CN1225132A - Hiv包膜多肽和疫苗 - Google Patents
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Abstract
本发明提供了编码gp120多肽(其来自用MN－rgp120的疫苗试验的逃逸分离物)的寡核苷酸序列和所编码的gp120多肽。利用亚单位疫苗中的一种或多种分离物的gp120多肽(通常与MN－rgp120一起),可提供抗一些HIV菌株的保护作用,这些HIV菌株与疫苗菌株(例如;MN－rgp120)有足够的差异,使得所说的疫苗不提供抗这些菌株的保护作用。本发明也提供了所述多肽诱导的抗体。
Description
发明背景发明所属技术领域
本发明涉及HIV包膜多肽和包含这些多肽的疫苗。相关技术的描述
获得性免疫缺陷综合症(AIDS)是由命名为人免疫缺陷病毒(HIV)的逆转录病毒引起的。过去为研制一种基于抗体或细胞反应诱导保护性免疫应答的疫苗付出了很大的努力。最近的尝试是利用亚单位疫苗，其中由于安全性原因，在疫苗中利用HIV蛋白质(而非稀释的或灭活的病毒)作为免疫原。一般地，亚单位疫苗包括gp120，即位于病毒表面的HIV包膜蛋白部分。
有关HIV包膜蛋白已有许多描述，并且人们熟知来自许多HIV菌株的氨基酸序列与编码HIV包膜的核酸序列(Myers,G.等，1992.人逆转录病毒和爱滋病。核酸和氨基酸序列的编缉与分析。Los Alamos国家实验室，Los Alamos，新墨西哥)。HIV包膜蛋白是约160kd的糖蛋白(gp160)，其在羧基末端区锚定在膜的双层分子上。其N端区段(gp120)伸出至围绕毒粒的含水环境中，且C端区段(gp41)跨越膜。通过宿主细胞媒介方法，将gp160切割成gp120和整合膜蛋白gp41。由于在gp120和gp41之间没有任何共价连接，有时从毒粒的表面释放出游离的gp120，并感染细胞。
gp120分子包含60,000道尔顿的多肽核心，该多肽核心广泛地被N-连接的糖基化作用所修饰，而使分子的表观分子量增加至120,000道尔顿。gp120的氨基酸序列含有散布五个高变结构域的五个相对保守结构域。在gp120初级序列中的18个半胱氨酸残基的位置，和在gp120序列中的大约24个N-连接的糖基化位点的13个位置，对所有gp120序列来说都是相同的。高变结构域包括大量的氨基酸取代，插入和缺失。这些结构域中的序列变化使得来自各种病毒分离物的gp120分子间产生了多达全序列30％的可变性。尽管有这一变异，所有gp120序列均保留了病毒结合病毒受体CD4的能力，且保留了与gp41相互作用而引起病毒和宿主细胞膜的融合的能力。
gp120曾是广泛研究的目标，因其是亚单位疫苗的疫苗候选者，并且是很有可能接近免疫进攻的病毒蛋白质。现在，利用gp120MN菌株的临床试验正在进行。然而，至今没有任何人类疫苗试验具有足够规模以确认或否认疫苗的有效性。
HIV-1疫苗候选者的研制由于缺乏HIV-1感染的体内或体外模型(其精确地近似于人类自然感染的条件)而遇到障碍。已描述了几种候选HIV-1疫苗[Berman等；病毒学杂志。7:4464-9(1992)；Haigwood等；病毒学杂志。66:172-82(1992)；Salmon-Ceron等；爱滋病研究和人逆转录病毒11:1479-86(1995)]广泛激发能够中和体外各种多样化的HIV-1分离物的交叉反应抗体。然而，体外试验与体内保护性免疫的相关性是不确定的。虽然已对黑猩猩提供了几种具有抗同源和异源HIV-1菌株的保护作用的疫苗，但是保护性反应并非总是与体外的中和试验有联系，其中这种体外中和试验在T细胞系上或在凝集素和细胞因子活化的外周血液单核细胞(PBMCs)上进行[Bermarn等；自然,345:622-5(1990)；Bruck等；疫苗，12(12):1141-8(1994)；El-Amad等；爱滋病，9:1313-22(1995)；Girard等；病毒学杂志,69:6239-48(1995)；和Fulz等；科学,256:1687-1690(1992)]。虽然在黑猩猩中成功获得的保护作用是鼓励人心的，并历史地证明是可靠的疫苗有效性指示剂，但所有HIV-1感染的实验模型的感染条件显著不同于人类自然感染条件。
体内和体外的HIV-1感染实验所受局限性是：HIV-1(为体外或体内感染实验，其需要制备病毒储备液)的体外扩增强加了一种遗传选择，它能导致病毒准种的光谱不同于用于建立培养物的临床样品中存在的变体的光谱[Kusumi等；病毒学杂志66:875(1992)；Meyerhans等；细胞58:901-10(1989)]。由于这些不确定性，以及所传输的病毒的量，初始复制所涉及的位点和细胞类型，和病毒散布的动力学更大的不确定性，使得当前以体外或体内试验有效可靠预测疫苗功效的能力尚无把握。
曾进入人类临床试验的HIV-1疫苗候选者之一是重组gp120，其由HIV-1的MN菌株在中国仓鼠卵巢(CHO)细胞中制备(MN-rgp120)(Berman等；病毒学杂志7:4464-9(1992))。至今，大约499个成年人曾参与该疫苗的1期和2期免疫原性和安全性试验。所收集的数据足以证明MN-rgp120的安全性，免疫原性，并且按照0,1和6个月免疫进度，在多于95％的免疫个体中激发了高效价的抗体[Belshe等；JAMA272(6):475-80(1994)；McElrath；癌生物学讨论会6:1-11(1995)]。然而，在这些试验的过程中，九个接收了MN-rgp120的被接种者由高风险行为被HIV-1感染。小型试验(如这些)，其群体具有低的感染速率和较小规模的无效对照组，没有足够的统计效应确认或者否认疫苗功效。
然而，仍然在寻求基于gp120或另外HIV蛋白质的有效的疫苗，以产生抗HIV另一些菌株的保护作用，从而阻止该疾病的传播。背景技术描述
重组亚单位疫苗见Berman等，PCT/US91/02250中所描述的(出版号W091/15238,19911十月7日)。也参见，例如Hu等，自然328:721-724(1987)(疫苗病毒-HIV包膜重组疫苗)；Arthur等，病毒学杂志63(12):5046-5053(1989)(纯化gp120)；和Berman等，Proc.Natl.Acad.Sci.美国85:5200-5204(1988)(重组包膜糖蛋白gp120)。
已知gp120的许多序列。本文所参考的gp120序列(其来自ⅢB亚菌株HIV-1LAI)是由Muesing等测定的，见核酸结构和人AIDS/淋巴结病逆转录病毒的表达，自然313:450-458(1985)。Myers等列出了来自HIV-1菌株的NY-5,Jrcsf,Z6,Z321，以HXB2的gp120的序列＂，人逆转录病毒及爱滋病；核酸和氨基酸序列的编缉和分析＂，Los Alamos国家实验室，Los Alamos，新墨西哥(1992)。泰国人分离物A244的序列由McCutchan等提供，＂泰国的HIV-1基因变体＂爱滋病研究和人类逆转录病毒8:1887-1895(1992)。MN1984克隆见Gurgo等所描述的＂，两种新的美国HIV-1分离物的包膜序列＂，病毒学164:531-536(1988)。如本文所使用的，MN,MN-rgp120,MN克隆或分离物指MNGEN。MNGEN的氨基酸序列见SEQ ID NO.29。
以上每一参考文献本文以其全文作为参考。
发明概要
本发明提供了编码gp120多肽(其来自用MN-rgp120的疫苗试验的逃逸(breakthrough)分离物)的寡核苷酸序列和所编码的gp120多肽。利用亚单位疫苗中的一种或多种分离物的gp120多肽(通常与MN-rgp120一起)，可提供抗一些HIV菌株的保护作用，这些HIV菌株与疫苗菌株(例如；MN-rgp120)有足够的差异，使得所说的疫苗不提供抗这些菌株的保护作用。本发明也提供了所述多肽诱导的抗体。
附图简述
图1说明在被HIV-1感染的被接种者中抗体对MN-rgp120反应的动力学。在所示的时间点收集血清，并测定与MN-rgp120(空心圈)或衍生自MN-rgp120V3结构域的合成肽(实心圈)的抗体反应性。箭头表明注射的日期。加号表明第一次检测到HIV-1感染的时间。阴影部分表明是在HIV-1感染之后所收集的数据。来自被接种者C6的数据在A组中显示；C8在B组；C7-C组；C11-D组；C10-E组；C17-F组；和C15-G组。
图2说明在HIV-1感染的被接种者中CD4阻断抗体反应的动力学。在所示的时间点收集血清，并测定能够阻止[125I]标记的MN-rgp120结合到CD4细胞表面的抗体。箭头表明注射的日期。加号表明第一次检测到HIV-1感染的时间。阴影部分表明是在HIV-1感染之后所收集的数据。被接种者C6的数据在A组中显示；C8对应于B组；C7-C组；C11-D组；C10-E组；C17-F组；和C15-G组。
图3说明来源于逃逸病毒的包膜糖蛋白(gp120)的预测的氨基酸序列。通过PCR将原病毒的DNA序列从PBMCs扩增，然后克隆进PRK5表达质粒中。对两个来自各感染的被接种者的克隆从双链质粒DNA测序。序列编号参考gp120的起始甲硫氨酸残基。出于比较目的，所显示的序列从成熟(完全加工的)包膜糖蛋白的第12位氨基酸开始(对应于gp120开放阅读框41位)。阴影部分表明在中和表位上的序列，黑色方块表明多态性，其被认为对与MN-rgp120反应性的病毒中和Mabs的结合是重要的。在序列上显示了保守(C)区和可变(V)区。方块表明序列同源性和多态性。
图4说明从逃逸病毒所制备的重组gp120的免疫沉淀法。来源于七种逃逸病毒的重组gp120通过293s细胞的瞬时转染制备。细胞用甲硫氨酸35S进行代谢标记，并且将生长调节细胞培养物上清液用MN-rgp120的多克隆抗血清进行免疫沉淀。用SDS-PAGE展开免疫沉淀，并用放射自显影法显影。C8道的a和b对应于克隆C8.3和C8.6；C6道的a和b对应于克隆C6.1和C6.5；C7道的a和b对应于克隆C7.2和C7.10；C17道的a和b对应于C17.1和C17.3；C11道的a和b对应于克隆C11.5和C11.7；C10道的a和b对应于克隆C10.5和C10.7；C15道的a和b对应于克隆C15.2和C15.3。
图5说明单克隆抗体对来源于逃逸病毒的重组gp120的结合。从被质粒瞬时转染的293s细胞中收集生长调节细胞培养物上清液，其中所说的质粒指导逃逸病毒包膜糖蛋白的表达。相对rgp120浓度由ELISA测定，其中利用对HSV-1糖蛋白D标记表位(该表位位于本文所描述的所有rgp120变体的氨基末端)特异性的MAb5B6。将所产生的rgp120制备物置于涂布有特异于gp120的C-端保守序列的多克隆抗体的微量滴定板的孔内。通过ELISA测定能中和与gp120反应性的单克隆抗体的病毒的结合。A，特异于HSV-1糖蛋白D标记表位的MAb(5B6)的结合；B，抗MN-rgp120的V3结构域的MAb(1034)的结合；C，抗合成肽(其对应于MN-rgp120的V3结构域)产生的MAb(50.1)结合；D，已知阻断gp120与CD4结合的人类MAb(15e)的结合。
图6描述来源于HIV-1MN菌株的MN克隆的成熟包膜糖蛋白(gp120)(SEQ.ID.NO.29)。高变结构域用粗体表示，并显示了V和C区(根据Modrow等，病毒学杂志61(2):570(1987))。潜在的糖基化位点以(*)标记。
发明详述
本发明提供了来源于HIV疫苗试验的逃逸分离物的gp120多肽。也提供了编码逃逸分离物(其可以用于表达gp120)的gp120的新寡核苷酸序列。利用来自亚单位疫苗中的一种或多种分离物的gp120多肽(通常与MN-rgp120一起)，可提供抗一些HIV菌株的保护作用，这些HIV菌株与疫苗菌株(例如；MN-rgp120)有足够的差异，使得所说的疫苗不提供抗这些菌株的保护作用。
在一个实施方案中，所说的疫苗基于使用来源于类MN病毒的MN-rgp120多肽(SEQ ID.NO.29)和gp120多肽，其中所说的病毒包含不存在于初始疫苗菌株中的中和表位，并且与疫苗菌株的那些病毒有足够的差异，能在MN-rgp120接种的个体中引起HIV-1感染(即；导致逃逸感染)的。使用初始疫苗菌株的经验性结论是：存在于包含另一些中和表位的群体中的病毒(其含有充分不同于疫苗菌株的那些的附加中和表位)脱逸由疫苗菌株诱导的保护作用。在疫苗中利用初始的典型gp120多肽充当筛，那么不受该疫苗菌株产生有效保护作用影响的病毒逃逸于该疫苗，并根据经验在指定的地区检测出另外一些菌株，其不受初始疫苗菌株的保护作用的影响。利用来源于那些逃逸分离物的gp120，通过提供另外的中和表位(其不存在于起始疫苗菌株内)以补充疫苗，因此创造更多的完全疫苗，该疫苗在所说的区域内具有抗若干不同病毒菌株的保护作用。
原来的HIV-1疫苗策略是基于合适的候选疫苗多肽(其根据同源性序列对比研究)的选择。然而，由于一些中和表位是依赖于构象的，且所有这些表位的位置尚未知，这一方法不可测定所有的在特定区域内在疫苗中应被包括的中和表位。相反，目前该方法利用所选择的代表菌株，和根据经验决定的完全不同的菌株，因此逃逸于由初始接种计划提供的保护屏障。在疫苗中也可包括那些菌株，以提供更多的在该区内抗HIV菌株的完全保护。此外，那些菌株也可单独使用，以产生抗逃逸病毒的保护作用。
在另一个实施方案中，本发明包括一种含有第一HIV gp120多肽序列和逃逸分离物HIV gp120多肽序列的疫苗，其中所说的多肽序列来源于用疫苗(其包含在合适载体中的第一HIV gp120多肽序列)所接种的被接种者。一种或两种HIV gp120多肽序列的片段可被一种或两种对应的HIV gp120多肽序列取代。
优选地，第一gp120多肽序列含有在一种或多种gp120多肽序列中发现的中和表位，其中所说的多肽序列存在于来源于初始疫苗(即，引起逃逸分离物的疫苗)施用地区的分离物中。更优选地，第一gp120多肽序列含有至少一个或多个该区域内共同的中和表位，以及最优选地是第一gp120多肽序列至少含有三个最普通的中和表位中的一个。
适于用作为第一gp120多肽序列的gp120多肽序列包括gp120MN，泰国人分离物A244序列(下文为＂gp120 A244＂),gp120 MN-GNEG(SEQ ID NO.31；在本领域内也称为＂gp120 GNE6＂),以及gp120MN-GNE8(SEQ ID NO.33；在本领域内也称为＂gp120 GNE8＂)等。对北美来说尤其优选利用gp120 MN,gp120 MN-GNEG，和gp120 MN-GNE8作为在初始疫苗中的第一gp120多肽序列。对泰国来说尤其优选利用gp120 A244作为在初始疫苗中的第一gp120多肽序列。
在本实施方案的改进方案中，疫苗包括与逃逸分离物HIV gp120多肽序列相组合的两个(即第一和第二)不同的gp120多肽序列或其片段。后者来源于以第一和第二HIV gp120多肽序列两者之一或两者进行接种的被接种者。
例证性疫苗包括含有gp120 MN,gp120 A244,gp120 MN-GNEG(SEQ ID.No.31)及gp120 MN-GNE8(SEQ ID NO.33)的组合体。尤其优选gp120 MN和gp120 A244或gp120 MN-GNE8(SEQ IDNO.33)与逃逸分离物HIV gp120多肽序列的组合体。
在包含gp120 MN的疫苗中，逃逸分离物HIV gp120多肽序列可以是选自由SEQ ID No.2,4,6,8,10,12,14,16,18,20,22,24,26和28，以及它们的片段组成的组的HIV gp120多肽序列。
如本领域所使用的，术语＂亚单位疫苗＂在本文中是指，不含有病毒但却含有一种或多种病毒蛋白质或病毒蛋白质的片段的病毒疫苗。如本文所使用的，术语＂多价＂，是指疫苗含有具有不同氨基酸序列的来源于至少两种HIV分离物的gp120。
如本领域所使用的，术语＂逃逸分离物＂或＂逃逸病毒＂在本文中是指从被接种者中分离的病毒。
与本领域中同样地，术语＂氨基酸序列＂，＂多肽序列＂，和＂多肽＂在本文中可交换使用，如同术语＂核酸序列＂，＂核苷酸序列＂，及＂寡核苷酸＂。来源于逃逸分离物的多肽
本发明的gp120多肽对应于在下表1中所说明的七种逃逸分离物的氨基酸序列。本发明的多肽包括表1中所说明的HIV gp120氨基酸序列(SEQ ID.NO.1,3,5,7,9,11,13,15,17,19,21,23,25和27)和它们的片段。本发明的多肽可包括由两个或更多的HIV gp120或者gp160氨基酸序列所融合的序列。
