile Ile Pro Asp Arg Glu445 450 455gtc ctc tac cga gag ttc gat gag atg gaa gag tgc tct cag cac tta 14103Val Leu Tyr Arg Glu Phe Asp Glu Met Glu Glu Cys Ser Gln His Leu460 465 470 475ccg tac atc gag caa ggg atg atg ctc gcc gag cag ttc aag cag aag 14151Pro Tyr Ile Glu Gln Gly Met Met Leu Ala Glu Gln Phe Lys Gln Lys480 485 490gcc ctc ggc ctc ctg cag acc gcg tcc cgt cag gca gag gtt atc gcc 14199Ala Leu Gly Leu Leu Gln Thr Ala Ser Arg Gln Ala Glu Val Ile Ala495 500 505cct gct gtc cag acc aac tgg caa aaa ctc gag acc ttc tgg gcg aag 14247Pro Ala Val Gln Thr Asn Trp Gln Lys Leu Glu Thr Phe Trp Ala Lys510 515 520cat atg tgg aac ttc atc agt ggg ata caa tac ttg gcg ggc ttg tca 14295His Met Trp Asn Phe Ile Ser Gly Ile Gln Tyr Leu Ala Gly Leu Ser525 530 535acg ctg cct ggt aac ccc gcc att gct tca ttg atg gct ttt aca gct 14343Thr Leu Pro Gly Asn Pro Ala Ile Ala Ser Leu Met Ala Phe Thr Ala540 545 550 555gct gtc acc agc cca cta acc act agc caa acc ctc ctc ttc aac ata 14391Ala Val Thr Ser Pro Leu Thr Thr Ser Gln Thr Leu Leu Phe Asn Ile560 565 570ttg ggg ggg tgg gtg gct gcc cag ctc gcc gcc ccc ggt gcc gct act 14439Leu Gly Gly Trp Val Ala Ala Gln Leu Ala Ala Pro Gly Ala Ala Thr575 580 585gcc ttt gtg ggc gct ggc tta gct ggc gcc gcc atc ggc agt gtt gga 14487Ala Phe Val Gly Ala Gly Leu Ala Gly Ala Ala Ile Gly Ser Val Gly590 595 G00ctg ggg aag gtc ctc ata gac atc ctt gca ggg tat ggc gcg ggc gtg 14535Leu Gly Lys Val Leu Ile Asp Ile Leu Ala Gly Tyr Gly Ala Gly Val605 610 615gcg gga gct ctt gtg gca ttc aag atc atg agc ggt gag gtc ccc tcc 14583Ala Gly Ala Leu Val Ala Phe Lys Ile Met Ser Gly Glu Val Pro Ser620 625 630 635acg gag gac ctg gtc aat cta ctg ccc gcc atc ctc tcg ccc gga gcc 14631Thr Glu Asp Leu Val Asn Leu Leu Pro Ala Ile Leu Ser Pro Gly Ala640 645 650ctc gta gtc ggc gtg gtc tgt gca gca ata ctg cgc cgg cac gtt ggc 14679Leu Val Val Gly Val Val Cys Ala Ala Ile Leu Arg Arg His Val Gly655 660 665ccg ggc gag ggg gca gtg cag tgg atg aac cgg ctg ata gcc ttc gcc 14727Pro Gly Glu Gly Ala Val Gln Trp Met Asn Arg Leu Ile Ala Phe Ala670 675 680tcc cgg ggg aac cat gtt tcc ccc acg cac tac gtg ccg gag agc gat 14775Ser Arg Gly Asn His Val Ser Pro Thr His Tyr Val Pro Glu Ser Asp685 690 695gca gct gcc cgc gtc act gcc ata ctc agc agc ctc act gta acc cag 14823Ala Ala Ala Arg Val Thr Ala Ile Leu Ser Ser Leu Thr Val Thr Gln700 705 710 715ctc ctg agg cga ctg cac cag tgg ata agc tcg gag tgt acc act cca 14871Leu Leu Arg Arg Leu His Gln Trp Ile Ser Ser Glu Cys Thr Thr Pro720 725 730tgc tcc ggt tcc tgg cta agg gac atc tgg gac tgg ata tgc gag gtg 14919Cys Ser Gly Ser Trp Leu Arg Asp Ile Trp Asp Trp Ile Cys Glu Val735 740 745ttg agc gac ttt aag acc tgg cta aaa gct aag ctc atg cca cag ctg 14967Leu Set Asp Phe Lys Thr Trp Leu Lys Ala Lys Leu Met Pro Gln Leu750 755 760cct ggg atc ccc ttt gtg tcc tgc cag cgc ggg tat aag ggg gtc tgg 15015Pro Gly Ile Pro Phe Val Ser Cys Gln Arg Gly Tyr Lys Gly Val Trp765 770 775cga ggg gac ggc atc atg cac act cgc tgc cac tgt gga gct gag atc 15063Arg Gly Asp Gly Ile Met His Thr Arg Cys His Cys Gly Ala Glu Ile780 785 790 795act gga cat gtc aaa aac ggg acg atg agg atc gtc ggt cct agg acc 15111Thr Gly His Val Lys Asn Gly Thr Met Arg Ile Val Gly Pro Arg Thr800 805 810tgc agg aac atg tgg agt ggg acc ttc ccc att aat gcc tac acc acg 15159Cys Arg Asn Met Trp Ser Gly Thr Phe Pro Ile Asn Ala Tyr Thr Thr815 820 825ggc ccc tgt acc ccc ctt cct gcg ccg aac tac acg ttc gcg cta tgg 15207Gly Pro Cys Thr Pro Leu Pro Ala Pro Asn Tyr Thr Phe Ala Leu Trp830 835 840agg gtg tct gca gag gaa tac gtg gag ata agg cag gtg ggg gac ttc 15255Arg Val Ser Ala Glu Glu Tyr Val Glu Ile Arg Gln Val Gly Asp Phe845 850 855cac tac gtg acg ggt atg act act gac aat ctt aaa tgc ccg tgc cag 15303His Tyr Val Thr Gly Met Thr Thr Asp Asn Leu Lys Cys Pro Cys Gln860 865 870 875gtc cca tcg ccc gaa ttt ttc aca gaa ttg gac ggg gtg cgc cta cat 15351Val Pro Ser Pro Glu Phe Phe Thr Glu Leu Asp Gly Val Arg Leu His880 885 890agg ttt gcg ccc ccc tgc aag ccc ttg ctg cgg gag gag gta tca ttc 15399Arg Phe Ala Pro Pro Cys Lys Pro Leu Leu Arg Glu Glu Val Ser Phe895 900 905aga gta gga ctc cac gaa tac ccg gta ggg tcg caa tta cct tgc gag 15447Arg Val Gly Leu His Glu Tyr Pro Val Gly Ser Gln Leu Pro Cys Glu910 915 920ccc gaa ccg gac gtg gcc gtg ttg acg tcc atg ctc act gat ccc tcc 15495Pro Glu Pro Asp Val Ala Val Leu Thr Ser Met Leu Thr Asp Pro Ser925 930 935cat ata aca gca gag gcg gcc ggg cga agg ttg gcg agg gga tca ccc 15543His Ile Thr Ala Glu Ala Ala Gly Arg Arg Leu Ala Arg Gly Ser Pro940 945 950 955ccc tct gtg gcc agc tcc tcg gct agc cag cta tcc gct cca tct ctc 15591Pro Ser Val Ala Ser Ser Ser Ala Ser Gln Leu Ser Ala Pro Ser Leu960 965 970aag gca act tgc acc gct aac cat gac tcc cct gat gct gag ctc ata 15639Lys Ala Thr Cys Thr Ala Asn His Asp Ser Pro Asp Ala Glu Leu Ile975 980 985gag gcc aac ctc cta tgg agg cag gag atg ggc ggc aac atc acc agg 15687Glu Ala Asn Leu Leu Trp Arg Gln Glu Met Gly Gly Asn Ile Thr Arg990 9951000gtt gag tca gaa aac aaa gtg gtg att ctg gac tcc ttc gat ccg ctt 15735Val Glu Ser Glu Asn Lys Val Val Ile Leu Asp Ser Phe Asp Pro Leu100510101015gtg gcg gag gag gac gag cgg gag atc tcc gta ccc gca gaa atc ctg 15783Val Ala Glu Glu Asp Glu Arg Glu Ile Ser Val Pro Ala Glu Ile Leu1020 102510301035cgg aag tct cgg aga ttc gcc cag gcc ctg ccc gtt tgg gcg cgg ccg 15831Arg Lys Ser Arg Arg Phe Ala Gln Ala Leu Pro Val Trp Ala Arg Pro104010451050gac tat aac ccc ccg cta gtg gag acg tgg aaa aag ccc gac tac gaa 15879Asp Tyr Asn Pro Pro Leu Val Glu Thr Trp Lys Lys Pro Asp Tyr Glu105510601065cca cct gtg gtc cat ggc tgc ccg ctt cca cct cca aag tcc cct cct 15927Pro Pro Val Val His Gly Cys Pro Leu Pro Pro Pro Lys Ser Pro Pro107010751080gtg cct ccg cct cgg aag aag cgg acg gtg gtc ctc act gaa tca acc 15975Val Pro Pro Pro Arg Lys Lys Arg Thr Val Val Leu Thr Glu Ser Thr108510901095cta tct act gcc ttg gcc gag ctc gcc acc aga agc ttt ggc agc tcc 16023Leu Ser Thr Ala Leu Ala Glu Leu Ala Thr Arg Ser Phe Gly Ser Ser1100 110511101115tca act tcc ggc att acg ggc gac aat acg aca aca tcc tct gag ccc 16071Ser Thr Ser Gly Ile Thr Gly Asp Asn Thr Thr Thr Ser Ser Glu Pro112011251130gcc cct tct ggc tgc ccc ccc gac tcc gac gct gag tcc tat tcc tcc 16119Ala Pro Ser Gly Cys Pro Pro Asp Ser Asp Ala Glu Ser Tyr Ser Ser113511401145atg ccc ccc ctg gag ggg gag cct ggg gat ccg gat ctt agc gac ggg 16167Met Pro Pro Leu Glu Gly Glu Pro Gly Asp Pro Asp Leu Ser Asp Gly115011551160rca tgg rca acg gtc agt agt gag gcc aac gcg gag gat gtc gtg tgc 16215Ser Trp Ser Thr Val Ser Ser Glu Ala Asn Ala Glu Asp Val Val Cys116511701175tgc tca atg tct tac tct tgg aca ggc gca ctc gtc acc ccg tgc gcc 16263Cys Ser Met Ser Tyr Ser Trp Thr Gly Ala Leu Val Thr Pro Cys Ala1180 118511901195gcg gaa gaa cag aaa ctg ccc atc aat gca cta agc aac tcg ttg cta 16311Ala Glu Glu Gln Lys Leu Pro Ile Asn Ala Leu Ser Asn Ser Leu Leu120012051210cgt cac cac aat ttg gtg tat tcc acc acc tca cgc agt gct tgc caa 16359Arg His His Asn Leu Val Tyr Ser Thr Thr Ser Arg Ser Ala Cys Gln121512201225agg cag aag aaa gtc aca ttt gac aga ctg caa gtt ctg gac agc cat 16407Arg Gln Lys Lys Val Thr Phe Asp Arg Leu Gln Val Leu Asp Ser His123012351240tac cag gac gta ctc aag gag gtt aaa gca gcg gcg tca aaa gtg aag 16455Tyr Gln Asp Val Leu Lys Glu Val Lys Ala Ala Ala Ser Lys Val Lys124512501255gct aac ttg cta tcc gta gag gaa gct tgc agc ctg acg ccc cca cac 16503Ala Asn Leu Leu Ser Val Glu Glu Ala Cys Ser Leu Thr Pro Pro His1260 126512701275tca gcc aaa tcc aag ttt ggt tat ggg gca aaa gac gtc cgt tgc cat 16551Ser Ala Lys Ser Lys Phe Gly Tyr Gly Ala Lys Asp Val Arg Cys His128012851290gcc aga aag gcc gta acc cac atc aac tcc gtg tgg aaa gac ctt ctg 16599Ala Arg Lys Ala Val Thr His Ile Asn Ser Val Trp Lys Asp Leu Leu129513001305gaa gac aat gta aca cca ata gac act acc atc atg gct aag aac gag 16647Glu Asp Asn Val Thr Pro Ile Asp Thr Thr Ile Met Ala Lys Asn Glu131013151320gtt ttc tgc gtt cag cct gag aag ggg ggt cgt aag cca gct cgt ctc 16695Val Phe Cys Val Gln Pro Glu Lys Gly Gly Arg Lys Pro Ala Arg Leu132513301335atc gtg ttc ccc gat ctg ggc gtg cgc gtg tgc gaa aag atg gct ttg 16743Ile Val Phe Pro Asp Leu Gly Val Arg Val Cys Glu Lys Met Ala Leu1340 134513501355tac gac gtg gtt aca aag ctc ccc ttg gcc gtg atg gga agc tcc tac 16791Tyr Asp Val Val Thr Lys Leu Pro Leu Ala Val Met Gly Ser Ser Tyr136013651370gga ttc caa tac tca cca gga cag cgg gtt gaa ttc ctc gtg caa gcg 16839Gly Phe Gln Tyr Ser Pro Gly Gln Arg Val Glu Phe Leu Val Gln Ala137513801385tgg aag tcc aag aaa acc cca atg ggg ttc tcg tat gat acc cgc tgc 16887Trp Lys Ser Lys Lys Thr Pro Met Gly Phe Ser Tyr Asp Thr Arg Cys139013951400ttt gac tcc aca gtc act gag agc gac atc cgt acg gag gag gca atc 16935Phe Asp Ser Thr Val Thr Glu Ser Asp Ile Arg Thr Glu Glu Ala Ile140514101415tac caa tgt tgt gac