该多肽也可以连接到另一个病毒蛋白质上，如标志(flag)表位氨基酸序列。本领域内术语＂标记表位＂在本文中是指包括被单克隆抗体识别的表位的氨基酸序列。标记表位有利于利用单一单克隆抗体对许多不同的重组体蛋白质进行亲和性纯化分析，其中每一蛋白质具有被单克隆抗体识别的标记表位。许多氨基酸序列可作为标记表位。疱疹单纯病毒(HSV-1)的糖蛋白D(gD-1)的N端序列便于用作为标记表位，其作用在实施例中得以详述。标记表位便于与HIV gp120多肽序列的N末端相融合。然而，rgp120序列中的识别中和表位的单克隆抗体可用来亲和纯化氨基酸序列，且可忽略标记表位。
此外，可将各种信号序列与本发明的多肽相连接。虽然在HIV培养物中rgp120分泌至一定程度，宿主细胞释放(分泌)的包膜糖蛋白的量在不同菌株间变化很大。通过将编码信号序列的核苷酸序列连接到编码rgp120的核苷酸序列上，把各种信号序列引入多肽序列中，以利于细胞分泌rgp120。例如，Chiron HIV gp120多肽包括来源于组织纤溶酶原激活物(TPA)的信号序列，这利于rgp120的分泌。附加信号序列为大家所熟知，其包括鼠类白血病病毒的表面蛋白gp70(Kayman等描述，病毒学杂志68:400-410(1984))的N端结构域。
表1说明本发明七种逃逸分离物各自的两个克隆的核苷酸和所推定的氨基酸序列。这些克隆是：C6.1；C6.5；C8.3；C8.6；C15.2；C15.3；C7.2；C7.10；C11.5；C11.7；C10.5；C10.7；C17.1和C17.3。这些序列是SEQ.ID.No.1-28，每个克隆的第一个序列号是核苷酸序列，第二个是氨基酸序列。MN核苷酸序列与所推定的MN-GNE6和MN-GNE8的氨基酸序列在下文列出的序列中说明。在MN-GNE6的列出序列中，终止密码子位于第51个氨基酸残基位置。这一终止密码子可被编码对应氨基酸(其来源于MN或MN-GNE8或其它分离物)的密码子所取代。
表1
克隆C6.1
GGG GTA CCT GTG TGG AAG GAA GCA ACC ACC ACT CTA 365 Gly Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu
1 5 10
TTT TGT GCA TCA GAT GCT AAA GCA TAT GAC ACA GAG GTG 75
Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp Thr Glu Val
15 20 2510 CAT AAT GTT TGG GCC ACA CAT GCT TGT GTA CCC ACA GAC 114
His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp
30 35
CCA AAC CCA CAA GAA ATG GTA TTG GAA AAT GTG ACA GAA 153
Pro Asn Pro Gln Glu Met Val Leu Glu Asn Val Thr Glu15 40 45 50
GAT TTT AAC ATG TGG AAA AAT GAC ATG GTA GAA CAG ATG 192
Asp Phe Asn Met Trp Lys Asn Asp Met Val Glu Gln Met
55 60
CAT GAG GAT ATA ATC AGT TTA TGG GAT CAA AGC CTA AAA 23120 His Glu Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu Lys
65 70 75
CCA TGT GTA AAA TTA ACC CCA CTC TGT ATT ACT TTA AAT 270
Pro Cys Val Lys Leu Thr Pro Leu Cys Ile Thr Leu Asn
80 85 9025 TGC ACC AAT TGG AAG AAG AAT GAT ACT AAA ACT AAT AGT 309
Cys Thr Asn Trp Lys Lys Asn Asp Thr Lys Thr Asn Ser
95 100
AGT AGT ACT ACA ACT AAT AAT AGT AGT GCT ACA GCT AAT 348
Ser Ser Thr Thr Thr Asn Asn Ser Ser Ala Thr Ala Asn30 105 110 115
AGT AGT AGT ACT ACA ACT AAT ACT AGT TGG GGA GAG ATA 387
Ser Ser Ser Thr Thr Thr Asn Ser Ser Trp Gly Glu Ile
120 125
AAG GAG GGA GAA ATA AAG AAC TGC TCT TTC AAT ATC ACC 42635 Lys Glu Gly Glu Ile Lys Asn Cys Ser Phe Asn Ile Thr
130 135 140
ACA ACC ATA AGA GAC AAG GTG AAG AAA GAA TAT GCA CTT 465
Thr Ser Ile Arg Asp Lys Val Lys Lys Glu Tyr Ala Leu
145 150 15540 TTT TAT AGC CTT GAT GTA GTA CCA ATA GAA AAT GAT AAT 504
Phe Tyr Ser Leu Asp Val Val Pro Ile Glu Asn Asp Asn
160 165
ACT AGC TAT AGG TTG AGA AGT TGT AAC ACC TCA GTC ATT 543
Thr Ser Tyr Arg Leu Arg Ser Cys Asn Thr Ser Val Ile45 170 175 180
ACA CAA GCC TGT CCA AAG GTA ACT TTT GAG CCA ATT CCC 582
Thr Gln Ala Cys Pro Lys Val Thr Phe Glu Pro Ile Pro
185 190
ATA CAT TAT TGT ACC CCG GCT GGT TTT GCG ATT CTG AAG 62150 Ile His Tyr Cys Thr Pro Ala Gly Pne Ala Ile Leu Lys
195 200 205
TGT AGA GAT AAA AAG TTC AAT GGA ACA GGA CCA TGC AAA 660
Cys Arg Asp Lys Lys Phe Asn Gly Thr Gly Pro Cys Lys
210 215 22055 AAT GTT AGC ACA GTA CAA TGT GCA CAT GGA ATT AAG CCA 699
Asn Val Ser Thr Val Gln Cys Ala His Gly Ile Lys Pro
225 230
GTA GTG TCA ACT CAA CTG CTG TTA AAT GGC AGC CTA GCA 738
Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala60 225 240 245
GAA GAA GAG GTA ATA ATT AGA TCT GCC AAT TTC TCA AAC 777
Glu Giu Glu Val Ile Ile Arg Ser Ala Asn Phe Ser Asn
250 255
AAT GCT AAA ATC ATA ATA GTA CAG TTG AGG GAA CCT GTA 816
Asn Ala Lys Ile Ile Ile Val Gln Leu Arg Glu Pro Val
260 265 270
GAA ATT AAT TGT ACA AGA CCC AGC AAC AAT ACA ATA AAA 855
Glu Ile Asn Cys Thr Arg Pro Ser Asn Asn Thr Ile Lys
275 280 285
GGT ATA CAC ATA GGA CCA GGG AGA GCA TTT TAT GCA ACA 894
Gly Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Ala Thr
290 29510 GGA GAC ATA CGA GGA GAT ATA AGA CAA GCA CAT TGT AAC 933
Gly Asp Ile Arg Gly Asp Ile Arg Gln Ala His Cys Asn
300 305 310
ATT AGT GGA GCA AAA TGG AAT AAC ACT TTA AAG AAG GTA 972
Ile Ser Gly Ala Lys Trp Ash Asn Thr Leu Lys Lys Val15 315 320
GTT AAA AAA TTA AAA GAA CAA TTT CCA AAT AAA ACA ATA 1011
Val Lys Lys Leu Lys Glu Gln Phe Pro Asn Lys Thr Ile
325 330 335
GTC TTT AAC CAT TCC TCA GGA GGG GAC CCA GAA ATT GTA 105020 Val Phe Asn His Ser Ser Gly Gly Asp Pro Glu Ile Val
340 345 350
ATG CAC AGT TTT AAT TGT CAA GGG GAA TTT TTC TAC TGT 1089
Met His Ser Phe Asn Cys Gln Gly Glu Phe Phe Tyr Cys
355 36025 AAT ACA ACA AAG CTG TTT AAT AGT ACT TGG AAT GAT ACT 1128
Asn Thr Thr Lys Leu Phe Asn Ser Thr Trp Asn Asp Thr
365 370 375
ACA GAG TCA AAT AAC AAT GAT AGT ACT ATT ACA CTC CCA 1167
Thr Glu Ser Asn Asn Asn Asp Ser Thr Ile Thr Leu Pro30 380 385
TGC AGA ATA AAA CAA ATT ATA AAC ATG TGG CAG GAA ATA 1206
Cys Arg Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Ile
390 395 400
GGA AAA GCA ATG TAT GCC CCT CCC ACC AGA GGA GAA ATT 124535 Gly Lys Ala Met Tyr Ala Pro Pro Thr Arg Gly Glu Ile
405 410 415
AAA TGT TCA TCA AAT ATT ACA GGA CTA CTG TTA ATA AGA 1284
Lys Cys Ser Ser Asn Ile Thr Gly Leu Leu Leu Ile Arg
420 42540 GAT GGT GGT ATT AAC ACT AGC GAT GCC ACC GAG ACC TTC 1323
Asp Gly Gly Ile Asn Thr Ser Asp Ala Thr Glu Thr Phe
430 435 440
AGA CCG GGA GGA GGA GAT ATG AGG GAC AAT TGG AGA AGT 1362
Arg Pro Gly Gly Gly Asp Mer Arg Asp Asn Trp Arg Ser45 445 450
GAA TTA TAT AAA TAT AAA GTA GTG AAA ATT GAG CCA TTA 1401
Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile Glu Pro Leu
455 460 465
GGA GTA GCA CCC ACC AAG GCA AAG AGA AGA GTG GTG CAG 144050 Gly Val Ala Pro Thr Lys Ala Lys Arg Arg Val Val Gln
470 475 480
AGA GAA AAA AGA GCA GTA ACA CTA GGA GCT ATG TTC CTT 1479
Arg Glu Lys Arg Ala Val Thr Leu Gly Ala Met Phe Leu
485 49055 GGG TTC TTA GGA GCA TAA AGC TTC 1503
Gly Phe Leu Gly Ala Xaa Ser Phe
495 500 501
克隆C6.560 GGG GTA CCT GTA TGG AAA GAA GCA ACC ACC ACT CTA 36
Gly Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu
1 5 10
TTT TGT GCA TCA GAT GCT AAA GCA TAT GAC ACA GAG GTG 75
Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp Thr Glu Val65 15 20 25
CAT AAT GTT TGG GCC ACA CAT GCT TGT GTA CCC ACA GAC 114
His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp
30 35
CCA AAC CCA CAA GAA ATG GTA TTG GAA AAT GTG ACA GAA 1535 Pro Asn Pro Gln Glu Met Val Leu Glu Asn Val Thr Glu
40 45 50
GAT TTT AAC ATG TGG AAA AAT GAC ATG GTA GAA CAG ATG 192
Asp Phe Asn Met Trp Lys Asn Asp Met Val Glu Gln Met
55 6010 CAT GAG ANT ATA ATC AGT TTA TGG GAT CAA AGC CTA AAA 231
His Glu Xaa Ile Ile Ser Leu Trp Asp Gln Ser Leu Lys
65 70 75
CCA TGT GTA AAA TTA ACC CCA CTC TGT ATT ACT TTA AAT 270
Pro Cys Val Lys Leu Thr Pro Leu Cys Ile Thr Leu Asn15 80 85 90
TGC ACC AAT TGG AAG GAG AAT GAT ACT AAA ACT AAT AGT 309
Cys Thr Asn Trp Lys Glu Asn Asp Thr Lys Thr Asn Ser
95 100
AGT AGT ACT ACA ACT AAT AAT AGT AGT GCT ACA GCT AAT 34820 Ser Ser Thr Thr Thr Asn Asn Ser Ser Ala Thr Ala Asn
105 110 115
AGT AGT AGT ACT ACA ACT AAT AGT AGT TGG GGA GAG ATA 387
Ser Ser Ser Thr Thr Thr Asn Ser Ser Trp Gly Glu Ile
120 12525 AAG GAG GGA GAA ATA AAG AAC TGC TCT TTC AAT ATC ACC 426
Lys Glu Gly Glu Ile Lys Asn Cys Ser Phe Asn Ile Thr
130 135 140
ACA GGC ATA AGA GAC AAG GTG AAG AAA GAA TAT GCA CTT 465
Thr Gly Ile Arg Asp Lys Val Lys Lys Glu Tyr Ala Leu30 145 150 155
TTT TAT AGC CTT GAT GTA GTA CCA ATA GAA AAT GAT AAT 504
Phe Tyr Ser Leu Asp Val Val Pro Ile Glu Asn Asp Asn
160 165
ACT AGC TAT AGG TTG AGA AGT TGT AAC ACC TCA GTC ATT 54335 Thr Ser Tyr Arg Leu Arg Ser Cys Asn Thr Ser Val Ile
170 175 180
ACA CAA GCC TGT CCA AAG GTA ACT TTT GAG CCA ATT CCC 582
Thr Gln Ala Cys Pro Lys Val Thr Phe Glu Pro Ile Pro
185 19040 ATA CAT TAT TGT ACC CCG GCT GGT TTT GCG ATT CTG AAG 621
Ile His Tyr Cys Thr Pro Ala Gly Phe Ala Ile Leu Lys
195 200 205
TGT AAA GAT AAA AAG TTC AAT GGA ACA GGA CCA TGC AAA 660
Cys Lys Asp Lys Lys Phe Asn Gly Thr Gly Pro Cys Lys45 210 215 220
AAT GTT AGC ACA GTA CAA TGT ACA CAT GGA ATT AAG CCA 699
Asn Val Ser Thr Val Gln Cys Thr His Gly Ile Lys Pro
225 230
GTA GTG TCA ACT CAA CTG CTG TTA AAT GGC AGC CTA GCA 73850 Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala
235 240 245
GAA GAA GAG GTA ATA ATT AGA TCT GCC AAT TTC TCA AAC 777
Glu Glu Glu Val Ile Ile Arg Ser Ala Asn Phe Ser Asn
250 25555 AAT GCT AAA ATC ATA ATA GTA CAG TTG AAG GAA CCT GTA 816
Asn Ala Lys Ile Ile Ile Val Gln Leu Lys Glu Pro Val
260 265 27
GAA ATT AAT TGT ACA AGA CCC AGC AAC AAT ACA ATA AAA 855
Glu Ile Asn Cys Thr Arg Pro Ser Asn Asn Thr Ile Lys60 275 280 285
GGT ATA CAC ATA GGA CCA GGG AGA GCA TTT TAT GCA ACA 894
Gly Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Ala Thr
290 295
GGA GAC ATA CGA GGA GAT ATA AGA CAA GCA CAT TGT AAC 933
Gly Asp Ile Arg Gly Asp Ile Arg Gln Ala His Cys Asn
300 305 310
ATT AGT GGA GCA AAA TGG AAT AAC ACT TTA AAG AAG GTA 9725 Ile Ser Gly Ala Lys Trp Asn Asn Thr Leu Lys Lys Val
315 320
GTT ATA AAA TTA AAA GAA CAA TTT CCA AAT AAA ACA ATA 1011
Val Ile Lys Leu Lys Glu Gln Phe Pro Asn Lys Thr Ile
325 330 33510 GTC TTT AAC CAT TCC TCA GGA GGG GAC CCA GAA ATT GTA 1050
Val Phe Asn His Ser Ser Gly Gly Asp Pro Glu Ile Val
340 345 350
ATG CAC AGT TTT AAT TGT CAA GGG GAA TTT TTC TAC TGT 1089
Met His Ser Phe Asn Cys Gln Gly Glu Phe Phe Tyr Cys15 355 360
AAT ACA ACG AAG CTG TTT AAT AGT ACT TGG AAT GAT ACT 1128
Asn Thr Thr Lys Leu Phe Asn Ser Thr Trp Asn Asp Thr
365 370 375
ACA GAG TCA AAT AAC AAT GAT AGT ACT ATT ACA CTC CCA 116720 Thr Glu Ser Asn Asn Asn Asp Ser Thr Ile Thr Leu Pro
380 385
TGC AGA ATA AAA CAA ATT ATA AAC ATG TGG CAG GAA GTA 1206
Cys Arg Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val
390 395 40025 GGA AAA GCA ATG TAT GCC CCT CCC ATC AGA GGA GAA ATT 1245
Gly Lys Ala Met Tyr Ala Pro Pro Ile Arg Gly Glu Ile
405 410 415
AAA TGT TCA TCA AAT ATT ACA GGA CTA CTG TTA ACA AGA 1284
Lys Cys Ser Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg30 420 425
GAT GGT GGT ATT AAC ACT AGC GAT GCC ACC GAG ACC TTC 1323
Asp Gly Gly Ile Asn Thr Ser Asp Ala Thr Glu Thr Phe
430 435 440
AGA CCG GGA GGA GGA GAT ATG AGG GAC AAT TGG AGA AGT 136235 Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp Arg Ser
445 450
GAA TTA TAT AAA TAT AAA GTA GTG AAA ATT GAG CCA TTA 1401
Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile Glu Pro Leu
455 460 46540 GGA GTA GCA CCC ACC AAG GCA AAG AGA AGA GTG GTG CAG 1440
Gly Val Ala Pro Thr Lys Ala Lys Arg Arg Val Val Gln
470 475 480
AGA GAA AAA AGA GCA GTA ACA CTA GGA GCT ATG TTC CTT 1479
Arg Glu Lys Arg Ala Val Thr Leu Gly Ala Met Phe Leu45 485 490
GGG TTC TTG GGA GCA TAA AGC TTC 1503
Gly Phe Leu Gly Ala Xaa Ser Phe
495 500 50150 克隆C8.3
G GTA CCT GTA TGG AAA GAA GCA ACC ACC ACT CTA TTT 37
Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu Phe
1 5 10
TGT GCA TCA GAT GCT AAA GCA TAT CAT ACA GAG GTA CAT 7655 Cys Ala Ser Asp Ala Lys Ala Tyr Asp Thr Glu Val His
15 20 25
AAT GTT TGG GCT ACA CAT GCC TGT GTA CCC ACA GAC CCC 115
Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro
30 3560 AAC CCA CAA GAA GTA GTA TTG GAA AAT GTA ACA GAA AAT 154
Asn Pro Gln Glu Val Val Leu Glu Asn Val Thr Glu Asn
40 45 50
TTT AAC ATG TGG AAA AAT AAC ATG GTA GAA CAG ATG CAT 193
Phe Asn Met Trp Lys Asn Asn Met Val Glu Gln Met His65 55 60
GAG GAT ATA ATC AGT TTA TGG GAT CAA AGT CTA AAG CCA 232
Glu Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu Lys Pro
65 70 75
TGT GTA AAA TTA ACC CCA CTC TGT GTT ACT TTA AAT TGC 2715 Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Asn Cys
80 85 90
ACT AAT TTG GAG AAT GCT AAT AAT ACC GAG AAT GCT AAT 310
Thr Asn Leu Glu Asn Ala Asn Asn Thr Glu Asn Ala Asn
95 10010 AAT ACC AAT AAT TAT ACC TTG GGG ATG GAG AGA GGT GAA 349
Asn Thr Asn Asn Tyr Thr Leu Gly Met Glu Arg Gly Glu
105 110 115
ATA AAA AAC TGC TCT TTC AAT ATC ACC ACA AGC TTA AGA 388
Ile Lys Asn Cys Ser Phe Asn Ile Thr Thr Ser Leu Arg15 120 125
GAT AAG GTG AAA AAA GAA TAT GCA TTG TTT TAT AAA CTT 427
Asp Lys Val Lys Lys Glu Tyr Ala Leu Phe Tyr Lys Leu
130 135 140
GAT GTA GTA CAA ATA GAT AAT AGT ACC AAC TAT AGG CTG 46620 Asp Val Val Gln Ils Asp Asn Ser Thr Asn Tyr Arg Leu
145 150 155
ATA AGT TGT AAT ACC TCA GTC ATT ACA CAG GCC TGT CCA 505
Ile Ser Cys Asn Thr Ser Val Ile Thr Gln Ala Cys Pro
160 16525 AAG GTA TCC TTT GAG CTA ATT CCC ATA CAT TAT TGT GCC 544
Lys Val Ser Phe Glu Leu Ile Pro Ile His Tyr Cys Ala
170 175 180
CCG GCT GGT TTT GCG ATT CTA AAG TGT AAA GAT AAG AAG 583
Pro Ala Gly Pha Ala Ile Leu Lys Cys Lys Asp Lys Lys30 185 190
TTC AAT GGA ACA GGA CCA TGT AAA AAT GTC AGC ACA GTA 622
Phe Asn Gly Thr Gly Pro Cys Lys Asn Val Ser Thr Val
195 200 205
CAA TGT ACA CAT GGA ATT AGA CCA GTA GTA TCA ACT CAA 66135 Gln Cys Thr His Gly Ile Arg Pro Val Val Ser Thr Gln
210 215 220
CTA CTG TTA AAT GGC AGT CTA GCA GAA GAA GAG ATA GTA 700
Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Ile Val
225 23040 ATT AGA TCT GAA AAT ATC ACA GAC AAT GCT AAA ACC ATA 739
Ile Arg Ser Glu Asn Ile Thr Asp Asn Ala Lys Thr Ile
235 240 245
ATA GTG CAG CTA AAT GAA TCT ATA GTG ATT AAT TGT ACA 778
Ile Val Gln Leu Asn Glu Ser Ile Val Ile Asn Cys Thr45 250 255
AGA CCC AAT AAC AAC ACA AGA AAA AGT ATA AAT ATA GGA 817
Arg Pro Asn Asn Asn Thr Arg Lys Ser Ile Asn Ile Gly
260 265 270
CCA GGG AGA GCA TTC TAT ACA ACA GGA GAC ATA ATA GGA 85650 Pro Gly Arg Ala Phe Tyr Thr Thr Gly Asp Ile Ile Gly
275 280 285
GAT ATA AGA CAA GCA CAT TGT AAC CTT AGT AAA ACA CAA 895
Asp Ile Arg Gln Ala His Cys Asn Leu Ser Lys Thr Gln
290 29555 TGG GAA AAA ACG TTA AGA CAG ATA GCT ATA AAA TTA GAA 934
Trp Glu Lys Thr Leu Arg Gln Ile Ala Ile Lys Leu Glu
300 305 310
GAA AAA TTT AAG AAT AAA ACA ATA GCC TTT AAT AAA TCC 973
Glu Lys Phe Lys Asn Lys Thr Ile Ala Phe Asn Lys Ser60 315 320
TCA GGA GGG GAC CCA GAA ATT GTA ATG CAC AGT TTT AAT 1012
Ser Gly Gly Asp Pro Glu Ile Val Met His Ser Phe Asn
325 330 335
TGT GGA GGG GAA TTT TTC TAC TGT AAT ACA ACA AAA CTG 1051
Cys Gly Gly Glu Phe Phe Tyr Cys Asn Thr Thr Lys Leu
340 345 350
TTT AAT AGT ACC TGG AAT TTA ACA CAA CCG TTT AGT AAT 10905 Phe Asn Ser Thr Trp Asn Leu Thr Gln Pro Phe Ser Asn
355 360
ACC GGG AAT CGT ACT GAA GAG TTA AAT ATT ACA CTC CCA 1129
Thr Gly Asn Arg Thr Glu Glu Leu Asn Ile Thr Leu Pro
365 370 37510 TGC AGA ATA AAA CAA ATC ATA AAC TTG TGG CAG GAA GTA 1168
Cys Arg Ile Lys Gln Ile Ile Asn Leu Trp Gln Glu Val
380 385
GGC AAA GCA ATG TAT GCC CCT CCC ATC AGA GGA CAA ATT 1207
Gly Lys Ala Met Tyr Ala Pro Pro Ile Arg Gly Gln Ile15 390 395 400
AGA TGT TCA TCA AAT ATT ACA GGG CTA CTA TTA ACA AGA 1246
Arg Cys Ser Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg
405 410 415
GAT GGT GGA AGT AAC ACC GGT GAC AAC AGG ACT GAG ACC 128520 Asp Gly Gly Ser Asn Thr Gly Asp Asn Arg Thr Glu Thr
420 425