ctc gac ccc caa gcc cgc gtg gcc atc aag tcc 16983Tyr Gln Cys Cys Asp Leu Asp Pro Gln Ala Arg Val Ala Ile Lys Ser1420 142514301435ctc acc gag agg ctt tat gtt ggg ggc cct ctt acc aat tca agg ggg 17031Leu Thr Glu Arg Leu Tyr Val Gly Gly Pro Leu Thr Asn Ser Arg Gly144014451450gag aac tgc ggc tat cgc agg tgc cgc gcg agc ggc gta ctg aca act 17079Glu Asn Cys Gly Tyr Arg Arg Cys Arg Ala Ser Gly Val Leu Thr Thr145514601465agc tgt ggt aac acc ctc act tgc tac atc aag gcc cgg gca gcc tgt 17127Ser Cys Gly Asn Thr Leu Thr Cys Tyr Ile Lys Ala Arg Ala Ala Cys147014751480cga gcc gca ggg ctc cag gac tgc acc atg ctc gtg tgt ggc gac gac 17175Arg Ala Ala Gly Leu Gln Asp Cys Thr Met Leu Val Cys Gly Asp Asp148514901495tta gtc gtt atc tgt gaa agc gcg ggg gtc cag gag gac gcg gcg agc 17223Leu Val Val Ile Cys Glu Ser Ala Gly Val Gln Glu Asp Ala Ala Ser1500 150515101515ctg aga gcc ttc acg gag gct atg acc agg tac tcc gcc ccc cct ggg 17271Leu Arg Ala Phe Thr Glu Ala Met Thr Arg Tyr Ser Ala Pro Pro Gly152015251530gac ccc cca caa cca gaa tac gac ttg gag ctc ata aca tca tgc tcc 17319Asp Pro Pro Gln Pro Glu Tyr Asp Leu Glu Leu Ile Thr Ser Cys Ser153515401545tcc aac gtg tca gtc gcc cac gac ggc gct gga aag agg gtc tac tac 17367Ser Asn Val Ser Val Ala His Asp Gly Ala Gly Lys Arg Val Tyr Tyr155015551560ctc acc cgt gac cct aca acc ccc ctc gcg aga gct gcg tgg gag aca 17415Leu Thr Arg Asp Pro Thr Thr Pro Leu Ala Arg Ala Ala Trp Glu Thr156515701575gca aga cac act cca gtc aat tcc tgg cta ggc aac ata atc atg ttt 17463Ala Arg His Thr Pro Val Asn Ser Trp Leu Gly Asn Ile Ile Met Phe1580 158515901595gcc ccc aca ctg tgg gcg agg atg ata ctg atg acc cat ttc ttt agc 17511Ala Pro Thr Leu Trp Ala Arg Met Ile Leu Met Thr His Phe Phe Ser160016051610gtc ctt ata gcc agg gac cag ctt gaa cag gcc ctc gat tgc gag atc 17559Val Leu Ile Ala Arg Asp Gln Leu Glu Gln Ala Leu Asp Cys Glu Ile161516201625tac ggg gcc tgc tac tcc ata gaa cca ctg gat cta cct cca atc att 17607Tyr Gly Ala Cys Tyr Ser Ile Glu Pro Leu Asp Leu Pro Pro Ile Ile163016351640caa aga ctc cat ggc ctc agc gca ttt tca ctc cac agt tac tct cca 17655Gln Arg Leu His Gly Leu Ser Ala Phe Ser Leu His Ser Tyr Ser Pro164516501655ggt gaa atc aat agg gtg gcc gca tgc ctc aga aaa ctt ggg gta ccg 17703Gly Glu Ile Asn Arg Val Ala Ala Cys Leu Arg Lys Leu Gly Val Pro1660 166516701675ccc ttg cga gct tgg aga cac cgg gcc cgg agc gtc cgc gct agg ctt 17751Pro Leu Arg Ala Trp Arg His Arg Ala Arg Ser Val Arg Ala Arg Leu168016851690ctg gcc aga gga ggc agg gct gcc ata tgt ggc aag tacctc ttc aac 17799Leu Ala Arg Gly Gly Arg Ala Ala Ile Cys Gly Lys Tyr Leu Phe Asn169517001705tgg gca gta aga aca aag ctc aaa ctc act cca ata gcg gcc gct ggc 17847Trp Ala Val Arg Thr Lys Leu Lys Leu Thr Pro Ile Ala Ala Ala Gly171017151720cag ctg gac ttg tcc ggc tgg ttc acg gct ggc tac agc ggg gga gac 17895Gln Leu Asp Leu Ser Gly Trp Phe Thr Ala Gly Tyr Ser Gly Gly Asp172517301735att tat cac agc gtg tct cat gcc cgg ccc cgc tgg atc tgg ttt tgc 17943lle Tyr His Ser Val Ser His Ala Arg Pro Arg Trp Ile Trp Phe Cys1740 174517501755cta ctc ctg ctt gct gca ggg gta ggc atc tac ctc ctc ccc aac cga 17991Leu Leu Leu Leu Ala Ala Gly Val Gly Ile Tyr Leu Leu Pro Asn Arg176017651770atg agc acg aat cct aaa cct caa aga aag acc aaa cgt aac acc aac 18039Met Ser Thr Asn Pro Lys Pro Gln Arg Lys Thr Lys Arg Asn Thr Asn177517801785cgg cgg ccg cag gac gtc aag ttc ccg ggt ggc ggt cag atc gtt ggt 18087Arg Arg Pro Gln Asp Val Lys Phe Pro Gly Gly Gly Gln Ile Val Gly179017951800gga gtt tac ttg ttg ccg cgc agg ggc cct aga ttg ggt gtg cgc gcg 18135Gly Val Tyr Leu Leu Pro Arg Arg Gly Pro Arg Leu Gly Val Arg Ala180518101815acg aga aag act tcc gag cgg tcg caa cct cga ggt aga cgt cag cct 18183Thr Arg Lys Thr Ser Glu Arg Ser Gln Pro Arg Gly Arg Arg Gln Pro1820 182518301835atc ccc aag gct cgt cgg ccc gag ggc agg acc tgg gct cag ccc ggg 18231Ile Pro Lys Ala Arg Arg Pro Glu Gly Arg Thr Trp Ala Gln Pro Gly184018451850tac cct tgg ccc ctc tat ggc aat gag ggc tgc ggg tgg gcg gga tgg 18279Tyr Pro Trp Pro Leu Tyr Gly Asn Glu Gly Cys Gly Trp Ala Gly Trp185518601865ctc ctg tct ccc cgt ggc tct cgg cct agc tgg ggc ccc aca gac ccc 18327Leu Leu Ser Pro Arg Gly Ser Arg Pro Ser Trp Gly Pro Thr Asp Pro187018751880cgg cgt agg tcg cgc aat ttg ggt aag gtc atc gat acc ctt acg tgc 18375Arg Arg Arg Ser Arg Asn Leu Gly Lys Val Ile Asp Thr Leu Thr Cys188518901895ggc ttc gcc gac ctc atg ggg tac ata ccg ctc gtc taatagtcga18421Gly Phe Ala Asp Leu Met Gly Tyr Ile Pro Leu Val1900 19051910ctttgttccc actgtacttt tagctcgtac aaaatacaat atacttttca tttctccgta 18481aacaacatgt tttcccatgt aatatccttt tctatttttc gttccgttac caactttaca 18541catactttat atagctattc acttctatac actaaaaaac taagacaatt ttaattttgc 18601tgcctgccat atttcaattt gttataaatt cctataattt atcctattag tagctaaaaa 18661aagatgaatg tgaatcgaat cctaagagaa ttggatctga tccacaggac gggtgtggtc 18721gccatgatcg cgtagtcgat agtggctcca agtagcgaag cgagcaggac tgggcggcgg 18781ccaaagcggt cggacagtgc tccgagaacg ggtgcgcata gaaattgcat caacgcatat 18841agcgctagca gcacgccata gtgactggcg atgctgtcgg aatggacgat atcccgcaag 18901aggcccggca gtaccggcat aaccaagcct atgcctacag catccagggt gacggtgccg 18961aggatgacga tgagcgcatt gttagatttc atacacggtg cctgactgcg ttagcaattt 19021aactgtgata aactaccgca ttaaagcttt ttctttccaa tttttttttt ttcgtcatta 19081taaaaatcat tacgaccgag attcccgggt aataactgat ataattaaat tgaagctcta 19141atttgtgagt ttagtataca tgcatttact tataatacag ttttttagtt ttgctggccg 19201catcttctca aatatgcttc ccagcctgct tttctgtaac gttcaccctc taccttagca 19261tcccttccct ttgcaaatag tcctcttcca acaataataa tgtcagatcc tgtagagacc 19321acatcatcca cggttctata ctgttgaccc aatgcgtctc ccttgtcatc taaacccaca 19381ccgggtgtca taatcaacca atcgtaacct tcatctcttc cacccatgtc tctttgagca 19441ataaagccga taacaaaatc tttgtcgctc ttcgcaatgt caacagtacc cttagtatat 19501tctccagtag atagggagcc cttgcatgac aattctgcta acatcaaaag gcctctaggt 19561tcctttgtta cttcttctgc cgcctgcttc aaaccgctaa caatacctgg gcccaccaca 19621ccgtgtgcat tcgtaatgtc tgcccattct gctattctgt atacacccgc agagtactgc 19681aatttgactg tattaccaat gtcagcaaat tttctgtctt cgaagagtaa aaaattgtac 19741ttggcggata atgcctttag cggcttaact gtgccctcca tggaaaaatc agtcaagata 19801tccacatgtg tttttagtaa acaaattttg ggacctaatg cttcaactaa ctccagtaat 19861tccttggtgg tacgaacatc caatgaagca cacaagtttg tttgcttttc gtgcatgata 19921ttaaatagct tggcagcaac aggactagga tgagtagcag cacgttcctt atatgtagct 19981ttcgacatga tttatcttcg tttcctgcag gtttttgttc tgtgcagttg ggttaagaat 20041actgggcaat ttcatgtttc ttcaacacta catatgcgta tatataccaa tctaagtctg 20101tgctccttcc ttcgttcttc cttctgttcg gagattaccg aatcaaaaaa atttcaagga 20161aaccgaaatc aaaaaaaaga ataaaaaaaa aatgatgaat tgaaaagctt atcgat 20217210172111911212PRT213人工序列220223人工序列的描述pd.delta.NS3NS5.pj.core14040017Met Ala Ala Tyr Ala Ala Gln Gly Tyr Lys Val Leu Val Leu Asn Pro1 5 10 15Ser Val Ala Ala Thr Leu Gly Phe Gly Ala Tyr Met Ser Lys Ala His20 25 30Gly Ile Asp Pro Asn Ile Arg Thr Gly Val Arg Thr Ile Thr Thr Gly35 40 45Ser Pro Ile Thr Tyr Ser Thr Tyr Gly Lys Phe Leu Ala Asp Gly Gly50 55 60Cys Ser Gly Gly Ala Tyr Asp Ile Ile Ile Cys Asp Glu Cys His Ser65 70 75 80Thr Asp Ala Thr Ser Ile Leu Gly Ile Gly Thr Val Leu Asp Gln Ala85 90 95Glu Thr Ala Gly Ala Arg Leu Val Val Leu Ala Thr Ala Thr Pro Pro100 105 110Gly Ser Val Thr Val Pro His Pro Asn Ile Glu Glu Val Ala Leu Ser115 120 125Thr Thr Gly Glu Ile Pro Phe Tyr Gly Lys Ala Ile Pro Leu Glu Val130 135 140Ile Lys Gly Gly Arg His Leu Ile Phe Cys His Ser Lys Lys Lys Cys145 150 155 160Asp Glu Leu Ala Ala Lys Leu Val Ala Leu Gly Ile Asn Ala Val Ala165 170 175Tyr Tyr Arg Gly Leu Asp Val Ser Val Ile Pro Thr Ser Gly Asp Val180 185 190Val Val Val Ala Thr Asp Ala Leu Met Thr Gly Tyr Thr Gly Asp Phe195 200 205Asp Ser Val Ile Asp Cys Asn Thr Cys Val Thr Gln Thr Val Asp Phe210 215 220Ser Leu Asp Pro Thr Phe Thr Ile Glu Thr Ile Thr Leu Pro Gln Asp225 230 235 240Ala Val Ser Arg Thr Gln Arg Arg Gly Arg Thr Gly Arg Gly Lys Pro245 250 255Gly Ile Tyr Arg Phe Val Ala Pro Gly Glu Arg Pro Ser Gly Met Phe260 265 270Asp Ser Ser Val Leu Cys Glu Cys Tyr Asp Ala Gly Cys Ala Trp Tyr275 280 285Glu Leu Thr Pro Ala Glu Thr Thr Val Arg Leu Arg Ala Tyr Met Asn290 295 300Thr Pro Gly Leu Pro Val Cys Gln Asp His Leu Glu Phe Trp Glu Gly305 310 315 320Val Phe Thr Gly Leu Thr His Ile Asp Ala His Phe Leu Ser Gln Thr325 330 335Lys Gln Ser Gly Glu Asn Leu Pro Tyr Leu Val Ala Tyr Gln Ala Thr340 345 350Val Cys Ala Arg Ala Gln Ala Pro Pro Pro Ser Trp Asp Gln Met Trp
355 360 365Lys Cys Leu Ile Arg Leu Lys Pro Thr Leu His Gly Pro Thr Pro Leu370 375 380Leu Tyr Arg Leu Gly Ala Val Gln Asn Glu Ile Thr Leu Thr His Pro385 390 395 400Val Thr Lys Tyr Ile Met Thr Cys Met Ser Ala Asp Leu Glu Val Val405 410 415Thr Ser Thr Trp Val Leu Val Gly Gly Val Leu Ala Ala Leu Ala Ala420 425 430Tyr Cys Leu Ser Thr Gly Cys Val Val Ile Val Gly Arg Val Val Leu435 440 445Ser Gly Lys Pro Ala Ile Ile Pro Asp Arg Glu Val Leu Tyr Arg Glu450 455 460Phe Asp Glu Met Glu Glu Cys Ser Gln His Leu Pro Tyr Ile Glu Gln465 470 475 480Gly Met Met Leu Ala Glu Gln Phe Lys Gln Lys Ala Leu Gly Leu Leu485 490 495Gln Thr Ala Ser Arg Gln Ala Glu Val Ile Ala Pro Ala Val Gln Thr500 505 510Asn Trp Gln Lys Leu Glu Thr Phe Trp Ala Lys His Met Trp Asn Phe515 520 525Ile Ser Gly Ile Gln Tyr Leu Ala Gly Leu Ser Thr Leu Pro Gly Asn530 535 540Pro Ala Ile Ala Ser Leu Met Ala Phe Thr Ala Ala Val Thr Ser Pro545 550 555 560Leu Thr Thr Ser Gln Thr Leu Leu Phe Asn Ile Leu Gly Gly Trp Val565 570 575Ala Ala Gln Leu Ala Ala Pro Gly Ala Ala Thr Ala Phe Val Gly Ala580 585 590Gly Leu Ala Gly Ala Ala Ile Gly Ser Val Gly Leu Gly Lys Val Leu595 600 605Ile Asp Ile Leu Ala Gly Tyr Gly Ala Gly Val Ala Gly Ala Leu Val610 615 620Ala Phe Lys Ile Met Ser Gly Glu Val Pro Ser Thr Glu Asp Leu Val625 630 635 640Asn Leu Leu Pro Ala Ile Leu Ser Pro Gly Ala Leu Val Val Gly Val645 650 655Val Cys Ala Ala Ile Leu Arg Arg His Val Gly Pro Gly Glu Gly Ala660 665 670Val Gln Trp Met Asn Arg Leu Ile Ala Phe Ala Ser Arg Gly Asn His675 680 685Val Ser Pro Thr His Tyr Val Pro Glu Ser Asp Ala Ala Ala Arg Val690 695 700Thr Ala Ile Leu Ser Ser Leu Thr Val Thr Gln Leu Leu Arg Arg Leu705 710 715 720His Gln Trp Ile Ser Ser Glu Cys Thr Thr Pro Cys Ser Gly Ser Trp725 730 735Leu Arg Asp Ile Trp Asp Trp Ile Cys Glu Val Leu Ser Asp Phe Lys740 745 750Thr Trp Leu Lys Ala Lys Leu Met Pro Gln Leu Pro Gly Ile Pro Phe755 760 765Val Ser Cys Gln Arg Gly Tyr Lys Gly Val Trp Arg Gly Asp Gly Ile770 775 780Met His Thr Arg Cys His Cys Gly Ala Glu Ile Thr Gly His Val Lys785 790 795 800Asn Gly Thr Met Arg Ile Val Gly Pro Arg Thr Cys Arg Asn Met Trp805 810 815Ser Gly Thr Phe Pro Ile Asn Ala Tyr Thr Thr Gly Pro Cys Thr Pro820 825 830Leu Pro Ala Pro Asn Tyr Thr Phe Ala Leu Trp Arg Val Ser Ala Glu835 840 845Glu Tyr Val Glu Ile Arg Gln Val Gly Asp Phe His Tyr Val Thr Gly850 855 860Met Thr Thr Asp Asn Leu Lys Cys Pro Cys Gln Val Pro Ser Pro Glu865 870 875 880Phe Phe Thr Glu Leu Asp Gly Val Arg Leu His Arg Phe Ala Pro Pro885 890 895Cys Lys Pro Leu Leu Arg Glu Glu Val Ser Phe Arg Val Gly Leu His900 905 910Glu Tyr Pro Val Gly Ser Gln Leu Pro Cys Glu Pro Glu Pro Asp Val915 920 925Ala Val Leu Thr Ser Met Leu Thr Asp Pro Ser His Ile Thr Ala Glu930 935 940Ala Ala Gly Arg Arg Leu Ala Arg Gly Ser Pro Pro Ser Val Ala Ser945 950 955 960Ser Ser Ala Ser Gln Leu Ser Ala Pro Ser Leu Lys Ala Thr Cys Thr965 970 975Ala Asn His Asp Ser Pro Asp Ala Glu Leu Ile Glu Ala Asn Leu Leu980 985 990Trp Arg Gln Glu Met Gly Gly Asn Ile Thr Arg Val Glu Ser Glu Asn99510001005Lys Val Val Ile Leu Asp Ser Phe Asp Pro Leu Val Ala Glu Glu Asp101010151020Glu Arg Glu Ile Ser Val Pro Ala Glu Ile Leu Arg Lys Ser Arg Arg025103010351040Phe Ala Gln Ala Leu Pro Val Trp Ala Arg Pro Asp Tyr Asn Pro Pro104510501055Leu Val Glu Thr Trp Lys Lys Pro Asp Tyr Glu Pro Pro Val Val His106010651070Gly Cys Pro Leu Pro Pro Pro Lys Ser Pro Pro Val Pro Pro Pro Arg107510801085Lys Lys Arg Thr Val Val Leu Thr Glu SerThr Leu Ser Thr Ala Leu109010951100Ala Glu Leu Ala Thr Arg Ser Phe Gly Ser Ser Ser Thr Ser Gly Ile105111011151120Thr Gly Asp Asn Thr Thr Thr Ser Ser Glu Pro Ala Pro Ser Gly Cys112511301135Pro Pro Asp Ser Asp Ala Glu Ser Tyr Ser Ser Met Pro Pro Leu Glu114011451150Gly Glu Pro Gly Asp Pro Asp Leu Ser Asp Gly Ser Trp Ser Thr Val115511601165Ser Ser Glu Ala Asn Ala Glu Asp Val Val Cys Cys Ser Met Ser Tyr117011751180Ser Trp Thr Gly Ala Leu Val Thr Pro Cys Ala Ala Glu Glu Gln Lys185119011951200Leu Pro Ile Asn Ala Leu Ser Asn Ser Leu Leu Arg His His Asn Leu120512101215ValTyr Ser Thr Thr Ser Arg Ser Ala Cys Gln Arg Gln Lys Lys Val122012251230Thr Phe Asp Arg Leu Gln Val Leu Asp Ser His Tyr Gln Asp Val Leu123512401245Lys Glu Val Lys Ala Ala Ala Ser Lys Val Lys Ala Asn Leu Leu Ser125012551260Val Glu Glu Ala Cys Ser Leu Thr Pro Pro His Ser Ala Lys Ser Lys265127012751280Phe Gly Tyr Gly Ala Lys Asp Val Arg Cys His Ala Arg Lys Ala Val128512901295Thr His Ile Asn Ser Val Trp Lys Asp Leu Leu Glu Asp Asn Val Thr130013051310Pro Ile Asp Thr Thr Ile Met Ala Lys Asn Glu Val Phe Cys Val Gln131513201325Pro Glu Lys Gly Gly Arg Lys Pro Ala Arg Leu Ile Val Phe Pro Asp133013351340Leu Gly Val Arg Val Cys Glu Lys Met Ala Leu Tyr Asp Val Val Thr345135013551360Lys Leu Pro Leu Ala Val Met Gly Ser Ser Tyr Gly Phe Gln Tyr Ser136513701375Pro Gly Gln Arg Val Glu Phe Leu Val Gln Ala Trp Lys Ser Lys Lys138013851390Thr Pro Met Gly Phe Ser Tyr Asp Thr Arg Cys Phe Asp Ser Thr Val139514001405Thr Glu Ser Asp Ile Arg Thr Glu Glu Ala Ile Tyr Gln Cys Cys Asp141014151420Leu Asp Pro Gln Ala Arg Val Ala Ile Lys Ser Leu Thr Glu Arg Leu425143014351440Tyr Val Gly Gly Pro Leu Thr Asn Ser Arg Gly Glu Asn Cys Gly Tyr144514501455Arg Arg Cys Arg Ala Ser Gly Val Leu Thr Thr Ser Cys Gly Asn Thr146014651470Leu Thr Cys Tyr Ile Lys Ala Arg Ala Ala Cys Arg Ala Ala Gly Leu147514801485Gln Asp Cys Thr Met Leu Val Cys Gly Asp Asp Leu Val Val Ile Cys14901495 1500Glu Ser Ala Gly Val Gln Glu Asp Ala Ala Ser Leu Arg Ala Phe Thr505151015151520Glu Ala Met Thr Arg Tyr Ser Ala Pro Pro Gly Asp Pro Pro Gln Pro152515301535Glu Tyr Asp Leu Glu Leu Ile Thr Ser Cys Ser Ser Asn Val Ser Val154015451550Ala His Asp Gly Ala Gly Lys Arg Val Tyr Tyr Leu Thr Arg Asp Pro155515601565Thr Thr Pro Leu Ala Arg Ala Ala Trp Glu Thr Ala Arg His Thr Pro157015751580Val Asn Ser Trp Leu Gly Asn Ile Ile Met Phe Ala Pro Thr Leu Trp585159015951600Ala Arg Met Ile Leu Met Thr His Phe Phe Ser Val Leu Ile Ala Arg160516101615Asp Gln Leu Glu Gln Ala Leu Asp Cys Glu Ile Tyr Gly Ala Cys Tyr162016251630Ser Ile Glu Pro Leu Asp Leu Pro Pro Ile Ile Gln Arg Leu His Gly163516401645Leu Ser Ala Phe Ser Leu His Ser Tyr Ser Pro Gly Glu Ile Asn Arg165016551660Val Ala Ala Cys Leu Arg Lys Leu Gly Val Pro Pro Leu Arg Ala Trp665167016751680Arg His Arg Ala Arg Ser Val Arg Ala Arg Leu Leu Ala Arg Gly Gly168516901695Arg Ala Ala Ile Cys Gly Lys Tyr Leu Phe Asn Trp Ala Val Arg Thr170017051710Lys Leu Lys Leu Thr Pro Ile Ala Ala Ala Gly Gln Leu Asp Leu Ser171517201725Gly Trp Phe Thr Ala Gly Tyr Ser Gly Gly Asp Ile Tyr His Ser Val173017351740Ser His Ala Arg Pro Arg Trp Ile Trp Phe Cys Leu Leu Leu Leu Ala745175017551760Ala Gly Val Gly Ile Tyr Leu Leu Pro Asn Arg Met Ser Thr Asn Pro176517701775Lys Pro Gln Arg Lys Thr Lys Arg Asn Thr Asn Arg Arg Pro Gln Asp178017851790Val Lys Phe Pro Gly Gly Gly Gln Ile Val Gly Gly Val Tyr Leu Leu179518001805Pro Arg Arg Gly Pro Arg Leu Gly Val Arg Ala Thr Arg Lys Thr Ser181018151820Glu Arg Ser Gln Pro Arg Gly Arg Arg Gln Pro Ile Pro Lys Ala Arg825183018351840Arg Pro Glu Gly Arg Thr Trp Ala Gln Pro Gly Tyr Pro Trp Pro Leu184518501855Tyr Gly Asn Glu Gly Cys Gly Trp Ala Gly Trp Leu Leu Ser Pro Arg186018651870Gly Ser Arg Pro Ser Trp Gly Pro Thr Asp Pro Arg Arg Arg Ser Arg187518801885Asn Leu Gly Lys Val Ile Asp Thr Leu Thr Cys Gly Phe Ala Asp Leu189018951900Met Gly Tyr Ile Pro Leu Val90519102101821120247212DNA213人工序列220223人工序列的描述pd.delta.NS3NS5.pj.core150220221CDS222(12679). (18441)40018atcgatccta ccccttgcgc taaagaagta tatgtgccta ctaacgcttg tctttgtctc 60tgtcactaaa cactggatta ttactcccag atacttattt tggactaatt taaatgattt 120cggatcaacg ttcttaatat cgctgaatct tccacaattg atgaaagtag ctaggaagag 180gaattggtat aaagtttttg tttttgtaaa tctcgaagta tactcaaacg aatttagtat 240tttctcagtg atctcccaga tgctttcacc ctcacttaga agtgctttaa gcattttttt 300actgtggcta tttcccttat ctgcttcttc cgatgattcg aactgtaatt gcaaactact 360tacaatatca gtgatatcag attgatgttt ttgtccatag taaggaataa ttgtaaattc 420ccaagcagga atcaatttct ttaatgaggc ttccagaatt gttgcttttt gcgtcttgta 480tttaaactgg agtgatttat tgacaatatc gaaactcagc gaattgctta tgatagtatt 540atagctcatg aatgtggctc tcttgattgc tgttccgtta tgtgtaatca tccaacataa 600ataggttagt tcagcagcac ataatgctat tttctcacct gaaggtcttt caaacctttc 660cacaaactga cgaacaagca ccttaggtgg tgttttacat aatatatcaa attgtggcat 720gcttagcgcc gatcttgtgt gcaattgata tctagtttca actactctat ttatcttgta 780tcttgcagta ttcaaacacg ctaactcgaa aaactaactt taattgtcct gtttgtctcg 840cgttctttcg aaaaatgcac cggccgcgca ttatttgtac tgcgaaaata attggtactg 900cggtatcttc atttcatatt ttaaaaatgc acctttgctg cttttcctta atttttagac 960ggcccgcagg ttcgttttgc ggtactatct tgtgataaaa agttgttttg acatgtgatc 1020tgcacagatt ttataatgta ataagcaaga atacattatc aaacgaacaa tactggtaaa 1080agaaaaccaa aatggacgac attgaaacag ccaagaatct gacggtaaaa gcacgtacag 1140cttatagcgt ctgggatgta tgtcggctgt ttattgaaat gattgctcct gatgtagata 1200ttgatataga gagtaaacgt aagtctgatg agctactctt tccaggatat gtcataaggc 1260ccatggaatc tctcacaacc ggtaggccgt atggtcttga ttctagcgca gaagattcca 1320gcgtatcttc tgactccagt gctgaggtaa ttttgcctgc tgcgaagatg gttaaggaaa 1380ggtttgattc gattggaaat ggtatgctct cttcacaaga agcaagtcag gctgccatag 1440atttgatgct acagaataac aagctgttag acaatagaaa gcaactatac