TTT AGA CCT GGA GGA GGA GAT ATG AGG GAC AAT TGG AGA 1324
Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp Arg
430 435 44025 AGT GAA TTA TAT AAA TAT AAA GTA GTA AGA ATT GAA CCA 1363
Ser Glu Leu Tyr Lys Tyr Lys Val Val Arg Ile Glu Pro
445 450
TTA GGA GTA GCA CCC ACC CAG GCA AAG AGA AGA GTG GTG 1402
Leu Gly Val Ala Pro Thr Gln Ala Lys Arg Arg Val Val30 455 460 465
CAA AGA GAA AAA AGA GCA GTG GGG ATA GGA GCT ATG TTC 1441
Gln Arg Glu Lys Arg Ala Val Gly Ile Gly Ala Met Phe
470 475 480
CTT GGG TTC TTG GGA GAT AA 146135 Leu Gly Phe Leu Gly Asp
485 486
克隆C8.6
G GTA CCT GTG TGG AAA GAA GCA ACC ACC ACT CTA TTT 3740 Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu Phe
1 5 10
TGT GCA TCA GAT GCT AAA GCA TAT GAT ACA GAG GTA CAT 76
Cys Ala Ser Asp Ala Lys Ala Tyr Asp Thr Glu Val His
15 20 2545 AAT GTT TGG GCT ACA CAT GCC TGT GTA CCC ACA GAC CCC 115
Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro
30 35
AAC CCA CAA GAA GTA GTA TTG GAA AAT GTA ACA GAA AAT 154
Asn Pro Gln Glu Val Val Leu Glu Asn Val Thr Glu Asn50 40 45 50
TTT AAC ATG TGG AAA AAT AAC ATG GTA GAA CAG ATG CAT 193
Phe Asn Met Trp Lys Asn Asn Met Val Glu Gln Met His
55 60
GAG GAT ATA ATC AGT TTA TGG GAT CAA AGT CTA AAG CCA 23255 Glu Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu Lys Pro
65 70 75
TGT GTA AAA TTA ACC CCA CTC TGT GTT ACT TTA AAT TGC 271
Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Asn Cys
80 85 9060 ACT AAT TTG GAG AAT GCT AAT AAT ACC GAG AAT GCT AAT 310
Thr Asn Leu Glu Asn Ala Asn Asn Thr Glu Asn Ala Asn
95 100
AAT ACC AAT AAT TAT ACC TTG GGG ATG GAG AGA GGT GAA 349
Asn Thr Asn Asn Tyr Thr Leu Gly Met Glu Arg Gly Glu65 105 110 115
AGA AAA AAC TGC TCT TTC AAT ATC ACC ACA AGC TTA AGA 388
Arg Lys Asn Cys Ser Phe Asn Ile Thr Thr Ser Leu Arg
120 125
GAT AAG GGG AAA AAA GAA TAT GCA TTG TTT TAT AAA CTT 4275 Asp Lys Gly Lys Lys Glu Tyr Ala Leu Phe Tyr Lys Leu
130 135 140
GAT GTA GTA CAA ATA GAT AAT AGT ACC AAC TAT AGG CTG 466
Asp Val Val Gln Ile Asp Asn Ser Thr Asn Tyr Arg Leu
145 150 15510 ATA AGT TGT AAT ACC TCA GTC ATT ACA CAG GCC TGT CCA 505
Ile Ser Cys Asn Thr Ser Val Ile Thr Gln Ala Cys Pro
160 165
AAG GTA TCC TTT GAG CCA ATT CCC ATA CAT TAT TGT GCC 544
Lys Val Ser Phe Glu Pro Ile Pro Ile His Tyr Cys Ala15 170 175 180
CCG GCT GGT TTT GCG ATT CTA AAG TGT AAA GAT AAG AAG 583
Pro Ala Gly Phe Ala Ile Leu Lys Cys Lys Asp Lys Lys
185 190
TTC AAT GGA ACA GGA CCA TGT AAA AAT GTC AGG ACA GTA 62220 Phe Asn Gly Thr Gly Pro Cys Lys Asn Val Arg Thr Val
195 200 205
CAA TGT ACA CAT GGA ATT AGA CCA GTA GTA TCA ACT CAA 661
Gln Cys Thr His Gly Ile Arg Pro Val Val Ser Thr Gln
210 215 22025 CTA CTG TTA AAT GGC AGT CTA GCA GAA GAA GAG ATA GTA 700
Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Ile Val
225 230
ATT AGA TCT GAA AAT ATC ACA GAC AAT GCT AAA ACC ATA 739
Ile Arg Ser Glu Asn Ile Thr Asp Asn Ala Lys Thr Ile30 235 240 245
ATA GTG CAG CTA AAT GAA TCT ATA GTG ATT AAT TGT ACA 778
Ile Val Gln Leu Asn Glu Ser Ile Val Ile Asn Cys Thr
250 255
AGA CCC AAT AAC AAC ACA AGA AAA AGT ATA AAT ATA GGA 81735 Arg Pro Asn Asn Asn Thr Arg Lys Ser Ile Asn Ile GLy
260 265 270
CCA GGG AGA GCA TTC TAT ACA ACA GGA GAC ATA ATA GGA 856
Pro Gly Arg Ala Phe Tyr Thr Thr Gly Asp Ile Ile Gly
275 280 28540 GAT ATA AGA CAA GCA CAT TGT AAC CTT AGT AAA ACA CAA 895
Asp Ile Arg Gln Ala His Cys Asn Leu Ser Lys Thr Gln
290 295
TGG GAA AAA ACG TTA AGA CAG ATA GCT ATA AAA TTA GAA 934
Trp Glu Lys Thr Leu Arg Gln Ile Ala Ile Lys Leu Glu45 300 305 310
GAA AAA TTT AAG AAT AAA ACA ATA GCC TTT AAT AAA TCC 973
Glu Lys Phe Lys Asn Lys Thr Ile Ala Phe Asn Lys Ser
315 320
TCA GGA GGG GAC CCA GAA ATT GTA ATG CAC AGT TTT AAT 101250 Ser Gly Gly Asp Pro Glu Ile Val Met His Ser Phe Asn
325 330 335
TGT GGA GGG GGA TTT TTC TAC TGT AGT ACG AGA AAA CTG 1051
Cys Gly Gly Gly Phe Phe Tyr Cys Ser Thr Arg Lys Leu
340 345 35055 TTT AAT AGT ACC TGG AAT TTA ACA CAA CCG TTT AGT AAT 1090
Phe Asn Ser Thr Trp Asn Leu Thr Gln Pro Phe Ser Asn
355 360
ACC GGG GAT CGT ACT GAA GAG TTA AAT ATT ACA CTC CCA 1129
Thr Gly Asp Arg Thr Glu Glu Leu Asn Ile Thr Leu Pro60 365 370 375
TGC AGA ATA AAA CAA ATC ATA AAC TTG TGG CAG GAA GTA 1168
Cys Arg Ile Lys Gln Ile Ile Asn Leu Trp Gln Glu Val
380 385
GGC AAA GCA ATG TAT GCC CCT CCC ATC AGA GGA CAA ATT 1207
Gly Lys Ala Met Tyr Ala Pro Pro Ile Arg Gly Gln Ile
390 395 400
AGA TGT TCA TCA AAT ATT ACA GGG CTA CTA TTA AGG AGA 12465 Arg Cys Ser Ser Asn Ile Thr Gly Leu Leu Leu Arg Arg
405 410 415
GAT GGT GGA AGT AAC ACC AGT GAC AAC CAG ACT GAG ACC 1285
Asp Gly Gly Ser Asn Thr Ser Asp Asn Gln Thr Glu Thr
420 42510 TTT AGA CCT GGG GGA GGA GAT ATG AGG GAC AAG TGG AGA 1324
Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Lys Trp Arg
430 435 440
AGT GAA TTA TAT AAA TAT AAA GTA GTA AGA ATT GAA CCA 1363
Ser Glu Leu Tyr Lys Tyr Lys Val Val Arg Ile Glu Pro15 445 450
TTA GGA GTA GCA CCC ACC CAG GCA AAG AGA AGA GTG GTG 1402
Leu Gly Val Ala Pro Thr Gln Ala Lys Arg Arg Val Val
455 460 465
CAA AGA GAA AAA AGA GCA GTG GGG ATA GGA GCT ATG TTC 144120 Gln Arg Glu Lys Arg Ala Val Gly Ile Gly Ala Met Phe
470 475 480
CTT AGG TTC TTA GGA GAT AAA GCT TCT AGA GTC 1474
Leu Arg Phe Leu Gly Asp Lys Ala Ser Arg Val
485 490 49125
克隆 C15.2
CTC GAG GTA CCT GTA TGG AAA GAA GCA ACT ACC ACT 36
Leu Glu Val Pro Val Trp Lys Glu Ala Thr Thr Thr
1 5 1030 CTA TTT TGT GCA TCA GAT GCT AAA GCA TAT AAT ACA GAG 75
Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asn Thr Glu
15 20 25
AAA CAT AAT GTT TGG GCC ACA CAC GCC TGT GTA CCC ACA 114
Lys His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr35 30 35
GAT CCC AAC CCA CAA GAA GTA GTA TTG GGA AAT GTG ACA 153
Asp Pro Asn Pro Gln Glu Val Val Leu Gly Asn Val Thr
40 45 50
GAA AAT TTT AAC ATG TGG AAA AAT AAC ATG GTA GAA CAA 19240 Glu Asn Phe Asn Met Trp Lys Asn Asn Met Val Glu Gln
55 60
ATG CAT GAA GAT ATA ATC AGT TTA TGG GAT CAA AGT CTA 231
Met His Glu Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu
65 70 7545 AAG CCA TGT GTA AAA TTA ACC CCA CTC TGT GTT ACT TTA 270
Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
80 85 90
AAT TGC ACT GAT GAT TTA GGG AAT GCT ACT AAT ACC AAT 309
Asn Cys Thr Asp Asp Leu Gly Asn Ala Thr Asn Thr Asn50 95 100
AGT AGT GCC ACT ACC AAT AGT AGT AGT TGG GAA GAA ATG 348
Ser Ser Ala Thr Thr Asn Ser Ser Ser Trp Glu Glu Met
105 110 115
AAG GGG GAA ATG AAA AGA TGC TCT TTC AAT ATC ACC ACA 38755 Lys Gly Glu Met Lys Arg Cys Ser Phe Asn Ile Thr Thr
120 125
AGC ATA AGA GAT AAG ATT AAG AAA GAA CAT GCA CTT TTC 426
Ser Ile Arg Asp Lys Ile Lys Lys Glu His Ala Leu Phe
130 135 14060 TAT AGA CTT GAT GTA GTA CCA ATA GAT AAT GAT AAT ACC 465
Tyr Arg Leu Asp Val Val Pro Ile Asp Asn Asp Asn Thr
145 150 155
ACA TAT AGG TTG ATA AAT TGT AAT ACC TCA GTC ATT ACA 504
Thr Tyr Arg Leu Ile Asn Cys Asn Thr Ser Val Ile Thr
160 165
CAG GCC TGT CCA AAG GTA TCA TTT GAG CCA ATT CCC ATA 5435 Gln Ala Cys Pro Lys Val Ser Phe Glu Pro Ile Pro Ile
170 175 180
CAT TTT TGT GCC CCG GCT GGT TTT GCG ATT CTA AAG TGT 582
His Phe Cys Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys
185 19010 AAT AAT AAG ACG TTC GAG GGA AAA GGA CCA TGT AAA AAT 621
Asn Asn Lys Thr Phe Glu Gly Lys Gly Pro Cys Lys Asn
195 200 205
GTC AGT ACA GTA CAA TGC ACA CAT GGA ATT AGG CCA GTA 660