aaatctattg 1500ctataataat aggaagattg cccgagaaag acaagaagag agctaccgaa atgctcatga 1560gaaaaatgga ttgtacacag ttattagtcc caccagctcc aacggaagaa gatgttatga 1620agctcgtaag cgtcgttacc caattgctta ctttagttcc accagatcgt caagctgctt 1680taataggtga tttattcatc ccggaatctc taaaggatat attcaatagt ttcaatgaac 1740tggcggcaga gaatcgttta cagcaaaaaa agagtgagtt ggaaggaagg actgaagtga 1800accatgctaa tacaaatgaa gaagttccct ccaggcgaac aagaagtaga gacacaaatg 1860caagaggagc atataaatta caaaacacca tcactgaggg ccctaaagcg gttcccacga 1920aaaaaaggag agtagcaacg agggtaaggg gcagaaaatc acgtaatact tctagggtat 1980gatccaatat caaaggaaat gatagcattg aaggatgaga ctaatccaat tgaggagtgg 2040cagcatatag aacagctaaa gggtagtgct gaaggaagca tacgataccc cgcatggaat 2100gggataatat cacaggaggt actagactac ctttcatcct acataaatag acgcatataa 2160gtacgcattt aagcataaac acgcactatg ccgttcttct catgtatata tatatacagg 2220caacacgcag atataggtgc gacgtgaaca gtgagctgta tgtgcgcagc tcgcgttgca 2280ttttcggaag cgctcgtttt cggaaacgct ttgaagttcc tattccgaag ttcctattct 2340ctagaaagta taggaacttc agagcgcttt tgaaaaccaa aagcgctctg aagacgcact 2400ttcaaaaaac caaaaacgca ccggactgta acgagctact aaaatattgc gaataccgct 2460tccacaaaca ttgctcaaaa gtatctcttt gctatatatc tctgtgctat atccctatat 2520aacctaccca tccacctttc gctccttgaa cttgcatcta aactcgacct ctacatcaac 2580aggcttccaa tgctcttcaa attttactgt caagtagacc catacggctg taatatgctg 2640ctcttcataa tgtaagctta tctttatcga atcgtgtgaa aaactactac cgcgataaac 2700ctttacggtt ccctgagatt gaattagttc ctttagtata tgatacaaga cacttttgaa 2760ctttgtacga cgaattttga ggttcgccat cctctggcta tttccaatta tcctgtcggc 2820tattatctcc gcctcagttt gatcttccgc ttcagactgc catttttcac ataatgaatc 2880tatttcaccc cacaatcctt catccgcctc cgcatcttgt tccgttaaac tattgacttc 2940atgttgtaca ttgtttagtt cacgagaagg gtcctcttca ggcggtagct cctgatctcc 3000tatatgacct ttatcctgtt ctctttccac aaacttagaa atgtattcat gaattatgga 3060gcacctaata acattcttca aggcggagaa gtttgggcca gatgcccaat atgcttgaca 3120tgaaaacgtg agaatgaatt tagtattatt gtgatattct gaggcaattt tattataatc 3180tcgaagataa gagaagaatg cagtgacctt tgtattgaca aatggagatt ccatgtatct 3240aaaaaatacg cctttaggcc ttctgatacc ctttcccctg cggtttagcg tgccttttac 3300attaatatct aaaccctctc cgatggtggc ctttaactga ctaataaatg caaccgatat 3360aaactgtgat aattctgggt gatttatgat tcgatcgaca attgtattgt acactagtgc 3420aggatcaggc caatccagtt ctttttcaat taccggtgtg tcgtctgtat tcagtacatg 3480tccaacaaat gcaaatgcta acgttttgta tttcttataa ttgtcaggaa ctggaaaagt 3540cccccttgtc gtctcgatta cacacctact ttcatcgtac accataggtt ggaagtgctg 3600cataatacat tgcttaatac aagcaagcag tctctcgcca ttcatatttc agttattttc 3660cattacagct gatgtcattg tatatcagcg ctgtaaaaat ctatctgtta cagaaggttt 3720tcgcggtttt tataaacaaa actttcgtta cgaaatcgag caatcacccc agctgcgtat 3780ttggaaattc gggaaaaagt agagcaacgc gagttgcatt ttttacacca taatgcatga 3840ttaacttcga gaagggatta aggctaattt cactagtatg tttcaaaaac ctcaatctgt 3900ccattgaatg ccttataaaa cagctataga ttgcatagaa gagttagcta ctcaatgctt 3960tttgtcaaag cttactgatg atgatgtgtc tactttcagg cgggtctgta gtaaggagaa 4020tgacattata aagctggcac ttagaattcc acggactata gactatacta gtatactccg 4080tctactgtac gatacacttc cgctcaggtc cttgtccttt aacgaggcct taccactctt 4140ttgttactct attgatccag ctcagcaaag gcagtgtgat ctaagattct atcttcgcga 4200tgtagtaaaa ctagctagac cgagaaagag actagaaatg caaaaggcac ttctacaatg 4260gctgccatca ttattatccg atgtgacgct gcattttttt tttttttttt tttttttttt 4320tttttttttt tttttttttt ttttttggta caaatatcat aaaaaaagag aatcttttta 4380agcaaggatt ttcttaactt cttcggcgac agcatcaccg acttcggtgg tactgttgga 4440accacctaaa tcaccagttc tgatacctgc atccaaaacc tttttaactg catcttcaat 4500ggctttacct tcttcaggca agttcaatga caatttcaac atcattgcag cagacaagat 4560agtggcgata gggttgacct tattctttgg caaatctgga gcggaaccat ggcatggttc 4620gtacaaacca aatgcggtgt tcttgtctgg caaagaggcc aaggacgcag atggcaacaa 4680acccaaggag cctgggataa cggaggcttc atcggagatg atatcaccaa acatgttgct 4740ggtgattata ataccattta ggtgggttgg gttcttaact aggatcatgg cggcagaatc 4800aatcaattga tgttgaactt tcaatgtagg gaattcgttc ttgatggttt cctccacagt 4860ttttctccat aatcttgaag aggccaaaac attagcttta tccaaggacc aaataggcaa 4920tggtggctca tgttgtaggg ccatgaaagc ggccattctt gtgattcttt gcacttctgg 4980aacggtgtat tgttcactat cccaagcgac accatcacca tcgtcttcct ttctcttacc 5040aaagtaaata cctcccacta attctctaac aacaacgaag tcagtacctt tagcaaattg 5100tggcttgatt ggagataagt ctaaaagaga gtcggatgca aagttacatg gtcttaagtt 5160ggcgtacaat tgaagttctt tacggatttt tagtaaacct tgttcaggtc taacactacc 5220ggtaccccat ttaggaccac ccacagcacc taacaaaacg gcatcagcct tcttggaggc 5280ttccagcgcc tcatctggaa gtggaacacc tgtagcatcg atagcagcac caccaattaa 5340atgattttcg aaatcgaact tgacattgga acgaacatca gaaatagctt taagaacctt 5400aatggcttcg gctgtgattt cttgaccaac gtggtcacct ggcaaaacga cgatcttctt 5460aggggcagac attacaatgg tatatccttg aaatatatat aaaaaaaaaa aaaaaaaaaa 5520aaaaaaaaaa atgcagcttc tcaatgatat tcgaatacgc tttgaggaga tacagcctaa 5580tatccgacaa actgttttac agatttacga tcgtacttgt tacccatcat tgaattttga 5640acatccgaac ctgggagttt tccctgaaac agatagtata tttgaacctg tataataata 5700tatagtctag cgctttacgg aagacaatgt atgtatttcg gttcctggag aaactattgc 5760atctattgca taggtaatct tgcacgtcgc atccccggtt cattttctgc gtttccatct 5820tgcacttcaa tagcatatct ttgttaacga agcatctgtg cttcattttg tagaacaaaa 5880atgcaacgcg agagcgctaa tttttcaaac aaagaatctg agctgcattt ttacagaaca 5940gaaatgcaac gcgaaagcgc tattttacca acgaagaatc tgtgcttcat ttttgtaaaa 6000caaaaatgca acgcgagagc gctaattttt caaacaaaga atctgagctg catttttaca 6060gaacagaaat gcaacgcgag agcgctattt taccaacaaa gaatctatac ttcttttttg 6120ttctacaaaa atgcatcccg agagcgctat ttttctaaca aagcatctta gattactttt 6180tttctccttt gtgcgctcta taatgcagtc tcttgataac tttttgcact gtaggtccgt 6240taaggttaga agaaggctac tttggtgtct attttctctt ccataaaaaa agcctgactc 6300cacttcccgc gtttactgat tactagcgaa gctgcgggtg cattttttca agataaaggc 6360atccccgatt atattctata ccgatgtgga ttgcgcatac tttgtgaaca gaaagtgata 6420gcgttgatga ttcttcattg gtcagaaaat tatgaacggt ttcttctatt ttgtctctat 6480atactacgta taggaaatgt ttacattttc gtattgtttt cgattcactc tatgaatagt 6540tcttactaca atttttttgt ctaaagagta atactagaga taaacataaa aaatgtagag 6600gtcgagttta gatgcaagtt caaggagcga aaggtggatg ggtaggttat atagggatat 6660agcacagaga tatatagcaa agagatactt ttgagcaatg tttgtggaag cggtattcgc 6720aatattttag tagctcgtta cagtccggtg cgtttttggt tttttgaaag tgcgtcttca 6780gagcgctttt ggttttcaaa agcgctctga agttcctata ctttctagag aataggaact 6840tcggaatagg aacttcaaag cgtttccgaa aacgagcgct tccgaaaatg caacgcgagc 6900tgcgcacata cagctcactg ttcacgtcgc acctatatct gcgtgttgcc tgtatatata 6960tatacatgag aagaacggca tagtgcgtgt ttatgcttaa atgcgtactt atatgcgtct 7020atttatgtag gatgaaaggt agtctagtac ctcctgtgat attatcccat tccatgcggg 7080gtatcgtatg cttccttcag cactaccctt tagctgttct atatgctgcc actcctcaat 7140tggattagtc tcatccttca atgctatcat ttcctttgat attggatcat atgcatagta 7200ccgagaaact agtgcgaagt agtgatcagg tattgctgtt atctgatgag tatacgttgt 7260cctggccacg gcagaagcac gcttatcgct ccaatttccc acaacattag tcaactccgt 7320taggcccttc attgaaagaa atgaggtcat caaatgtctt ccaatgtgag attttgggcc 7380attttttata gcaaagattg aataaggcgc atttttcttc aaagctttat tgtacgatct 7440gactaagtta tcttttaata attggtattc ctgtttattg cttgaagaat tgccggtcct 7500atttactcgt tttaggactg gttcagaatt cctcaaaaat tcatccaaat atacaagtgg 7560atcgatgata agctgtcaaa catgagaatt cttgaagacg aaagggcctc gtgatacgcc 7620tatttttata ggttaatgtc atgataataa tggtttctta gacgtcaggt ggcacttttc 7680ggggaaatgt gcgcggaacc cctatttgtt tatttttcta aatacattca aatatgtatc 7740cgctcatgag acaataaccc tgataaatgc ttcaataata ttgaaaaagg aagagtatga 7800gtattcaaca tttccgtgtc gcccttattc ccttttttgc ggcattttgc cttcctgttt 7860ttgctcaccc agaaacgctg gtgaaagtaa aagatgctga agatcagttg ggtgcacgag 7920tgggttacat cgaactggat ctcaacagcg gtaagatcct tgagagtttt cgccccgaag 7980aacgttttcc aatgatgagc acttttaaag ttctgctatg tggcgcggta ttatcccgtg 8040ttgacgccgg gcaagagcaa ctcggtcgcc gcatacacta ttctcagaat gacttggttg 8100agtactcacc agtcacagaa aagcatctta cggatggcat gacagtaaga gaattatgca 8160gtgctgccat aaccatgagt gataacactg cggccaactt acttctgaca acgatcggag 8220gaccgaagga gctaaccgct tttttgcaca acatggggga tcatgtaact cgccttgatc 8280gttgggaacc ggagctgaat gaagccatac caaacgacga gcgtgacacc acgatgcctg 8340cagcaatggc aacaacgttg cgcaaactat taactggcga actacttact ctagcttccc 8400ggcaacaatt aatagactgg atggaggcgg ataaagttgc aggaccactt ctgcgctcgg 8460cccttccggc tggctggttt attgctgata aatctggagc cggtgagcgt gggtctcgcg 8520gtatcattgc agcactgggg ccagatggta agccctcccg tatcgtagtt atctacacga 8580cggggagtca ggcaactatg gatgaacgaa atagacagat cgctgagata ggtgcctcac 8640tgattaagca ttggtaactg tcagaccaag tttactcata tatactttag attgatttaa 8700aacttcattt ttaatttaaa aggatctagg tgaagatcct ttttgataat ctcatgacca 8760aaatccctta acgtgagttt tcgttccact gagcgtcaga ccccgtagaa aagatcaaag 8820gatcttcttg agatcctttt tttctgcgcg taatctgctg cttgcaaaca aaaaaaccac 8880cgctaccagc ggtggtttgt ttgccggatc aagagctacc aactcttttt ccgaaggtaa 8940ctggcttcag cagagcgcag