Val Ser Thr Val Gln Cys Thr His Gly Ile Arg Pro Val15 210 215 220
GTG TCA ACT CAA CTG CTG TTA AAT GGC AGT CTA GCA GAA 699
Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu
225 230
GAA GAG GTA ATA ATT AGA TCT GAC AAT ATC ACA GAC AAT 73820 Glu Glu Val Ile Ile Arg Ser Asp Asn Ile Thr Asp Asn
235 240 245
ACT AAA ACC ATT ATA GTA CAG CTA AAC GAA TCT GTA GTA 777
Thr Lys Thr Ile Ile Val Gln Leu Asn Glu Ser Val Val
250 25525 ATT AAT TGT ACA AGA CCC AAC AAC AAT ACA AGA AAA AGT 816
Ile Asn Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys Ser
260 265 270
ATA CAT ATA GGA CCA GGG AGT GCA TTT TTT GCA ACA GGA 855
Ile His Ile Gly Pro Gly Ser Ala Phe Phe Ala Thr Gly30 275 280 285
GAA ATA ATA GGA GAT ATA AGA CAA GCA CAC TGT AAC CTT 894
Glu Ile Ile Gly Asp Ile Arg Gln Ala His Cys Asn Leu
290 295
AGT AGA ACA CAA TGG AAT AAC ACT TTA GGA AAG ATA GTC 93335 Ser Arg Thr Gln Trp Asn Asn Thr Leu Gly Lys Ile Val
300 305 310
ATA AAA TTA AGA GAA CAA TTT AGA AAA CAA TTT GGA GAA 972
Ile Lys Leu Arg Glu Gln Phe Arg Lys Gln Phe Gly Glu
315 32040 AAA ACA ATA GTC TTT AAT CGA TCC TCA GGA GGG GAC CCG 1011
Lys Thr IIe Val Phe Asn Arg Ser Ser Gly Gly Asp Pro
325 330 335
GAA ATT GCA ATG CAC AGT TTT AAT TGT GGA GGG GAA TTT 1050
Glu Ile Ala Met His Ser Phe Asn Cys Gly Gly Glu Phe45 340 345 350
TTC TAC TGT AAC ACA ACA GCA CTG TTT AAT AGT ACC TGG 1089
Phe Tyr Cys Asn Thr Thr Ala Leu Phe Asn Ser Thr Trp
355 360
AAT GTT ACT AAA GGG TTG AAT AAC ACT GAA GGA AAT AGC 112850 Asn Val Thr Lys Gly Leu Asn Asn Thr Glu Gly Asn Ser
365 370 375
ACA GGA GAT GAA AAT ATC ATA CTC CCA TGT AGA ATA AAA 1167
Thr Gly Asp Glu Asn Ile Ile Leu Pro Cys Arg Ile Lys
380 38555 CAA ATT ATA AAC ATG TGG CAG GAA GTA GGA AAA GCA ATG 1206
Gln Ile Ile Asn Met Trp Gln Glu Val Gly Lys Ala Met
390 395 400
TAT GCC CCT CCC ATC AGT GGA CAA ATT AGA TGT TCA TCA 1245
Tyr Ala Pro Pro Ile Ser Gly Gln Ile Arg Cys Ser Ser60 405 410 415
AAC ATT ACA GGG CTG CTA CTA ACA AGA GAT GGT GGT AGT 1284
Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly Ser
420 425
AAG AAC GAG AGC ATC ACC ACC GAG GTC TTC AGA CCT GGA 1323
Lys Asn Glu Ser Ile Thr Thr Glu Val Phe Arg Pro Gly
430 435 440
GGA GGA GAT ATG AGG GAC AAT TGG AGA AGT GAA TTA TAT 1362
Gly Gly Asp Met Arg Asp Asn Trp Arg Ser Glu Leu Tyr
445 450
AAA TAT AAA GTA GTA AAA ATT GAA CCA TTA GGA GTA GCG 1401
Lys Tyr Lys Val Val Lys Ile Glu Pro Leu Gly Val Ala
455 460 46510 CCC ACC AAG GCA AAG AGA AGA GTG GTG CAG AGA GAA AAA 1440
Pro Thr Lys Ala Lys Arg Arg Val Val Gln Arg Glu Lys
470 475 480
AGA GCA GTG GGA ACA ATA GGA GCT ATG TTC CTT GGG TTC 1479
Arg Ala Val Gly Thr Ile Gly Ala Met Phe Leu Gly Phe15 485 490
TTG GGA GCA TAA AGC TTC TAG AGT CGA CCT GCA 1512
Leu Gly Ala Xaa Ser Phe Xaa Ser Arg Pro Ala
495 500 50420 克隆 C15.3
CTC GAG GTA CCT GTG TGG AAA GAA GCA ACT ACC ACT 36
Leu Glu Val Pro Val Trp Lys Glu Ala Thr Thr Thr
1 5 10
CTA TTT TGT GCA TCA GAT GCT AAA GCA TAT AAT ACA GAG 7525 Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asn Thr Glu
15 20 25
AAA CAT AAT GTT TGG GCC ACA CAC GCC TGT GTA CCC ACA 114
Lys His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr
30 3530 GAT CCC AAC CCA CAA GAA GTA GTA TTG GGA AAT GTG ACA 153
Asp Pro Asn Pro Gln Glu Val Val Leu Gly Asn Val Thr
40 45 50
GAA AAT TTT AAC ATG TGG AAA AAT AAC ATG GTA GAA CAA 192
Glu Asn Phe Asn Met Trp Lys Asn Asn Met Val Glu Gln35 55 60
ATG CAT GAA GAT ATA ATC AGT TTA TGG GAT CAA AGT CTA 231
Met His Glu Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu
65 70 75
AAG CCA TGT GTA AAA TTA ACC CCA CTC TGT GTT ACT TTA 27040 Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
80 85 90
AAT TGC ACT GAT GAT TTA GGG AAT GCT ACT AAT ACC AAT 309
Asn Cys Thr Asp Asp Leu Gly Asn Ala Thr Asn Thr Asn
95 10045 AGC AGT GCC ACT ACC AAT AGT AGT AGT TGG GAA GAA ATG 348
Ser Ser Ala Thr Thr Asn Ser Ser Ser Trp Glu Glu Met
105 110 115
AAG GGG GAA ATG AAA AGG TGC TCT TTC AAT ATC ACC ACA 387
Lys Gly Glu Met Lys Arg Cys Ser Phe Asn Ile Thr Thr50 120 125
AGC ATA AGA GAT AAG ATT AAG AAA GAA CAT GCA CTT TTC 426
Ser Ile Arg Asp Lys Ile Lys Lys Glu His Ala Leu Phe
130 135 140
TAT AGA CTT GAT GTA GTA CCA ATA GAT AAT GAT AAT ACC 46555 Tyr Arg Leu Asp Val Val Pro Ile Asp Asn Asp Asn Thr
145 150 155
ACA TAT AGG TTG ATA AAT TGT AAT ACC TCA GTC ATT ACA 504
Thr Tyr Arg Leu Ile Asn Cys Ash Thr Ser Val Ile Thr
160 16560 CAG GCC TGT CCA AAG GTA TCA TTT GAG CCA ATT CCC ATA 543
Gln Ala Cys Pro Lys Val Ser Phe Glu Pro Ile Pro Ile
170 175 180
CAT TTT TGT GCC CCG GCT GGT TTT GCG ATT CTA AAG TGT 582
His Phe Cys Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys65 185 190
AAT AAT AAG ACG TTC GAG GGA AAA GGA CCA TGT AAA AAT 621
Asn Asn Lys Thr Phe Glu Gly Lys Gly Pro Cys Lys Asn
195 200 205
GTC AGT ACA GTA CAA TGC ACA CAT GGA ATT AGG CCA GTA 6605 Val Ser Thr Val Gln Cys Thr His Gly Ile Arg Pro Val
210 215 220
GTG TCA ACT CAA CTG CTG TTA AAT GGC AGT CTA GCA GAA 699
Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu
225 23010 GAA GAG GTA ATA ATT AGA TCT GGC AAT ATC ACA GAC AAT 738
Glu Glu Val Ile Ile Arg Ser Gly Asn Ile Thr Asp Asn
235 240 245
ACT AAA ACC ATT ATA GTA CAG CTA AAC GAA TCT GTA GTA 777
Thr Lys Thr Ile Ile Val Gln Leu Asn Glu Ser Val Val15 250 255
ATT AAT TGT ACA AGA TCC AAC AAC AAT ACA AGA AAA AGT 816
Ile Asn Cys Thr Arg Ser Asn Asn Asn Thr Arg Lys Ser
260 265 270
ATA CAT ATA GGA CCA GGG AGT GCA TTT TTT GCA ACA GGA 85520 Ile His Ile Gly Pro Gly Ser Ala Phe Phe Ala Thr Gly
275 280 285
GAA ATA ATA GGA GAT ATA AGA CAA GCA CAC TGT AAC CTT 894
Glu Ile Ile Gly Asp Ile Arg Gln Ala His Cys Asn Leu
290 29525 AGT AGA ACA CAA TGG AAT AAC ACT TTA GGA AAG ATA GTC 933
Ser Arg Thr Gln Trp Asn Asn Thr Leu Gly Lys Ile Val
300 305 310
ATA AAA TTA AGA GAA CAA TTT AGA AAA CAA TTT GGA GAA 972
Ile Lys Leu Arg Glu Gln Phe Arg Lys Gln Phe Gly Glu30 315 320
AAA ACAATA GTC TTT AAT CGA TCC TCA GGA GGG GAC CCG 1011
Lys Thr Ile Val Phe Asn Arg Ser Ser Gly Gly Asp Pro
325 330 335
GAA ATT GCA ATG CAC AGT TTT AAT TGT GGA GGG GAA TTT 105035 Glu Ile Ala Met His Ser Phe Asn Cys Gly Gly Glu Phe
340 345 350
TTC TAC TGT AAC ACA ACA GCA CTG TTT AAT AGT ACC TGG 1089
Phe Tyr Cys Asn Thr Thr Ala Leu Phe Asn Ser Thr Trp
355 36040 AAT GTT ACT AAA GGG TTG AAT AAC ACT GAA GGA AAT AGC 1128
Asn Val Thr Lys Gly Leu Asn Asn Thr Glu Gly Asn Ser
365 370 375
ACA GGG GAT GAA AAT ATC ATA CTC CCA TGT AGA ATA AAA 1167
Thr Gly Asp Glu Asn Ile Ile Leu Pro Cys Arg Ile Lys45 380 385
CAA ATT ATA AAC ATG TGG CAG GAA GTA GGA AAA GCA ATG 1206
Gln Ile Ile Asn Met Trp Gln Glu Val Gly Lys Ala Met
390 395 400
TAT GCC CCT CCC ATC AGT GGA CAA ATT AGA TGT TCA TCA 124550 Tyr Ala Pro Pro Ile Ser Gly Gln Ile Arg Cys Ser Ser
405 410 415
AAT ATT ACA GGG CTG CTA CTA ACA AGA GAT GGT GGT AGT 1284
Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly Ser
420 42555 AAG AAC GAG AGC ATC ACC ACC GAG GTC TTC AGA CCT GGA 1323
Lys Asn Glu Ser Ile Thr Thr Glu Val Phe Arg Pro Gly
430 435 440
GGA GGA GAT ATG AGG GAC AAT TGG AGA AGT GAA TTA TAT 1362
Gly Gly Asp Met Arg Asp Asn Trp Arg Ser Glu Leu Tyr60 445 450
AAA TAT AAA GTA GTA AAA ATT GAA CCA TTA GGA GTA GCG 1401
Lys Tyr Lys Val Val Lys Ile Glu Pro Leu Gly Val Ala
455 460 465