ataccaaata ctgtccttct agtgtagccg tagttaggcc 9000accacttcaa gaactctgta gcaccgccta catacctcgc tctgctaatc ctgttaccag 9060tggctgctgc cagtggcgat aagtcgtgtc ttaccgggtt ggactcaaga cgatagttac 9120cggataaggc gcagcggtcg ggctgaacgg ggggttcgtg cacacagccc agcttggagc 9180gaacgaccta caccgaactg agatacctac agcgtgagct atgagaaagc gccacgcttc 9240ccgaagggag aaaggcggac aggtatccgg taagcggcag ggtcggaaca ggagagcgca 9300cgagggagct tccaggggga aacgcctggt atctttatag tcctgtcggg tttcgccacc 9360tctgacttga gcgtcgattt ttgtgatgct cgtcaggggg gcggagccta tggaaaaacg 9420ccagcaacgc ggccttttta cggttcctgg ccttttgctg gccttttgct cacatgttct 9480ttcctgcgtt atcccctgat tctgtggata accgtattac cgcctttgag tgagctgata 9540ccgctcgccg cagccgaacg accgagcgca gcgagtcagt gagcgaggaa gcggaagagc 9600gcctgatgcg gtattttctc cttacgcatc tgtgcggtat ttcacaccgc atatggtgca 9660ctctcagtac aatctgctct gatgccgcat agttaagcca gtatacactc cgctatcgct 9720acgtgactgg gtcatggctg cgccccgaca cccgccaaca cccgctgacg cgccctgacg 9780ggcttgtctg ctcccggcat ccgcttacag acaagctgtg accgtctccg ggagctgcat 9840gtgtcagagg ttttcaccgt catcaccgaa acgcgcgagg cagctgcggt aaagctcatc 9900agcgtggtcg tgaagcgatt cacagatgtc tgcctgttca tccgcgtcca gctcgttgag 9960tttctccaga agcgttaatg tctggcttct gataaagcgg gccatgttaa gggcggtttt 10020ttcctgtttg gtcactgatg cctccgtgta agggggattt ctgttcatgg gggtaatgat 10080accgatgaaa cgagagagga tgctcacgat acgggttact gatgatgaac atgcccggtt 10140actggaacgt tgtgagggta aacaactggc ggtatggatg cggcgggacc agagaaaaat 10200cactcagggt caatgccagc gcttcgttaa tacagatgta ggtgttccac agggtagcca 10260gcagcatcct gcgatgcaga tccggaacat aatggtgcag ggcgctgact tccgcgtttc 10320cagactttac gaaacacgga aaccgaagac cattcatgtt gttgctcagg tcgcagacgt 10380tttgcagcag cagtcgcttc acgttcgctc gcgtatcggt gattcattct gctaaccagt 10440aaggcaaccc cgccagccta gccgggtcct caacgacagg agcacgatca tgcgcacccg 10500tggccaggac ccaacgctgc ccgagatgcg ccgcgtgcgg ctgctggaga tggcggacgc 10560gatggatatg ttctgccaag ggttggtttg cgcattcaca gttctccgca agaattgatt 10620ggctccaatt cttggagtgg tgaatccgtt agcgaggtgc cgccggcttc cattcaggtc 10680gaggtggccc ggctccatgc accgcgacgc aacgcgggga ggcagacaag gtatagggcg 10740gcgcctacaa tccatgccaa cccgttccat gtgctcgccg aggcggcata aatcgccgtg 10800acgatcagcg gtccaatgat cgaagttagg ctggtaagag ccgcgagcga tccttgaagc 10860tgtccctgat ggtcgtcatc tacctgcctg gacagcatgg cctgcaacgc gggcatcccg 10920atgccgccgg aagcgagaag aatcataatg gggaaggcca tccagcctcg cgtcgcgaac 10980gccagcaaga cgtagcccag cgcgtcggcc gccatgccgg cgataatggc ctgcttctcg 11040ccgaaacgtt tggtggcggg accagtgacg aaggcttgag cgagggcgtg caagattccg 11100aataccgcaa gcgacaggcc gatcatcgtc gcgctccagc gaaagcggtc ctcgccgaaa 11160atgacccaga gcgctgccgg cacctgtcct acgagttgca tgataaagaa gacagtcata 11220agtgcggcga cgatagtcat gccccgcgcc caccggaagg agctgactgg gttgaaggct 11280ctcaagggca tcggtcgagg atccttcaat atgcgcacat acgctgttat gttcaaggtc 11340ccttcgttta agaacgaaag cggtcttcct tttgagggat gtttcaagtt gttcaaatct 11400atcaaatttg caaatcccca gtctgtatct agagcgttga atcggtgatg cgatttgtta 11460attaaattga tggtgtcacc attaccaggt ctagatatac caatggcaaa ctgagcacaa 11520caataccagt ccggatcaac tggcaccatc tctcccgtag tctcatctaa tttttcttcc 11580ggatgaggtt ccagatatac cgcaacacct ttattatggt ttccctgagg gaataataga 11640atgtcccatt cgaaatcacc aattctaaac ctgggcgaat tgtatttcgg gtttgttaac 11700tcgttccagt caggaatgtt ccacgtgaag ctatcttcca gcaaagtctc cacttcttca 11760tcaaattgtg gagaatactc ccaatgctct tatctatggg acttccggga aacacagtac 11820cgatacttcc caattcgtct tcagagctca ttgtttgttt gaagagacta atcaaagaat 11880cgttttctca aaaaaattaa tatcttaact gatagtttga tcaaaggggc aaaacgtagg 11940ggcaaacaaa cggaaaaatc gtttctcaaa ttttctgatg ccaagaactc taaccagtct 12000tatctaaaaa ttgccttatg atccgtctct ccggttacag cctgtgtaac tgattaatcc 12060tgcctttcta atcaccattc taatgtttta attaagggat tttgtcttca ttaacggctt 12120tcgctcataa aaatgttatg acgttttgcc cgcaggcggg aaaccatcca cttcacgaga 12180ctgatctcct ctgccggaac accgggcatc tccaacttat aagttggaga aataagagaa 12240tttcagattg agagaatgaa aaaaaaaaac ccttagttca taggtccatt ctcttagcgc 12300aactacagag aacaggggca caaacaggca aaaaacgggc acaacctcaa tggagtgatg 12360caacctgcct ggagtaaatg atgacacaag gcaattgacc cacgcatgta tctatctcat 12420tttcttacac cttctattac cttctgctct ctctgatttg gaaaaagctg aaaaaaaagg 12480ttgaaaccag ttccctgaaa ttattcccct acttgactaa taagtatata aagacggtag 12540gtattgattg taattctgta aatctatttc ttaaacttct taaattctac ttttatagtt 12600agtctttttt ttagttttaa aacaccaaga acttagtttc gaataaacac acataaacaa 12660acaagcttac aaaacaaa atg gct gca tat gca gct cag ggc tat aag gtg 12711Met Ala Ala Tyr Ala Ala Gln Gly Tyr Lys Val1 5 10cta gta ctc aac ccc tct gtt gct gca aca ctg ggc ttt ggt gct tac 12759Leu Val Leu Asn Pro Ser Val Ala Ala Thr Leu Gly Phe Gly Ala Tyr15 20 25atg tcc aag gct cat ggg atc gat cct aac atc agg acc ggg gtg aga 12807Met Ser Lys Ala His Gly Ile Asp Pro Asn Ile Arg Thr Gly Val Arg30 35 40aca att acc act ggc agc ccc atc acg tac tcc acc tac ggc aag ttc 12855Thr Ile Thr Thr Gly Ser Pro Ile Thr Tyr Ser Thr Tyr Gly Lys Phe45 50 55ctt gcc gac ggc ggg tgc tcg ggg ggc gct tat gac ata ata att tgt 12903Leu Ala Asp Gly Gly Cys Ser Gly Gly Ala Tyr Asp Ile Ile Ile Cys60 65 70 75gac gag tgc cac tcc acg gat gcc aca tcc atc ttg ggc att ggc act 12951Asp Glu Cys His Ser Thr Asp Ala Thr Ser Ile Leu Gly Ile Gly Thr80 85 90gtc ctt gac caa gca gag act gcg ggg gcg aga ctg gtt gtg ctc gcc 12999Val Leu Asp Gln Ala Glu Thr Ala Gly Ala Arg Leu Val Val Leu Ala95 100 105acc gcc acc cct ccg ggc tcc gtc act gtg ccc cat ccc aac atc gag 13047Thr Ala Thr Pro Pro Gly Ser Val Thr Val Pro His Pro Asn Ile Glu110 115 120gag gtt gct ctg tcc acc acc gga gag atc cct ttt tac ggc aag gct 13095Glu Val Ala Leu Ser Thr Thr Gly Glu Ile Pro Phe Tyr Gly Lys Ala125 130 135atc ccc ctc gaa gta atc aag ggg ggg aga cat ctc atcttc tgt cat 13143Ile Pro Leu Glu Val Ile Lys Gly Gly Arg His Leu Ile Phe Cys His140 145 150 155tca aag aag aag tgc gac gaa ctc gcc gca aag ctg gtc gca ttg ggc 13191Ser Lys Lys Lys Cys Asp Glu Leu Ala Ala Lys Leu Val Ala Leu Gly160 165 170atc aat gcc gtg gcc tac tac cgc ggt ctt gac gtg tcc gtc atc ccg 13239Ile Asn Ala Val Ala Tyr Tyr Arg Gly Leu Asp Val Ser Val Ile Pro175 180 185acc agc ggc gat gtt gtc gtc gtg gca acc gat gcc ctc atg acc ggc 13287Thr Ser Gly Asp Val Val Val Val Ala Thr Asp Ala Leu Met Thr Gly190 195 200tat acc ggc gac ttc gac tcg gtg ata gac tgc aat acg tgt gtc acc 13335Tyr Thr Gly Asp Phe Asp Ser Val Ile Asp Cys Asn Thr Cys Val Thr205 210 215cag aca gtc gat ttc agc ctt gac cct acc ttc acc att gag aca atc 13383Gln Thr Val Asp Phe Ser Leu Asp Pro Thr Phe Thr Ile Glu Thr Ile220 225 230 235acg ctc ccc caa gat gct gtc tcc cgc act caa cgt cgg ggc agg act 13431Thr Leu Pro Gln Asp Ala Val Ser Arg Thr Gln Arg Arg Gly Arg Thr240 245 250ggc agg ggg aag cca ggc atc tac aga ttt gtg gca ccg ggg gag cgc 13479Gly Arg Gly Lys Pro Gly Ile Tyr Arg Phe Val Ala Pro Gly Glu Arg255 260 265ccc tcc ggc atg ttc gac tcg tcc gtc ctc tgt gag tgc tat gac gca 13527Pro Ser Gly Met Phe Asp Ser Ser Val Leu Cys Glu Cys Tyr Asp Ala270 275 280ggc tgt gct tgg tat gag ctc acg ccc gcc gag act aca gtt agg cta 13575Gly Cys Ala Trp Tyr Glu Leu Thr Pro Ala Glu Thr Thr Val Arg Leu285 290 295cga gcg tac atg aac acc ccg ggg ctt ccc gtg tgc cag gac cat ctt 13623Arg Ala Tyr Met Asn Thr Pro Gly Leu Pro Val Cys Gln Asp His Leu300 305 310 315gaa ttt tgg gag ggc gtc ttt aca ggc ctc act cat ata gat gcc cac 13671Glu Phe Trp Glu Gly Val Phe Thr Gly Leu Thr His Ile Asp Ala His320 325 330ttt cta tcc cag aca aag cag agt ggg gag aac ctt cct tac ctg gta 13719Phe Leu Ser Gln Thr Lys Gln Ser Gly Glu Asn Leu Pro Tyr Leu Val335 340 345gcg tac caa gcc acc gtg tgc gct agg gct caa gcc cct ccc cca tcg 13767Ala Tyr Gln Ala Thr Val Cys Ala Arg Ala Gln Ala Pro Pro Pro Ser350 355 360tgg gac cag atg tgg aag tgt ttg att cgc ctc aag ccc acc ctc cat 13815Trp Asp Gln Met Trp Lys Cys Leu Ile Arg Leu Lys Pro Thr Leu His365 370 375ggg cca aca ccc ctg cta tac aga ctg ggc gct gtt cag aat gaa atc 13863Gly Pro Thr Pro Leu Leu Tyr Arg Leu Gly Ala Val Gln Asn Glu Ile380 385 390 395acc ctg acg cac cca gtc acc aaa tac atc atg aca tgc atg tcg gcc 13911Thr Leu Thr His Pro Val Thr Lys Tyr Ile Met Thr Cys Met Ser Ala400 405 410gac ctg gag gtc gtc acg agc acc tgg gtg ctc gtt ggc ggc gtc ctg 13959Asp Leu Glu Val Val Thr Ser Thr Trp Val Leu Val Gly Gly Val Leu415 420 425gct gct ttg gcc gcg tat tgc ctg tca aca ggc tgc gtg gtc ata gtg 14007Ala Ala Leu Ala Ala Tyr Cys Leu Ser Thr Gly Cys Val Val Ile Val430 435 440ggc agg gtc gtc ttg tcc ggg aag ccg gca atc ata cct gac agg gaa 14055Gly Arg Val Val Leu Ser Gly Lys Pro Ala Ile Ile Pro Asp Arg Glu445 450 455gtc ctc tac cga gag ttc gat gag atg gaa gag tgc tct cag cac tta 14103Val Leu Tyr Arg Glu Phe Asp Glu Met Glu Glu Cys Ser Gln His Leu460 465 470 475ccg tac atc gag caa ggg atg atg ctc gcc gag cag ttc aag cag aag 14151Pro Tyr Ile Glu Gln Gly Met Met Leu Ala Glu Gln Phe Lys Gln Lys480 485 490gcc ctc ggc ctc ctg cag acc gcg tcc cgt cag gca gag gtt atc gcc 14199Ala Leu Gly Leu Leu Gln Thr Ala Ser Arg Gln Ala Glu Val Ile Ala495 500 505cct gct gtc cag acc aac tgg caa aaa ctc gag acc ttc tgg gcg aag 14247Pro Ala Val Gln Thr Asn Trp Gln Lys Leu Glu Thr Phe Trp Ala Lys510 515 520cat atg tgg aac ttc atc agt ggg ata caa tac ttg gcg ggc ttg tca 14295His Met Trp Asn Phe Ile Ser Gly Ile Gln Tyr Leu Ala Gly Leu Ser525 530 535acg ctg cct ggt aac ccc gcc att gct tca ttg atg gct ttt aca gct 14343Thr Leu Pro Gly Asn Pro Ala Ile Ala Ser Leu Met Ala Phe Thr Ala540 545 550 555gct gtc acc agc cca cta acc act agc caa acc ctc ctc ttc aac ata 14391Ala Val Thr Ser Pro Leu Thr Thr Ser Gln Thr Leu Leu Phe Asn Ile560 565 570ttg ggg ggg tgg gtg gct gcc cag ctc gcc gcc ccc ggt gcc gct act 14439Leu Gly Gly Trp Val Ala Ala Gln Leu Ala Ala Pro Gly Ala Ala Thr575 580 585gcc ttt gtg ggc gct ggc tta gct ggc gcc gcc atc ggc agt gtt gga 14487Ala Phe Val Gly Ala Gly Leu Ala Gly Ala Ala Ile Gly Ser Val Gly590 595 600ctg ggg aag gtc ctc ata gac atc ctt gca ggg tat ggc gcg ggc gtg 14535Leu Gly Lys Val Leu Ile Asp Ile Leu Ala Gly Tyr Gly Ala Gly Val605 610 615gcg gga gct ctt gtg gca ttc aag atc atg agc ggt gag gtc ccc tcc 14583Ala Gly Ala Leu Val Ala Phe Lys Ile Met Ser Gly Glu Val Pro Ser620 625 630 635acg gag gac ctg gtc aat cta ctg ccc gcc atc ctc tcg ccc gga gcc 14631Thr Glu Asp Leu Val Asn Leu Leu Pro Ala Ile Leu Ser Pro Gly Ala640 645 650ctc gta gtc ggc gtg gtc tgt gca gca ata ctg cgc cgg cac gtt ggc 14679Leu Val Val Gly Val Val Cys Ala Ala Ile Leu Arg Arg His Val Gly655 660 665ccg ggc gag ggg gca gtg cag tgg atg aac cgg ctg ata gcc ttc gcc 14727Pro Gly Glu Gly Ala Val Gln Trp Met Asn Arg Leu Ile Ala Phe Ala670 675 680tcc cgg ggg aac cat gtt tcc ccc acg cac tac gtg ccg gag agc gat 14775Ser Arg Gly Asn His Val Ser Pro Thr His Tyr Val Pro Glu Ser Asp685 690 695gca gct gcc cgc gtc act gcc ata ctc agc agc ctc act gta acc cag 14823Ala Ala Ala Arg Val Thr Ala Ile Leu Ser Ser Leu Thr Val Thr Gln700 705 710 715ctc ctg agg cga ctg cac cag tgg ata agc tcg gag tgt acc act cca 14871Leu Leu Arg Arg Leu His Gln Trp Ile Ser Ser Glu Cys Thr Thr Pro720 725 730tgc tcc ggt tcc tgg cta agg gac atc tgg gac tgg ata tgc gag gtg 14919Cys Ser Gly Ser Trp Leu Arg Asp Ile Trp Asp Trp Ile Cys Glu Val735 740 745ttg agc gac ttt aag acc tgg cta aaa gct aag ctc atg cca cag ctg 14967Leu Ser Asp Phe Lys Thr Trp Leu Lys Ala Lys Leu Met Pro Gln Leu750 755 760cct ggg atc ccc ttt gtg tcc tgc cag cgc ggg tat aag ggg gtc tgg 15015Pro Gly Ile Pro Phe Val Ser Cys Gln Arg Gly Tyr Lys Gly Val Trp765 770 775cga ggg gac ggc atc atg cac act cgc tgc cac tgt gga gct gag atc 15063Arg Gly Asp Gly Ile Met His Thr Arg Cys His Cys Gly Ala Glu Ile780 785 790 795act gga cat gtc aaa aac ggg acg atg agg atc gtc ggt cct agg acc 15111Thr Gly His Val Lys Asn Gly Thr Met Arg Ile Val Gly Pro Arg Thr800 805 810tgc agg aac atg tgg agt ggg acc ttc ccc att aat gcc tac acc acg 15159Cys Arg Asn Met Trp Ser Gly Thr Phe Pro Ile Asn Ala Tyr Thr Thr815 820 825ggc ccc tgt acc ccc ctt cct gcg ccg aac tac acg ttc gcg cta tgg 15207Gly Pro Cys Thr Pro Leu Pro Ala Pro Asn Tyr Thr Phe Ala Leu Trp830 835 840agg gtg tct gca gag gaa tac gtg gag ata agg cag gtg ggg gac ttc 15255Arg Val Ser Ala Glu Glu Tyr Val Glu Ile Arg Gln Val Gly Asp Phe845 850 855cac tac gtg acg ggt atg act act gac aat ctt aaa tgc ccg tgc cag 15303His Tyr Val Thr Gly Met Thr Thr Asp Asn Leu Lys Cys Pro Cys Gln860 865 870 875gtc cca tcg ccc gaa ttt ttc aca gaa ttg gac ggg gtg cgc cta cat 15351Val Pro Ser Pro Glu Phe Phe Thr Glu Leu Asp Gly Val Arg Leu His880 885 890agg ttt gcg ccc ccc tgc aag ccc ttg ctg cgg gag gag gta tca ttc 15399Arg Phe Ala Pro Pro Cys Lys Pro Leu Leu Arg Glu Glu Val Ser Phe895 900 905aga gta gga ctc cac gaa tac ccg gta ggg tcg caa tta cct tgc gag 15447Arg Val Gly Leu His Glu Tyr Pro Val Gly Ser Gln Leu Pro Cys Glu910 915 920ccc gaa ccg gac gtg gcc gtg ttg acg tcc atg ctc act gat ccc tcc 15495Pro Glu Pro Asp Val Ala Val Leu Thr Ser Met Leu Thr Asp Pro Ser925 930 935cat ata aca gca gag gcg gcc ggg cga agg ttg gcg agg gga tca ccc 15543His Ile Thr Ala Glu Ala Ala Gly Arg Arg Leu Ala Arg Gly Ser Pro940 945 950 955ccc tct gtg gcc agc tcc tcg gct agc cag cta tcc gct cca tct ctc 15591Pro Ser Val Ala Ser Ser Ser Ala Ser Gln Leu Ser Ala Pro Ser Leu960 965 970aag gca act tgc acc gct aac cat gac tcc cct gat gct gag ctc ata 15639Lys Ala Thr Cys Thr Ala Asn His Asp Ser Pro Asp Ala Glu Leu Ile975 980 985gag gcc aac ctc cta tgg agg cag gag atg ggc ggc aac atc acc agg 15687Glu Ala Asn Leu Leu Trp Arg Gln Glu Met Gly Gly Asn Ile Thr Arg990 9951000gtt gag tca gaa aac aaa gtg gtg att ctg gac tcc ttc gat ccg ctt 15735Val Glu Ser Glu Asn Lys Val Val Ile Leu Asp Ser Phe Asp Pro Leu100510101015gtg gcg gag gag gac gag cgg gag atc tcc gta ccc gca gaa atc ctg 15783Val Ala Glu Glu Asp Glu Arg Glu Ile Ser Val Pro Ala Glu Ile Leu1020 102510301035cgg aag tct cgg aga ttc gcc cag gcc ctg ccc gtt tgg gcg cgg ccg 15831Arg Lys Ser Arg Arg Phe Ala Gln Ala Leu Pro Val Trp Ala Arg Pro104010451050gac tat aac ccc ccg cta gtg gag acg tgg aaa aag ccc gac tac gaa 15879Asp Tyr Asn Pro Pro Leu Val Glu Thr Trp Lys Lys Pro Asp Tyr Glu105510601065cca cct gtg gtc cat ggc tgc ccg ctt cca cct cca aag tcc cct cct 15927Pro Pro Val Val His Gly Cys Pro Leu Pro Pro Pro Lys Ser Pro Pro107010751080gtg cct ccg cct cgg aag aag cgg acg gtg gtc ctc act gaa tca acc 15975Val Pro Pro Pro Arg Lys Lys Arg Thr Val Val Leu Thr Glu Ser Thr108510901095cta tct act gcc ttg gcc gag ctc gcc acc aga agc ttt ggc agc tcc 16023Leu Ser Thr Ala Leu Ala Glu Leu Ala Thr Arg Ser Phe Gly Ser Ser1100 110511101115tca act tcc ggc att acg ggc gac aat acg aca aca tcc tct gag ccc 16071Ser Thr Ser Gly Ile Thr Gly Asp Asn Thr Thr Thr Ser Ser Glu Pro112011251130gcc cct tct ggc tgc ccc ccc gac tcc gac gct gag tcc tat tcc tcc 16119Ala Pro Ser Gly Cys Pro Pro Asp Ser Asp Ala Glu Ser Tyr Ser Ser113511401145atg ccc ccc ctg gag ggg gag cct ggg gat ccg gat ctt agc gac ggg 16167Met Pro Pro Leu Glu Gly Glu Pro Gly Asp Pro Asp Leu Ser Asp Gly115011551160tca tgg tca acg gtc agt agt gag gcc aac gcg gag gat gtc gtg tgc 16215Ser Trp Ser Thr Val Ser Ser Glu Ala Asn Ala Glu Asp Val Val Cys116511701175tgc tca atg tct tac tct tgg aca ggc gca ctc gtc acc ccg tgc gcc 16263Cys Ser Met Ser Tyr Ser Trp Thr Gly Ala Leu Val Thr Pro Cys Ala1180 118511901195gcg gaa gaa cag aaa ctg ccc atc aat gca cta agc aac tcg ttg cta 16311Ala Glu Glu Gln Lys Leu Pro Ile Asn Ala Leu Ser Asn Ser Leu Leu120012051210cgt cac cac aat ttg gtg tat tcc acc acc tca cgc agt gct tgc caa 16359Arg His His Asn Leu Val Tyr Ser Thr Thr Ser Arg Ser Ala Cys Gln121512201225agg cag aag aaa gtc aca ttt gac aga ctg caa gtt ctg gac agc cat 16407Arg Gln Lys Lys Val Thr Phe Asp Arg Leu Gln Val Leu Asp Ser His123012351240tac cag gac gta ctc aag gag gtt aaa gca gcg gcg tca aaa gtg aag 16455Tyr Gln Asp Val Leu Lys Glu Val Lys Ala Ala Ala Ser Lys Val Lys124512501255gct aac ttg cta tcc gta gag gaa gct tgc agc ctg acg ccc cca cac 16503Ala Asn Leu Leu Ser Val Glu Glu Ala Cys Ser Leu Thr Pro Pro His1260 126512701275tca gcc aaa tcc aag ttt ggt tat ggg gca aaa gac gtc cgt tgc cat 16551Ser Ala Lys Ser Lys Phe Gly Tyr Gly Ala Lys Asp Val Arg Cys His128012851290gcc aga aag gcc gta acc cac atc aac tcc gtg tgg aaa gac ctt ctg 16599Ala Arg Lys Ala Val Thr His Ile Asn Ser Val Trp Lys Asp Leu Leu129513001305gaa gac aat gta aca cca ata gac act acc atc atg gct aag aac gag 16647Glu Asp Asn Val Thr Pro Ile Asp Thr Thr Ile Met Ala Lys Asn Glu131013151320gtt ttc tgc gtt cag cct gag aag ggg ggt cgt aag cca gct cgt ctc 16695Val Phe Cys Val Gln Pro Glu Lys Gly Gly Arg Lys Pro Ala Arg Leu132513301335atc gtg ttc ccc gat ctg ggc gtg cgc gtg tgc gaa aag atg gct ttg 16743Ile Val Phe Pro Asp Leu Gly Val Arg Val Cys Glu Lys Met Ala Leu1340 134513501355tac gac gtg gtt aca aag ctc ccc ttg gcc gtg atggga agc tcc tac 16791Tyr Asp Val Val Thr Lys Leu Pro Leu Ala Val Met Gly Ser Ser Tyr136013651370gga ttc caa tac tca cca gga cag cgg gtt gaa ttc ctc gtg caa gcg 16839Gly Phe Gln Tyr Ser Pro Gly Gln Arg Val Glu Phe Leu Val Gln Ala137513801385tgg aag tcc aag aaa acc cca atg ggg ttc tcg tat gat acc cgc tgc 16887Trp Lys Ser Lys Lys Thr Pro Met Gly Phe Ser Tyr Asp Thr Arg Cys139013951400ttt gac tcc aca gtc act gag agc gac atc cgt acg gag gag gca atc 16935Phe Asp Ser Thr Val Thr Glu Ser Asp Ile Arg Thr Glu Glu Ala Ile140514101415tac caa tgt tgt gac ctc gac ccc caa gcc cgc gtg gcc atc aag tcc 16983Tyr Gln Cys Cys Asp Leu Asp Pro Gln Ala Arg Val Ala Ile Lys Ser1420 142514301435ctc acc gag agg ctt tat gtt ggg ggc cct ctt acc aat tca agg ggg 17031Leu Thr Glu Arg Leu Tyr Val Gly Gly Pro Leu Thr Asn Ser Arg