CCC ACC AAG GCA AAG AGA AGA GTG GTG CAG AGA GAA AAA 1440
Pro Thr Lys Ala Lys Arg Arg Val Val Gln Arg Glu Lys
470 475 480
AGA GCA GTG GGA ACA ATA GGA GCT ATG TTC CTT GGG TTC 1475
Arg Ala Val Gly Thr Ile Gly Ala Met Phe Leu Gly Phe
485 490
TTA GGA GCA TAA AGC TTC TAG A 1501
Leu Gly Ala Xaa Ser Phe Xaa
495 50010
克隆 C7.2
GG GAA TTC GGA TCC GGG GTA CCT GTG TGG AAG GAA GCA 38
Glu Phe Gly Ser Gly Val Pro Val Trp Lys Glu Ala
1 5 1015 ACC ACC ACT CTA TTC TGT GCA TCA GAT GCT AGA GCA TAT 77
Thr Thr Thr Leu Phe Cys Ala Ser Asp Ala Arg Ala Tyr
15 20 25
GAC ACA GAG GTA CAT AAT GTT TGG GCC ACA CAT GCC TGT 116
Asp Thr Glu Val His Asn Val Trp Ala Thr His Ala Cys20 30 35
GTA CCC ACA GAC CCT AGT CCA CAA GAA GTA GTT TTG GAA 155
Val Pro Thr Asp Pro Ser Pro Gln Glu Val Val Leu Glu
40 45 50
AAT GTG ACA GAA AAT TTT AAC ATG TGG AAA AAT AAC ATG 19425 Asn Val Thr Glu Asn Phe Asn Met Trp Lys Asn Asn Met
55 60
GTA GAA CAA ATG CAT GAG GAT ATA ATT AGT TTA TGG GAT 233
Val Glu Gln Met His Glu Asp Ile Ile Ser Leu Trp Asp
65 70 7530 CAA AGC TTA AAG CCA TGT GTA AAA TTA ACC CCA CTC TGT 272
Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys
80 85 90
GTT ACT TTA AAT TGC AGT GAT TAT AGG AAT GCT ACT GAT 311
Val Thr Leu Asn Cys Ser Asp Tyr Arg Asn Ala Thr Asp35 95 100
TAT AAG AAT GCT ACT GAT ACC ACT AGT AGT AAC GAGGGA 350
Tyr Lys Asn Ala Thr Asp Thr Thr Ser Ser Asn Glu Gly
105 110 115
AAG ATG GAG AGA GGA GAA ATA AAA AAC TGC TCT TTC AAT 38940 Lys Met Glu Arg Gly Glu Ile Lys Asn Cys Ser Phe Asn
120 125
ATT ACC ACA AGC ATA AAA AAT AAG ATG CAG AAA GAA TAT 428
Ile Thr Thr Ser Ile Lys Asn Lys Met Gln Lys Glu Tyr
130 135 14045 GCA CTT TTC TAT AAA CTT GAT ATA GTA CCA ATA GAT AAT 467
Ala Leu Phe Tyr Lys Leu Asp Ile Val Pro Ile Asp Asn
145 150 155
ACA AGC TAT ACA TTG ATA AGT TGT AAC ACC TCA GTC ATT 506
Thr Ser Tyr Thr Leu Ile Ser Cys Asn Thr Ser Val Ile50 160 165
ACA CAG GCC TGT CCA AAG GTA TCC TTT GAA CCA ACT CCC 545
Thr Gln Ala Cys Pro Lys Val Ser Phe Glu Pro Thr Pro
170 175 180
ATA CAT TAT TGT GCT CCG GCT GGT TTT GCG ATT CTA AAG 58455 Ile His Tyr Cys Ala Pro Ala Gly Phe Ala Ile Leu Lys
185 190
TGT AAT GAT AAG AAG TTC AGT GGA AAA GGA GAA TGT AAA 623
Cys Asn Asp Lys Lys Phe Ser Gly Lys Gly Glu Cys Lys
195 200 20560 AAT GTC AGC ACA GTA CAA TGT ACA CAT GGA ATT AGG CCA 662
Asn Val Ser Thr Val Gln Cys Thr His Gly Ile Arg Pro
210 215 220
GTA GTA TCA ACT CAA CTG CTG TTA AAT GGC AGT CTA GCA 701
Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala65 225 230
GAA GAA GAG GTG GTA ATT AGA TCT GAC AAT TTC ATA GAC 740
Glu Glu Glu Val Val Ile Arg Ser Asp Asn Phe Ile Asp
235 240 245
AAT ACT AAA ACC ATA ATA GTA CAG CTG AAA GAA TCT GTA 7795 Asn Thr Lys Thr Ile Ile Val Gln Leu Lys Glu Ser Val
250 255
GAA ATT AAT TGT ATA AGA CCC AAC AAT AAT ACA AGA AAA 818
Glu Ile Asn Cys Ile Arg Pro Asn Asn Asn Thr Arg Lys
260 265 27010 GGT ATA CAT ATA GGA CCA GGG AGA GCA TGG TAT GCA ACA 857
Gly Ile His Ile Gly Pro Gly Arg Ala Trp Tyr Ala Thr
275 280 285
GGA GAA ATA GTA GGA GAT ATA AGA AAG GCA TAT TGT AAC 896
Gly Glu Ile Val Gly Asp Ile Arg Lys Ala Tyr Cys Asn15 290 295
ATT AGT AGA ACA AAA TGG AAT AAC ACT TTA ATA CAG ATA 935
Ile Ser Arg Thr Lys Trp Asn Asn Thr Leu Ile Gln Ile
300 305 310
GCT AAC AAA TTA AAA GAA AAA TAT AAT ACA ACA ATA AGC 97420 Ala Asn Lys Leu Lys Glu Ly5 Tyr Asn Thr Thr Ile Ser
315 320
TTT AAT CGA TCC TCA GGA GGG GAC CCA GAA ATT GTA ACG 1013
Phe Asn Arg Ser Ser Gly Gly Asp Pro Glu Ile Val Thr
325 330 33525 CAT AGT TTT AAT TGT GGA GGG GAG TTT TTC TAC TGT GAT 1052
His Ser Phe Asn Cys Gly Gly Glu Phe Phe Tyr Cys Asp
340 345 350
TCA ACA CAA CTG TTT AAT AGT ACT TGG AAT TTA AAT GGT 1091
Ser Thr Gln Leu Phe Asn Ser Thr Trp Asn Leu Asn Gly30 355 360
ACT TGG AAT TTT ACT GCA GGG TCA AAT GAA ACT GAA GGC 1130
Thr Trp Asn Phe Thr Ala Gly Ser Asn Glu Thr Glu Gly
365 370 375
AAT ATC ACA CTC CCA TGC AGA ATA AAA CAA ATT ATA AAC 116935 Asn Ile Thr Leu Pro Cys Arg Ile Lys Gln Ile Ile Asn
380 385
AGG TGG CAG GAA GTA GGG AAA GCA ATG TAT GCC CCT CCC 1208
Arg Trp Gln Glu Val Gly Lys Ala Met Tyr Ala Pro Pro
390 395 40040 ATC AGT GGA CAA ATA AAA TGC TCA TCA AAC ATT ACA GGG 1247
Ile Ser Gly Gln Ile Lys Cys Ser Ser Asn Ile Thr Gly
405 410 415
ATG ATA TTA ACA AGG GAT GGT GGT AAC GAG AAC AAT AAT 1285
Met Ile Leu Thr Arg Asp Gly Gly Asn Glu Asn Asn Asn45 420 425
GAG AGC AGT ACT ACT GAG ACC TTC AGA CCG GGA GGA GGA 1325
Glu Ser Ser Thr Thr Glu Thr Phe Arg Pro Gly Gly Gly
430 435 440
GAT ATG AGG AAC AAT TGG AGA AGT GAA TTA TAT AAA TAT 136450 Asp Met Arg Asn Asn Trp Arg Ser Glu Leu Tyr Lys Tyr
445 450
AAA GTA GTA AAA ATT GAA CCA TTA GGA GTA GCA CCC ACC 1403
Lys Val Val Lys Ile Glu Pro Leu Gly Val Ala Pro Thr
455 460 46555 AAG GCA AAG AGA AGA GTG GTG CAG AGA GAA AAA AGA GCA 1442
Lys Ala Lys Arg Arg Val Val Gln Arg Glu Lys Arg Ala
470 475 480
GTG GGA GCG CTA GGA GCT ATG TTC CTT GGG TTC TTA GGA 1481
Val Gly Ala Leu Gly Ala Met Phe Leu Gly Phe Leu Gly60 485 490
GCA TAA AGC TTC TAG ACC GAC TCT AGA GGA TCC 1514
Ala Xaa Ser Phe Xaa Thr Asp Ser Arg Gly Ser
495 500 504
克隆 C7.10
G CTA CCT GTC TGG AAG GAA GCA ACC ACC ACT CTA TTC 37
Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu Phe
1 5 105 TGT GCA TCA GAT GCT AGA GCA TAT GAC ACA GAG GTA CAT 76
Cys Ala Ser Asp Ala Arg Ala Tyr Asp Thr Glu Val His
15 20 25
AAT GTT TGG GCC ACA CAT GCC TGT GTA CCC ACA GAC CCT 115
Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro10 30 35
AGT CCA CAA GAA GTA TTT TTG GGA AAT GTG ACA GAA AAT 154
Ser Pro Gln Glu Val Phe Leu Gly Asn Val Thr Glu Asn
40 45 50
TTT AAT ATG TGG AAA AAT AAC ATG GTA GAA CAA ATG TAT 19315 Phe Asn Met Trp Lys Asn Asn Met Val Glu Gln Met Tyr
55 60
GAG GAT ATA ATT AGT TTA TGG CAT CAA AGC TTA AAG CCA 232
Glu Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu Lys Pro
65 70 7520 TGT GTA AAA TTA ACC CCA CTC TGI GTT ACT TTA AAT TGC 271
Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Asn Cys
80 85 90
AGT GAT TAT AGG AAT GCT ACT GAT TAT AAG AAT GCT ACT 310
Ser Asp Tyr Arg Asn Ala Thr Asp Tyr Lys Asn Ala Thr25 95 100
GAT ACC ACT AGT AGT AAC GAG GGA AAG ATG GAG AGA GGA 349
Asp Thr Thr Ser Ser Asn Glu Gly Lys Mec GIu Arg Gly
105 110 115
GAA ATA AAA AAC TGC TCT TTC AAT ATC ACC ACA AGC ATA 38830 Glu Ile Lys Asn Cys Ser phs Asn Ile Thr Thr Ser Ile
120 125
AAA AAT AAG ATG CAG AAA GAA TAT GCA CTT TTC TAT AAA 427
Lys Asn Lys Met Gln Lys Glu Tyr Ala Leu Phe Tyr Lys
130 135 l4035 CTT AAT ATA GTA CCA ATA GAT AAT ACA AGC TAT ACA TTG 466
Leu Asn Ile Val Pro Ile Asp Asn Thr Ser Tyr Thr Leu
145 150 l55
ATA AGT TGT AAC ACC TCA GTC ATT ACA CAG GCC TGT CCA 505
Ile Ser Cys Asn Thr Ser Val Ile Thr Gln Ala Cys Pro40 160 165
AAG GTA TCC TTT GAA CCA ATT CCC ATA CAT TAT TGT GCT 544
Lys Val Ser Phe Glu Pro Ile Pro Ile His Tyr Cys Ale
170 175 180
CCG GCT GGT TTT GCG ATT CTA AAG TGT AAT GAT AAG AAG 58345 Pro Ala Gly Phe Ala Ile Leu Lys Cys Asn Asp Lys Lys
185 190
TTC AGT GGA AAA GGA GAA TGT AAA AAT GTC AGC ACA GTA 622
Phs Ser Gly Lys Gly Glu Cys Lys Asn Val Ser Thr Vsl
195 200 20550 CAA TGT ACA CAT GGA ATT AGG CCA GTA GTA TCA ACT CAA 661
Gln Cys Thr His Gly Ile Arg Pro Val Val Ser Thr Gln
210 215 220
CTG CTG TTA AAT GGC AGT CTA GCA GAA GAA GAG GTG GTA 700
Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Val Val55 225 230
ATT AGA TCT GAC AAT TTC ACA GAC AAT ACT AAA ACC ATA 739
Ile Arg Ser Asp Asn Phe Thr Asp Asn Thr Lys Thr Ile
235 240 245
ATA GTA CAG CTG AAA GAA TCT GTA GAA ATT AAT TGT ATA 77860 Ile Val Gln Leu Lye Glu Ser Val Glu Ile Asn Cys Ile
250 255
AGA CCC AAC AAT AAT ACA AGA AAA GGT ATA CAT ATA GGA 817
Arg Pro Asn Asn Asn Thr Arg Lys Gly Ile His Ile Gly
260 265 270
CCA GGG AGA GCA TGG TAT GCA ACA GGA GAA ATA GTA GGA 856
Pro Gly Arg Ala Trp Tyr Ala Thr Gly Glu Ile Val Gly
275 280 285
GAT ATA AGA CAG GCA TAT TGT AAC ATT AGT AGA ACA AAA 8955 Asp Ile Arg Gln Ala Tyr Cys Asn Ile Ser Arg Thr Lys
290 295
TGG AAT AAC ACT TTA ATA CAG ATA GCT AAC AAA TTA AAA 934
Trp Asn Asn Thr Leu Ile Gln Ile Ala Asn Lys Leu Lys
300 305 31010 GAA AAA TAT AAT ACA ACA ATA AGC TTT AAT CGA TCC TCA 973
Glu Lys Tyr Asn Thr Thr Ile Ser Phe Asn Arg Ser Ser
315 320
GGA GGG GAC CCA GAA ATT GTA ACC CAT AGT TTT AAT TGT 1012
Gly Gly Asp Pro Glu Ile Val Thr His Ser Phe Asn Cys15 325 330 335
GGA GGG GAA TTT TTC TAC TGT AAT TCA ACA CAA CTG TTT 1051
Gly Gly Glu Phe Phe Tyr Cys Asn Ser Thr Gln Leu Phe
340 345 350
AAT AGT ACT TGG AAT TTA AAT GGT ACT TGG AAT TTT ACT 109020 Asn Ser Thr Trp Asn Leu Asn Gly Thr Trp Asn Phe Thr
355 360
GCA GGG TCA AAT GAA ACT GAA GGC AAT ATC ACA CTC CCA 1129
Ala Gly Ser Asn Glu Thr Glu Gly Asn Ile Thr Leu Pro
365 370 37525 TGC AGA ATA AAA CAA ATT ATA AAC AGG TGG CAG GAA GTA 1168
Cys Arg Ile Lys Gln Ile Ile Asn Arg Trp Gln Glu Val
380 385
GGA AAA GCA ATG TAT GCC CCT CCC ATC AGT GGA CAA ATA 1207
Gly Lys Ala Met Tyr Ala Pro Pro Ile Ser Gly Gln Ile30 390 395 400
AGA TGC TCA TCA AAC ATT ACA GGG ATG ATA TTA ACA AGG 1246
Arg Cys Ser Ser Asn Ile Thr Gly Met Ile Leu Thr Arg
405 410 415
GAT GGT GGT AAC GAG AAC AAT AAT GAG AGC AGT ACT ACT 128535 Asp Gly Gly Asn Glu Asn Asn Asn Glu Ser Ser Thr Thr
420 425
GAG ACC TTC AGA CCG GGA GGA GGA GAT ATG AGG AAC AAT 1324
Glu Thr Phe Arg Pro Gly Gly Gly Asp Met Arg Asn Asn
430 435 44040 TGG AGA AGT GAA TTA TAT AAA TAT AAA GTA GTA AAA ATT 1363
Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile
445 450
GAG CCA TTA GGA GTA GCA CCC ACC GAC TCT AGA GGA TCC 1402
Glu Pro Leu Gly Val Ala Pro Thr Asp Ser Arg Gly Ser45 455 460 465
TCT AGA 1408
Ser Arg
46950 克隆 C11.5
GAG GTA CCT GTG TGG AAA GAA GCA ACC ACT ACT CTA 36
Glu Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu
1 5 10
TTT TGT GCA TCA GAT GCT AAA GCA TAT GAC ACA GGG GTG 7555 Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp Thr Gly Val
15 20 25
CAT AAT GTT TGG GCC ACA CAT GCC TGT GTA CCC ACA GAC 114
His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp
30 3560 CCC AAC CCA CAA GAA ATA GAA TTG GTA AAT GTG ACA GAA 153
Pro Asn Pro Gln Glu Ile Glu Leu Val Asn Val Thr Glu
40 45 50
GAT TTT AAC ATG TGG AAA AAT AAA ATG GTA GAC CAG ATG 192
Asp Phe Asn Met Trp Lys Asn Lys Met Val Asp Gln Met65 55 60
CAT GAG GAT ATA ATC AGT TTA TGG GAT GAA AGC CTA AAG 231
His Glu Asp Ile Ile Ser Leu Trp Asp Glu Ser Leu Lys
65 70 75
CCA TGT GTA AAG TTA ACC CCA CTT TGT GTT ACT CTA AAC 2705 Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Asn
80 85 90
TGC AGT GAT GTG AAC AAT TCC ACA AAT CCT AAT GAT ACT 309
Cys Ser Asp Val Asn Asn Ser Thr Asn Pro Asn Asp Thr
95 10010 AAT ACT AAT TCC ACT AAT ACT ACT TCC TCT ACT CCT ACG 348
Asn Thr Asn Ser Thr Asn Thr Thr Ser Ser Thr Pro Thr
105 110 115
GCC ACT ACT AGT AGC GAG GAA AAG ATG GAG AAG GGA GAA 387
Ala Thr Thr Ser Ser Glu Glu Lys Met Glu Lys Gly Glu15 120 125
ATA AAA AAC TGC TCT TTC AAT ATC ACC ACA CAC ATG AAA 426
Ile Lys Asn Cys Ser Phe Asn Ile Thr Thr His Met Lys
130 135 140
GAT AAG GCA CAG AAA GAA TAT GCA CTT TTT TAT AAA CTT 46520 Asp Lys Ala Gln Lys Glu Tyr Ala Leu Phe Tyr Lys Leu
145 150 155
GAT ATA GTA CCA ATA GAT GAT AAT AAT GCC AGC TAT AGG 504
Asp Ile Val Pro Ile Asp Asp Asn Asn Ala Ser Tyr Arg
160 16525 TTG ATA AGT TGT AAT ACC TCA GAC ATT ACA CAG GCC TGT 543
Leu Ile Ser Cys Asn Thr Ser Asp Ile Thr Gln Ala Cys
17C 175 180
CCA AAG GTG ACC TTT GAG CCA ATT CCC ATA CAT TAT TGT 582
Pro Lys Val Thr Phe Glu Pro Ile Pro Ile His Tyr Cys30 l85 190
GCC CCG GCT GGT TTT GCG ATT CTA AAG TGT AAA GAT AAG 621
Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys Lys Asp Lys
195 200 205
AAG TTC AAT GGA ACA GGA CCA TGT TCA AAG GTC AGC ACA 66035 Lys Phe Asn Gly Thr Gly Pro Cys Ser Lys Val Ser Thr
210 215 220
GTA CAA TGT ACA CAT GGA ATT AGG CCA GTA GTA TCA ACT 699
Val Gln Cys Thr His Gly Ile Arg Pro Val Val Ser Thr
225 23040 CAA CTG TTG TTA AAT GGC AGT CTT GCA GAA GAA GAA GTA 738
Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Val
235 240 245
GTA ATT AGA TCT GTC AAT TTC ACA GAC AAT GCT AAA ATC 777
Val Ile Arg Ser Val Asn Pne Thr Asp Asn Ala Lys Ile45 250 255
ATA ATA GTA CAG CTG AAA GAA CCT GTA GCA ATT AAT TGT 816
Ile Ile Val Gln Leu Lys Glu Pro Val Ala Ile Asn Cys
260 265 270
ACA AGA CCC AAC AAC AAT ACA AGA AAA GGT ATA CAT CTA 85550 Thr Arg Pro Asn Asn Asn Thr Arg Lys Gly Ile His Leu
275 280 285
GGA CCA GGG AGC ACA TTT TAT ACA ACA GGA GAA ATA ATA 894
Gly Pro Gly Ser Thr Pne Tyr Thr Thr Gly Glu Ile Ile
290 29555 GGA GAC ATA AGA AAA GCA TAT TGC AAG ATT AGT AAA GAA 933
Gly Asp Ile Arg Lys Ala Tyr Cys Lys Ile Ser Lys Glu
300 305 310
AAA TGG AAT AAC ACT TTA AGA CAG GTA GTT AAA AAA TTA 972
Lys Trp Asn Asn Thr Leu Arg Gln Val Val Lys Lys Leu60 315 320
AGA GAA CAA TTT GGG AAT AAA ACA ATA ATT TTT AAT CGA 1011
Arg Glu Gln Phe Gly Asn Lys Thr Ils Ile Phs Asn Arg
325 330 335
TCC TCA GGA GGG GAC CCA GAA ATT GTA ATG CAC AGT TTT 1050
Ser Ser Gly Gly Asp Pro Glu Ile Val Met His Ser Phe
340 345 350
AAC TGT GGA GGG GAG TTT TTC TAC TGT AAT ACA ACA CAA 1089
Asn Cys Gly Gly Glu Phe Phe Tyr Cys Asn Thr Thr Gln
355 360
CTG TTT AAT AGT ACT TGG AAT AAT ACT GAA GGG ACA AAT 1128
Leu Phe Asn Ser Thr Trp Asn Asn Thr Glu Gly Thr Asn
365 370 37510 AGC ACT GAA GGA AAT AGC ACA ATC ACA CTC CCA TGC AGA 1167
Ser Thr Glu Gly Asn Ser Thr Ile Thr Leu Pro Cys Arg
380 385
ATA AAA CAA ATT ATA AAT ATG TGG CAG GAA GTA GGA AAA 1206
Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Lys15 390 395 400
GCA ACG TAT GCC CCT CCC ATC AGA GGA CGA ATT AGA TGC 1245
Ala Thr Tyr Ala Pro Pro Ile Arg Gly Arg Ile Arg Cys
405 410 415
ATA TCA AAT ATT ACA GGA CTG CTA TTA ACA AGA GAT GGT 128420 Ile Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly
420 425
GGT AGG AAT GTC ACA AAC AAT ACC GAA ACC TTC AGA CCT 1323
Gly Arg Asn Val Thr Asn Asn Thr Glu Thr Phe Arg Pro
430 435 44025 GGA GGA GGA GAC ATG AGG GAC AAT TGG AGA AGT GAA TTA 1362
Gly Gly Gly Asp Met Arg Asp Asn Trp Arg Ser Glu Leu
445 450
TAT AAA TAT AAA GTA GTA AAA GTT GAA CCA TTA GGA ATA 1401
Tyr Lys Tyr Lys Val Val Lys Val Glu Pro Leu Gly Ile30 455 460 465
GCA CCC ACC AAG GCA AAG AGA AGA GTG GTG CAC AGA GAC 1440
Ala Pro Thr Lys Ala Lys Arg Arg Val Val His Arg Asp
470 475 480
AAA AGA GCA GCA CTA GGA GCC TTG TTC CTT GGG TTC TTA 147935 Lys Arg Ala Ala Leu Gly Ala Leu Phe Leu Gly Phe Leu
485 490
GGA GCA TAA AAG CTT CTA GA 1499
Gly Ala Xaa Lys Leu Leu
495 49940 克隆 C11.7
GAG GTA CCT GTA TGG AAA GAA GGA ACC ACT ACT CTA 36
Glu Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu
1 5 1045 TTT TGT GCA TCA GAT GCT AAA GCA TAT GAC ACA GAG GTG 75
Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp Thr Glu Val