Gly144014451450gag aac tgc ggc tat cgc agg tgc cgc gcg agc ggc gta ctg aca act 17079Glu Asn Cys Gly Tyr Arg Arg Cys Arg Ala Ser Gly Val Leu Thr Thr145514601465agc tgt ggt aac acc ctc act tgc tac atc aag gcc cgg gca gcc tgt 17127Ser Cys Gly Asn Thr Leu Thr Cys Tyr Ile Lys Ala Arg Ala Ala Cys147014751480cga gcc gca ggg ctc cag gac tgc acc atg ctc gtg tgt ggc gac gac 17175Arg Ala Ala Gly Leu Gln Asp Cys Thr Met Leu Val Cys Gly Asp Asp148514901495tta gtc gtt atc tgt gaa agc gcg ggg gtc cag gag gac gcg gcg agc 17223Leu Val Val lle Cys Glu Ser Ala Gly Val Gln Glu Asp Ala Ala Ser1500 150515101515ctg aga gcc ttc acg gag gct atg acc agg tac tcc gcc ccc cct ggg 17271Leu Arg Ala Phe Thr Glu Ala Met Thr Arg Tyr Ser Ala Pro Pro Gly152015251530gac ccc cca caa cca gaa tac gac ttg gag ctc ata aca tca tgc tcc 17319Asp Pro Pro Gln Pro Glu Tyr Asp Leu Glu Leu Ile Thr Ser Cys Ser153515401545tcc aac gtg tca gtc gcc cac gac ggc gct gga aag agg gtc tac tac 17367Ser Asn Val Ser Val Ala His Asp Gly Ala Gly Lys Arg Val Tyr Tyr155015551560ctc acc cgt gac cct aca acc ccc ctc gcg aga gct gcg tgg gag aca 17415Leu Thr Arg Asp Pro Thr Thr Pro Leu Ala Arg Ala Ala Trp Glu Thr156515701575gca aga cac act cca gtc aat tcc tgg cta ggc aac ata atc atg ttt 17463Ala Arg His Thr Pro Val Asn Ser Trp Leu Gly Asn Ile Ile Met Phe1580 158515901595gcc ccc aca ctg tgg gcg agg atg ata ctg atg acc cat ttc ttt agc 17511Ala Pro Thr Leu Trp Ala Arg Met Ile Leu Met Thr His Phe Phe Ser160016051610gtc ctt ata gcc agg gac cag ctt gaa cag gcc ctc gat tgc gag atc 17559Val Leu Ile Ala Arg Asp Gln Leu Glu Gln Ala Leu Asp Cys Glu Ile161516201625tac ggg gcc tgc tac tcc ata gaa cca ctg gat cta cct cca atc att 17607Tyr Gly Ala Cys Tyr Ser Ile Glu Pro Leu Asp Leu Pro Pro Ile Ile163016351640caa aga ctc cat ggc ctc agc gca ttt tca ctc cac agt tac tct cca 17655Gln Arg Leu His Gly Leu Ser Ala Phe Ser Leu His Ser Tyr Ser Pro164516501655ggt gaa atc aat agg gtg gcc gca tgc ctc aga aaa ctt ggg gta ccg 17703Gly Glu Ile Asn Arg Val Ala Ala Cys Leu Arg Lys Leu Gly Val Pro1660 166516701675ccc ttg cga gct tgg aga cac cgg gcc cgg agc gtc cgc gct agg ctt 17751Pro Leu Arg Ala Trp Arg His Arg Ala Arg Ser Val Arg Ala Arg Leu
168016851690ctg gcc aga gga ggc agg gct gcc ata tgt ggc aag tac ctc ttc aac 17799Leu Ala Arg Gly Gly Arg Ala Ala Ile Cys Gly Lys Tyr Leu Phe Asn169517001705tgg gca gta aga aca aag Gtc aaa ctc act cca ata gcg gcc gct ggc 17847Trp Ala Val Arg Thr Lys Leu Lys Leu Thr Pro Ile Ala Ala Ala Gly171017151720cag ctg gac ttg tcc ggc tgg ttc acg gct ggc tac agc ggg gga gac 17895Gln Leu Asp Leu Ser Gly Trp Phe Thr Ala Gly Tyr Ser Gly Gly Asp172517301735att tat cac agc gtg tct cat gcc cgg ccc cgc tgg atc tgg ttt tgc 17943Ile Tyr His Ser Val Ser His Ala Arg Pro Arg Trp Ile Trp Phe Cys1740 174517501755cta ctc ctg ctt gct gca ggg gta ggc atc tac ctc ctc ccc aac cga 17991Leu Leu Leu Leu Ala Ala Gly Val Gly Ile Tyr Leu Leu Pro Asn Arg176017651770atg agc acg aat cct aaa cct caa aga aag acc aaa cgt aac acc aac 18039Met Ser Thr Asn Pro Lys Pro Gln Arg Lys Thr Lys Arg Asn Thr Asn177517801785cgg cgg ccg cag gac gtc aag ttc ccg ggt ggc ggt cag atc gtt ggt 18087Arg Arg Pro Gln Asp Val Lys Phe Pro Gly Gly Gly Gln Ile Val Gly179017951800gga gtt tac ttg ttg ccg cgc agg ggc cct aga ttg ggt gtg cgc gcg 18135Gly Val Tyr Leu Leu Pro Arg Arg Gly Pro Arg Leu Gly Val Arg Ala180518101815acg aga aag act tcc gag cgg tcg caa cct cga ggt aga cgt cag cct 18183Thr Arg Lys Thr Ser Glu Arg Ser Gln Pro Arg Gly Arg Arg Gln Pro1820 182518301835atc ccc aag gct cgt cgg ccc gag ggc agg acc tgg gct cag ccc ggg 18231lle Pro Lys Ala Arg Arg Pro Glu Gly Arg Thr Trp Ala Gln Pro Gly184018451850tac cct tgg ccc ctc tat ggc aat gag ggc tgc ggg tgg gcg gga tgg 18279Tyr Pro Trp Pro Leu Tyr Gly Asn Glu Gly Cys Gly Trp Ala Gly Trp185518601865ctc ctg tct ccc cgt ggc tct cgg cct agc tgg ggc ccc aca gac ccc 18327Leu Leu Ser Pro Arg Gly Ser Arg Pro Ser Trp Gly Pro Thr Asp Pro187018751880cgg cgt agg tcg cgc aat ttg ggt aag gtc atc gat acc ctt acg tgc 18375Arg Arg Arg Ser Arg Asn Leu Gly Lys Val Ile Asp Thr Leu Thr Cys188518901895ggc ttc gcc gac ctc atg ggg tac ata ccg ctc gtc ggc gcc cct ctt 18423Gly Phe Ala Asp Leu Met Gly Tyr Ile Pro Leu Val Gly Ala Pro Leu1900 190519101915gga ggc gct gcc agg gcc taatagtcga ctttgttccc actgtacttt 18471Gly Gly Ala Ala Arg Ala1920tagctcgtac aaaatacaat atacttttca tttctccgta aacaacatgt tttcccatgt 18531aatatccttt tctatttttc gttccgttac caactttaca catactttat atagctattc 18591acttctatac actaaaaaac taagacaatt ttaattttgc tgcctgccat atttcaattt 18651gttataaatt cctataattt atcctattag tagctaaaaa aagatgaatg tgaatcgaat 18711cctaagagaa ttggatctga tccacaggac gggtgtggtc gccatgatcg cgtagtcgat 18771agtggctcca agtagcgaag cgagcaggac tgggcggcgg ccaaagcggt cggacagtgc 18831tccgagaacg ggtgcgcata gaaattgcat caacgcatat agcgctagca gcacgccata 18891gtgactggcg atgctgtcgg aatggacgat atcccgcaag aggcccggca gtaccggcat 18951aaccaagcct atgcctacag catccagggt gacggtgccg aggatgacga tgagcgcatt 19011gttagatttc atacacggtg cctgactgcg ttagcaattt aactgtgata aactaccgca 19071ttaaagcttt ttctttccaa tttttttttt ttcgtcatta taaaaatcat tacgaccgag 19131attcccgggt aataactgat ataattaaat tgaagctcta atttgtgagt ttagtataca 19191tgcatttact tataatacag ttttttagtt ttgctggccg catcttctca aatatgcttc 19251ccagcctgct tttctgtaac gttcaccctc taccttagca tcccttccct ttgcaaatag 19311tcctcttcca acaataataa tgtcagatcc tgtagagacc acatcatcca cggttctata 19371ctgttgaccc aatgcgtctc ccttgtcatc taaacccaca ccgggtgtca taatcaacca 19431atcgtaacct tcatctcttc cacccatgtc tctttgagca ataaagccga taacaaaatc 19491tttgtcgctc ttcgcaatgt caacagtacc cttagtatat tctccagtag atagggagcc 19551cttgcatgac aattctgcta acatcaaaag gcctctaggt tcctttgtta cttcttctgc 19611cgcctgcttc aaaccgctaa caatacctgg gcccaccaca ccgtgtgcat tcgtaatgtc 19671tgcccattct gctattctgt atacacccgc agagtactgc aatttgactg tattaccaat 19731gtcagcaaat tttctgtctt cgaagagtaa aaaattgtac ttggcggata atgcctttag 19791cggcttaact gtgccctcca tggaaaaatc agtcaagata tccacatgtg tttttagtaa 19851acaaattttg ggacctaatg cttcaactaa ctccagtaat tccttggtgg tacgaacatc 19911caatgaagca cacaagtttg tttgcttttc gtgcatgata ttaaatagct tggcagcaac 19971aggactagga tgagtagcag cacgttcctt atatgtagct ttcgacatga tttatcttcg 20031tttcctgcag gtttttgttc tgtgcagttg ggttaagaat actgggcaat ttcatgtttc 20091ttcaacacta catatgcgta tatataccaa tctaagtctg tgctccttcc ttcgttcttc 20151cttctgttcg gagattaccg aatcaaaaaa atttcaagga aaccgaaatc aaaaaaaaga 20211ataaaaaaaa aatgatgaat tgaaaagctt atcgat 20247210192111921212PRT213人工序列220223人工序列的描述pd.delta.NS3NS5.pj.core15040019Met Ala Ala Tyr Ala Ala Gln Gly Tyr Lys Val Leu Val Leu Asn Pro1 5 10 15Ser Val Ala Ala Thr Leu Gly Phe Gly Ala Tyr Met Ser Lys Ala His20 25 30Gly Ile Asp Pro Asn Ile Arg Thr Gly Val Arg Thr Ile Thr Thr Gly35 40 45Ser Pro Ile Thr Tyr Ser Thr Tyr Gly Lys Phe Leu Ala Asp Gly Gly50 55 60Cys Ser Gly Gly Ala Tyr Asp Ile Ile Ile Cys Asp Glu Cys His Ser65 70 75 80Thr Asp Ala Thr Ser Ile Leu Gly Ile Gly Thr Val Leu Asp Gln Ala85 90 95Glu Thr Ala Gly Ala Arg Leu Val Val Leu Ala Thr Ala Thr Pro Pro100 105 110Gly Ser Val Thr Val Pro His Pro Asn Ile Glu Glu Val Ala Leu Ser115 120 125Thr Thr Gly Glu Ile Pro Phe Tyr Gly Lys Ala Ile Pro Leu Glu Val130 135 140Ile Lys Gly Gly Arg His Leu Ile Phe Cys His Ser Lys Lys Lys Cys145 150 155 160Asp Glu Leu Ala Ala Lys Leu Val Ala Leu Gly Ile Asn Ala Val Ala165 170 175Tyr Tyr Arg Gly Leu Asp Val Ser Val Ile Pro Thr Ser Gly Asp Val180 185 190Val Val Val Ala Thr Asp Ala Leu Met Thr Gly Tyr Thr Gly Asp Phe195 200 205Asp Ser Val Ile Asp Cys Asn Thr Cys Val Thr Gln Thr Val Asp Phe210 215 220Ser Leu Asp Pro Thr Phe Thr Ile Glu Thr Ile Thr Leu Pro Gln Asp225 230 235 240Ala Val Ser Arg Thr Gln Arg Arg Gly Arg Thr Gly Arg Gly Lys Pro245 250 255Gly Ile Tyr Arg Phe Val Ala Pro Gly Glu Arg Pro Ser Gly Met Phe
260 265 270Asp Ser Ser Val Leu Cys Glu Cys Tyr Asp Ala Gly Cys Ala Trp Tyr275 280 285Glu Leu Thr Pro Ala Glu Thr Thr Val Arg Leu Arg Ala Tyr Met Asn290 295 300Thr Pro Gly Leu Pro Val Cys Gln Asp His Leu Glu Phe Trp Glu Gly305 310 315 320Val Phe Thr Gly Leu Thr His Ile Asp Ala His Phe Leu Ser Gln Thr325 330 335Lys Gln Ser Gly Glu Asn Leu Pro Tyr Leu Val Ala Tyr Gln Ala Thr340 345 350Val Cys Ala Arg Ala Gln Ala Pro Pro Pro Ser Trp Asp Gln Met Trp355 360 365Lys Cys Leu Ile Arg Leu Lys Pro Thr Leu His Gly Pro Thr Pro Leu370 375 380Leu Tyr Arg Leu Gly Ala Val Gln Asn Glu Ile Thr Leu Thr His Pro385 390 395 400Val Thr Lys Tyr Ile Met Thr Cys Met Ser Ala Asp Leu Glu Val Val405 410 415Thr Ser Thr Trp Val Leu Val Gly Gly Val Leu Ala Ala Leu Ala Ala420 425 430Tyr Cys Leu Ser Thr Gly Cys Val Val Ile Val Gly Arg Val Val Leu435 440 445Ser Gly Lys Pro Ala Ile Ile Pro Asp Arg Glu Val Leu Tyr Arg Glu450 455 460Phe Asp Glu Met Glu Glu Cys Ser Gln His Leu Pro Tyr Ile Glu Gln465 470 475 480Gly Met Met Leu Ala Glu Gln Phe Lys Gln Lys Ala Leu Gly Leu Leu485 490 495Gln Thr Ala Ser Arg Gln Ala Glu Val Ile Ala Pro Ala Val Gln Thr500 505 510Asn Trp Gln Lys Leu Glu Thr Phe Trp Ala Lys His Met Trp Asn Phe515 520 525Ile Ser Gly Ile Gln Tyr Leu Ala Gly Leu Ser Thr Leu Pro Gly Asn530 535 540Pro Ala Ile Ala Ser Leu Met Ala Phe Thr Ala Ala Val Thr Ser Pro545 550 555 560Leu Thr Thr Ser Gln Thr Leu Leu Phe Asn Ile Leu Gly Gly Trp Val565 570 575Ala Ala Gln Leu Ala Ala Pro Gly Ala Ala Thr Ala Phe Val Gly Ala
580 585 590Gly Leu Ala Gly Ala Ala Ile Gly Ser Val Gly Leu Gly Lys Val Leu595 600 605Ile Asp Ile Leu Ala Gly Tyr Gly Ala Gly Val Ala Gly Ala Leu Val610 615 620Ala Phe Lys Ile Met Ser Gly Glu Val Pro Ser Thr Glu Asp Leu Val625 630 635 640Asn Leu Leu Pro Ala Ile Leu Ser Pro Gly Ala Leu Val Val Gly Val645 650 655ValCys Ala Ala Ile Leu Arg Arg His Val Gly Pro Gly Glu Gly Ala660 665 670Val Gln Trp Met Asn Arg Leu Ile Ala Phe Ala Ser Arg Gly Asn His675 680 685Val Ser Pro Thr His Tyr Val Pro Glu Ser Asp Ala Ala Ala Arg Val690 695 700Thr Ala Ile Leu Ser Ser Leu Thr Val Thr Gln Leu Leu Arg Arg Leu705 710 715 720His Gln Trp Ile Ser Ser Glu Cys Thr Thr Pro Cys Ser Gly Ser Trp725 730 735Leu Arg Asp Ile Trp Asp Trp Ile Cys Glu Val Leu Ser Asp Phe Lys740 745 750Thr Trp Leu Lys Ala Lys Leu Met Pro Gln Leu Pro Gly Ile Pro Phe755 760 765Val Ser Cys Gln Arg Gly Tyr Lys Gly Val Trp Arg Gly Asp Gly Ile770 775 780Met His Thr Arg Cys His Cys Gly Ala Glu Ile Thr Gly His Val Lys785 790 795 800Asn Gly Thr Met Arg Ile Val Gly Pro Arg Thr Cys Arg Asn Met Trp805 810 815Ser Gly Thr Phe Pro Ile Asn Ala Tyr Thr Thr Gly Pro Cys Thr Pro820 825 830Leu Pro Ala Pro Asn Tyr Thr Phe Ala Leu Trp Arg Val Ser Ala Glu835 840 845Glu Tyr Val Glu Ile Arg Gln Val Gly Asp Phe His Tyr Val Thr Gly850 855 860Met Thr Thr Asp Asn Leu Lys Cys Pro Cys Gln Val Pro Ser Pro Glu865 870 875 880Phe Phe Thr Glu Leu Asp Gly Val Arg Leu His Arg Phe Ala Pro Pro885 890 895Cys Lys Pro Leu Leu Arg Glu Glu Val Ser Phe Arg Val Gly Leu His900 905 910Glu Tyr Pro Val Gly Ser Gln Leu Pro Cys Glu Pro Glu Pro Asp Val915 920 925Ala Val Leu Thr Ser Met Leu Thr Asp Pro Ser His Ile Thr Ala Glu930 935 940Ala Ala Gly Arg Arg Leu Ala Arg Gly Ser Pro Pro Ser Val Ala Ser945 950 955 960Ser Ser Ala Ser Gln Leu Ser Ala Pro Ser Leu Lys Ala Thr Cys Thr965 970 975Ala Asn His Asp Ser Pro Asp Ala Glu Leu Ile Glu Ala Asn Leu Leu980 985 990Trp Arg Gln Glu Met Gly Gly Asn Ile Thr Arg Val Glu Ser Glu Asn99510001005Lys Val Val Ile Leu Asp Ser Phe Asp Pro Leu Val Ala Glu Glu Asp101010151020Glu Arg Glu Ile Ser Val Pro Ala Glu Ile Leu Arg Lys Ser Arg Arg025103010351040Phe Ala Gln Ala Leu Pro Val Trp Ala Arg Pro Asp Tyr Asn Pro Pro104510501055Leu Val Glu Thr Trp Lys Lys Pro Asp Tyr Glu Pro Pro Val Val His106010651070Gly Cys Pro Leu Pro Pro Pro Lys Ser Pro Pro Val Pro Pro Pro Arg107510801085Lys Lys Arg Thr Val Val Leu Thr Glu Ser Thr Leu Ser Thr Ala Leu109010951100Ala Glu Leu Ala Thr Arg Ser Phe Gly Ser Ser Ser Thr Ser Gly Ile105111011151120Thr Gly Asp Asn Thr Thr Thr Ser Ser Glu Pro Ala Pro Ser Gly Cys112511301135Pro Pro Asp Ser Asp Ala Glu Ser Tyr Ser Ser Met Pro Pro Leu Glu114011451150Gly Glu Pro Gly Asp Pro Asp Leu Ser Asp Gly Ser Trp Ser Thr Val115511601165Ser Ser Glu Ala Asn Ala Glu Asp Val Val Cys Cys Ser Met Ser Tyr117011751180Ser Trp Thr Gly Ala Leu Val Thr Pro Cys Ala Ala Glu Glu Gln Lys185119011951200Leu Pro Ile Asn Ala Leu Ser Asn Ser Leu Leu Arg His His Asn Leu120512101215Val Tyr Ser Thr Thr Ser Arg Ser Ala Cys Gln Arg Gln Lys Lys Val122012251230Thr Phe Asp Arg Leu Gln Val Leu Asp Ser His Tyr Gln Asp Val Leu123512401245Lys Glu Val Lys Ala Ala Ala Ser Lys Val Lys Ala Asn Leu Leu Ser125012551260Val Glu Glu Ala Cys Ser Leu Thr Pro Pro His Ser Ala Lys Ser Lys265127012751280Phe Gly Tyr Gly Ala Lys Asp Val Arg Cys His Ala Arg Lys Ala Val128512901295Thr His Ile Asn Ser Val Trp Lys Asp Leu Leu Glu Asp Asn Val Thr130013051310Pro Ile Asp Thr Thr Ile Met Ala Lys Asn Glu Val Phe Cys Val Gln131513201325Pro Glu Lys Gly Gly Arg Lys Pro Ala Arg Leu Ile Val Phe Pro Asp133013351340Leu Gly Val Arg Val Cys Glu Lys Met Ala Leu Tyr Asp Val Val Thr345135013551360Lys Leu Pro Leu Ala Val Met Gly Ser Ser Tyr Gly Phe Gln Tyr Ser136513701375Pro Gly Gln Arg Val Glu Phe Leu Val Gln Ala Trp Lys Ser Lys Lys138013851390Thr Pro Met Gly Phe Ser Tyr Asp Thr Arg Cys Phe Asp Ser Thr Val139514001405Thr Glu Ser Asp Ile Arg Thr Glu Glu Ala Ile Tyr Gln Cys Cys Asp141014151420Leu Asp Pro Gln Ala Arg Val Ala Ile Lys Ser Leu Thr Glu Arg Leu425143014351440Tyr Val Gly Gly Pro Leu Thr Asn Ser Arg Gly Glu Asn Cys Gly Tyr144514501455Arg Arg Cys Arg Ala Ser Gly Val Leu Thr Thr Ser Cys Gly Asn Thr146014651470Leu Thr Cys Tyr Ile Lys Ala Arg Ala Ala Cys Arg Ala Ala Gly Leu147514801485Gln Asp Cys Thr Met Leu Val Cys Gly Asp Asp Leu Val Val Ile Cys149014951500Glu Ser Ala Gly Val Gln Glu Asp Ala Ala Ser Leu Arg Ala Phe Thr505151015151520Glu Ala Met Thr Arg Tyr Ser Ala Pro Pro Gly Asp Pro Pro Gln Pro152515301535Glu Tyr Asp Leu Glu Leu Ile Thr Ser Cys Ser Ser Asn Val Ser Val154015451550Ala His Asp Gly Ala Gly Lys Arg Val Tyr Tyr Leu Thr Arg Asp Pro
155515601565Thr Thr Pro Leu Ala Arg Ala Ala Trp Glu Thr Ala Arg His Thr Pro157015751580Val Asn Ser Trp Leu Gly Asn lle Ile Met Phe Ala Pro Thr Leu Trp585159015951600Ala Arg Met Ile Leu Met Thr His Phe Phe Ser Val Leu Ile Ala Arg160516101615Asp Gln Leu Glu Gln Ala Leu Asp Cys Glu Ile Tyr Gly Ala Cys Tyr162016251630Ser Ile Glu Pro Leu Asp Leu Pro Pro Ile Ile Gln Arg Leu His Gly163516401645Leu Ser Ala Phe Ser Leu His Ser Tyr Ser Pro Gly Glu Ile Asn Arg165016551660Val Ala Ala Cys Leu Arg Lys Leu Gly Val Pro Pro Leu Arg Ala Trp665167016751680Arg His Arg Ala Arg Ser Val Arg Ala Arg Leu Leu Ala Arg Gly Gly168516901695Arg Ala Ala Ile Cys Gly Lys Tyr Leu Phe Asn Trp Ala Val Arg Thr170017051710Lys Leu Lys Leu Thr Pro Ile Ala Ala Ala Gly Gln Leu Asp Leu Ser171517201725Gly Trp Phe Thr Ala Gly Tyr Ser Gly Gly Asp Ile Tyr His Ser Val173017351740Ser His Ala Arg Pro Arg Trp Ile Trp Phe Cys Leu Leu Leu Leu Ala745175017551760Ala Gly Val Gly Ile Tyr Leu Leu Pro Asn Arg Met Ser Thr Asn Pro176517701775Lys Pro Gln Arg Lys Thr Lys Arg Asn Thr Asn Arg Arg Pro Gln Asp178017851790Val Lys Phe Pro Gly Gly Gly Gln Ile Val Gly Gly Val Tyr Leu Leu179518001805Pro Arg Arg Gly Pro Arg Leu Gly Val Arg Ala Thr Arg Lys Thr Ser181018151820Glu Arg Ser Gln Pro Arg Gly Arg Arg Gln Pro Ile Pro Lys Ala Arg825183018351840Arg Pro Glu Gly Arg Thr Trp Ala Gln Pro Gly Tyr Pro Trp Pro Leu184518501855Tyr Gly Asn Glu Gly Cys Gly Trp Ala Gly Trp Leu Leu Ser Pro Arg186018651870Gly Ser Arg Pro Ser Trp Gly Pro Thr Asp Pro Arg Arg Arg Ser Arg187518801885Asn Leu Gly Lys Val Ile Asp Thr Leu Thr Cys Gly Phe Ala Asp Leu189018951900Met Gly Tyr Ile Pro Leu Val Gly Ala Pro Leu Gly Gly Ala Ala Arg905191019151920Ala
權利要求
1.一種分離的突變型非結構(「NS」)HCV多肽，它含有在NS3的催化結構域發生突變的多肽，其特徵在於，所述突變破壞了該催化結構域的功能。
2.如權利要求1所述的多肽，其特徵在於，所述突變是刪除性突變。
3.如權利要求1所述的多肽，其特徵在於，所述突變是取代性突變。
4.如權利要求1-3中任一項所述的多肽，其特徵在於，所述NS多肽包含NS3、NS4和NS5。
5.如權利要求1-3中任一項所述的多肽，其特徵在於，所述NS多肽由NS3、NS4和NS5組成。
6.如權利要求1-3中任一項所述的多肽，其特徵在於，所述NS多肽由NS3和NS5組成。
7.如權利要求6所述的多肽，其特徵在於，所述NS5是NS5a。
8.如權利要求6所述的多肽，其特徵在於，所述NS5是NS5b。
9.如權利要求1-3中任一項所述的多肽，其特徵在於，所述NS多肽由NS3和NS4組成。
10.如權利要求9所述的多肽，其特徵在於，所述NS4是NS4a。
11.如權利要求9所述的多肽，其特徵在於，所述NS4是NS4b。
12.如權利要求4所述的多肽，其特徵在於，所述多肽還包含不是HCV的NS3、NS4或NS5、而是另外的一條病毒多肽。
13.如權利要求12所述的多肽，其特徵在於，所述另一條病毒多肽含有HCV核心多肽(「C」)或其片段。
14.如權利要求13所述的多肽，其特徵在於，所述C多肽被截短。
15.如權利要求14所述的多肽，其特徵在於，截短部位在第121個胺基酸。
16.如權利要求12所述的多肽，其特徵在於，所述多肽還包含HCV包膜蛋白(「E」)。
17.如權利要求16所述的多肽，其特徵在於，所述E是E1。
18.如權利要求16所述的多肽，其特徵在於，所述E是E2。
19.一種組合物，它含有(a) 權利要求1-18中任一項所述的多肽；和(b) 藥學上可接受的賦形劑。
20.一種經分離純化的多核苷酸，它編碼權利要求1-18中任一項所述的突變型HCV多肽。
21.一種組合物，它含有(a) 權利要求20所述的經分離純化的多核苷酸；和(b) 藥學上可接受的賦形劑。
22.如權利要求21所述的組合物，其特徵在於，所述多核苷酸是DNA。
23.如權利要求21所述的組合物，其特徵在於，所述多核苷酸存在於質粒中。
24.一種表達載體，它含有權利要求20所述的多核苷酸。
25.一種表達載體，它含有SEQ ID NO8的多核苷酸。
26.一種宿主細胞，它含有權利要求20所述的多核苷酸。
27.如權利要求26所述的宿主細胞，其特徵在於，所述細胞是酵母細胞。
28.如權利要求26所述的宿主細胞，其特徵在於，所述細胞是哺乳動物細胞。
29.如權利要求26所述的宿主細胞，其特徵在於，所述細胞是昆蟲細胞。
30.如權利要求26所述的宿主細胞，其特徵在於，所述細胞是植物細胞。
31.如權利要求26所述的宿主細胞，其特徵在於，所述多核苷酸包含SED IDNO8的序列。
32.如權利要求1所述的多肽，其特徵在於，所述多肽還含有SEQ ID NO9。
33.一種製備突變型NS HCV多肽的方法，它包括a.在所述多肽被表達的條件下，使用權利要求24所述的表達載體轉化宿主細胞；b.分離出所述多肽。
34.如權利要求33所述的方法，其特徵在於，所述宿主細胞是酵母細胞。
35.如權利要求33所述的方法，其特徵在於，所述宿主細胞是哺乳動物細胞。
36.如權利要求33所述的方法，其特徵在於，所述宿主細胞是昆蟲細胞。
37.如權利要求33所述的方法，其特徵在於，所述宿主細胞是植物細胞。
38.一種抗體，它特異性地與權利要求1-18中任一項所述的多肽結合。
39.如權利要求38所述的抗體，其特徵在於，所述抗體是單克隆抗體。
40.如權利要求38所述的抗體，其特徵在於，所述抗體是經純化的多克隆抗體。
41.一種引起受檢對象免疫應答的方法，它包括向該受檢對象給予權利要求1-18中任一項所述的多肽。
42.一種引起受檢對象免疫應答的方法，它包括向該受檢對象給予權利要求20所述的多核苷酸。
全文摘要
本發明公開了含有突變型非結構C型肝炎病毒的多肽，它可在診斷和/或免疫原性組合物中使用，其中，該突變是破壞了NS3的催化結構域的功能的N－末端突變。本發明還公開了編碼這些多肽的多核苷酸、經這些多核苷酸轉化的宿主細胞和使用這些多肽和多核苷酸的方法。
文檔編號C12P21/08GK1425027SQ00818577
公開日2003年6月18日 申請日期2000年11月22日 優先權日1999年11月24日
發明者D·科伊特, A·梅迪納-塞爾比, M·塞爾比, M·霍頓 申請人:希龍公司