15 20 25
CAT AAT GTT TGG GCC ACA CAT GCC TGT GTA CCC ACA GAC 114
His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp50 30 35
CCC AAC CCA CAA GAA ATA GAA TTG GTA AAT GTG ACA GAA 153
Pro Asn Pro Gln Glu Ile Glu Leu Val Asn Val Thr Glu
40 45 50
GAT TTT AAC ATG TGG AAA AAT AAA ATG GTA GAC CAG ATG 19255 Asp Phe Asn Met Trp Lys Asn Lys Met Val Asp Gln Met
55 60
CAT GAG GAT ATA ATC AGT TTA TGG GAT GAA AGC CTA AAG 231
His Glu Asp Ile Ile Ser Leu Trp Asp Glu Ser Leu Lys
65 70 7560 CCA TGT GTA AAG TTA ACC CCA CTT TGT GTT ACT CTA AAC 270
Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Asn
80 85 90
TGC AGT GAT GTG AAC AAT TCC ACA AAT CCT AAT GAT ACT 309
Cys Ser Asp Val Asn Asn Ser Thr Asn Pro Asn Asp Thr65 95 100
AAT ACT AAT TCC ACT AAT ACT ACT TCC TCT ACT CCT ACG 348
Asn Thr Asn Ser Thr Asn Thr Thr Ser Ser Thr Pro Thr
105 110 115
GCC ACT ACT AGT AGC GAG GAA AAG ATG GAG AAG GGA GAA 3875 Ala Thr Thr Ser Ser Glu Glu Lys Met Glu Lys Gly Glu
120 125
ATA AAA AAC TGC TCT TTC AAT ATC ACC ACA CAC ATG AAA 426
Ile Lys Asn Cys Ser Phe Asn Ile Thr Thr His Met Lys
130 135 14010 GAT AAG GTA CAG AAA GAA TAT GCA CTT TTT TAT AAA CTT 465
Asp Lys Val Gln Lys Glu Tyr Ala Leu Phe Tyr Lys Leu
145 150 155
GAT ATA GTA CCA ATA GAT GAT AAT AAT ACC AGC TAT AGG 504
Asp Ile Val Pro Ile Asp Asp Asn Asn Thr Ser Tyr Arg15 160 165
TTG ATA AGT TGT AAT ACC TCA GTC ATT ACA CAG GCC TGT 543
Leu Ile Ser Cys Asn Thr Ser Val Ile Thr Gln Ala Cys
170 175 180
CCA ATG GTG ACC TTT GAG CCA ATT CCC ATA CAT TAT TGT 58220 Pro Met Val Thr Phe Glu Pro Ile Pro Ile Mis Tyr Cys
185 190
GCC CCG GCT GGT TTT GCG ATT CTA AAG TGT AAA GAT AAG 621
Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys Lys Asp Lys
195 200 20525 AAG TTC AAT GGA ACA GGA CCA TGT TCA AAG GTC AGC ACA 660
Lys Phe Asn Gly Thr Gly Pro Cys Ser Lys Val Ser Thr
210 215 220
GTA CAA TGT ACA CAT GGA ATT AGG CCA GTA GTA TCA ACT 699
Val Gln Cys Thr His Gly Ile Arg Pro Val Val Ser Thr30 225 230
CAA CTG TTG TTA AAT GGC AGT CTT GCA GAA GAA GAA GTA 738
Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Val
235 240 245
GTA ATT AGA TCT GTC AAT TTC ACA GAC AAT GCT AAA ATC 77735 Val Ile Arg Ser Val Asn Phe Thr Asp Asn Ala Lys Ile
250 255
ATA ATA GTA CAG CTG AAA GAA CCT GTA GCA ATT AAT TGT 816
Ile Ile Val Gln Leu Lys Glu Pro Val Ala Ile Asn Cys
260 265 27040 ACA AGA CCC AAC AAC AAT ACA AGA AAA GGT ATA CAT CTA 855
Thr Arg Pro Asn Asn Asn Thr Arg Lys Gly Ile His Leu
275 280 285
GGA CCA GGG AGC ACA TTT TAT ACA ACA GGA GAA ATA ATA 894
Gly Pro Gly Ser Thr Phe Tyr Thr Thr Gly Glu Ile Ile45 290 295
GGA GAC ATA AGA AAA GCA TAT TGC AAG ATT AGT AAA GAA 933
Gly Asp Ile Arg Lys Ala Tyr Cys Lys Ile Ser Lys Glu
300 305 310
AAA TGG AAT AAC ACT TTA AGA CAG GTA GTT AAA AAA TTA 97250 Lys Trp Asn Asn Thr Leu Arg Gln Val Val Lys Lys Leu
315 320
AGA GAA CAA TTT GGG AAT AAA ACA ATA ATT TTT AAT CGA 1011
Arg Glu Gln Phe Gly Asn Lys Thr Ile Ile Phe Asn Arg
325 330 33555 TCC TCA GGA GGG GAC CCA GAA ATT GTA ATG CAC AGT TTT 1050
Ser Ser Gly Gly Asp Pro Glu Ile Val Met His Ser Phe
340 345 350
AAC TGT GGA GGG GAG TTT TTC TAC TGT AAT ACA ACA CAA 1089
Asn Cys Gly Gly Glu Phe Phe Tyr Cys Asn Thr Thr Gln60 355 360
CTG TTT AAT AGT ACT TGG AAT AAT ACT GAA GGG ACA AAT 1128
Leu Phe Asn Ser Thr Trp Asn Asn Thr Glu Gly Thr Asn
365 370 375
AGC ACT GAA GGA AAT AGC ACA ATC ACA CTC CCA TGC AGA 1167
Ser Thr Glu Gly Asn Ser Thr Ile Thr Leu Pro Cys Arg
380 385
ATA AAA CAA ATT ATA AAT ATG TGG CAG GAA GTA GGA AAA 12065 Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Lys
390 395 400
GCA ACG TAT GCC CCT CCC ATC AGA GGA CGA ATT AGA TGC 1245
Ala Thr Tyr Ala Pro Pro Ile Arg Gly Arg Ile Arg Cys
405 410 41510 ATA TCA AAT ATT ACA GGA CTG CTA TTA ACA AGA GAT GGT 1284
Ile Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly
420 425
GGT AGG AAT GTC ACA AAC AAT ACC GAN NCC TTC AGA CCT 1323
Gly Arg Asn Val Thr Asn Asn Thr Xaa Xaa Phe Arg Pro15 430 435 440
GGA GGA GGA GAC ATG AGG GAC AAT TGG AGA AGT GAA TTA 1362
Gly Gly GIy Asp Met Arg Asp Asn Trp Arg Ser Glu Leu
445 450
TAT AAA TAT AAA GTA GTA AAA GTT GAA CCA TTA GGA ATA 140120 Tyr Lys Tyr Lys Val Val Lys Val Glu Pro Leu Gly Ile
455 460 465
GCA CCC ACC AAG GCA AAG AGA AGA GTG GTG CAC AGA GAC 1440
Ala Pro Thr Lys Ala Lys Arg Arg Val Val His Arg Asp
470 475 48025 AAA AGA GCA GCA CTA GGA GCT TTG TTC CTT GGG TTC TTA 1479
Lys Arg Ala Ala Leu Gly Ala Leu Phe Leu Gly Phe Leu
485 490
GGA GCA TAA AAG CTT CTA GA 1499
Gly Ala Xaa Lys Leu Leu30 495 499
克隆C10.5
G GTA CCT GTG TGG AAA GAA GCA AAC ACA ACT CTA TTT 37
Val Pro Val Trp Lys Glu Ala Asn Thr Thr Leu Phe35 1 5 10
TGT GCA TCA GAT GCT AAA GCA TAT GAT AGA GAA GTA CAT 76
Cys Ala Ser Asp Ala Lys Ala Tyr Asp Arg Glu Val His
15 20 25
AAT GTT TGG GCA ACA CAT GCC TGT GTA CCC ACA GAC CCC 11540 Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro
30 35
AAC CCA CAA GAA ATA GTA TTG GGA AAT GTG ACA GAA AAT 154
Asn Pro Gln Glu Ile Val Leu Gly Asn Val Thr Glu Asn
40 45 5045 TTT AAC ATG TGG AAA AAT AAC ATG GTA GAA CAA ATG CAT 193
Phe Asn Met Trp Lys Asn Asn Met Val Glu Gln Met His
55 60
GAG GAT ATA ATC AAT TTA TGG GAT CAA AGC TTA AAG CCA 232
Glu Asp Ile Ile Asn Leu Trp Asp Gln Ser Leu Lys Pro50 65 70 75
TGT GTA AAG TTA ACT CCA CTC TGT GTT ACT TTA AAG TGC 271
Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Lys Cys
80 85 90
AAG GAT CTG GAG AGG AAT ACT ACC TAT AAT AGC ACT ATT 31055 Lys Asp Leu Glu Arg Asn Thr Thr Tyr Asn Ser Thr Ile
95 100
ACC AAT AAT AGT AGT TTG GAG GGA CTA AGA GAA CAA ATG 349
Thr Asn Asn Ser Ser Leu Glu Gly Leu Arg Glu Gln Met
105 110 11560 ACA AAC TGC TCT TTC AAC ATC ACC ACA AGT ATA AGA GAT 388
Thr Asn Cys Ser Phe Asn Ile Thr Thr Ser Ile Arg Asp
120 125
AAG GTG CAG AAA GAA TAT GCA CTT TTG TAT AAA CTT GAT 427
Lys Val Gln Lys Glu Tyr Ala Leu Leu Tyr Lys Leu Asp65 130 135 140
GTA GTA CCA ATA GAA GAA GAT GAC AAT ACT AGC TAT AGA 466
Val Val Pro Ile Glu Glu Asp Asp Asn Thr Ser Tyr Arg
145 150 155
TTG ATA AGT TGT AAC ACC TCA GTC ATT ACA CAG GCT TGT 5055 Leu Ile Ser Cys Asn Thr Ser Val Ile Thr Gln Ala Cys
160 165
CCA AAG ACA TCC TTT GAG CCA ATT CCC ATA CAT TAT TGT 544
Pro Lys Thr Ser Phe Glu Pro Ile Pro Ile His Tyr Cys
170 175 18010 GCC CCG GCT GGT TTT GCG ATT CTA AAG TGT AAT GAT AAG 583
Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys Asn Asp Lys
185 190
AAG TTC AAT GGA ACA GGA CCA TGT AAA AAT GTC AGC ACA 622
Lys Phe Asn Gly Thr Gly Pro Cys Lys Asn Val Ser Thr15 195 200 205
GTA CAA TGT ACA CAT GGA ATT AGG CCA GTA GTA TCA ACT 661
Val Gln Cys Thr His Gly Ile Arg Pro Val Val Ser Thr
210 215 220
CAA CTG TTG TTA AAT GGC AGT CTA GCA GAA GAA GAG GTA 70020 Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Val
225 230
GTA ATC AGA TCT GCC AAT TTC ACA GAC AAT GCT AAA ACC 739
Val Ile Arg Ser Ala Asn Phe Thr Asp Asn Ala Lys Thr
235 240 24525 ATA ATA GTA CAT CTA AAT GAA ACT GTA AAA ATT AAT TCT 778
Ile Ile Val His Leu Asn GIu Thr Val Lys Ile Asn Cys
250 255
ACA AGA CTT GGC AAC AAT ACA AGA AAA AGT ATA AAT ATA 817
Thr Arg Leu Gly Asn Asn Thr Arg Lys Ser Ile Asn Ile30 250 265 270
GGA CCA GGG AGA GTA CTC TAT GCA ACA GGA GAA ATA ATA 856
Gly Pro Gly Arg Val Leu Tyr Ala Thr Gly Glu Ile Ile
275 280 285
GGA GAC ATA AGA CAA GCA CAT TGT AAC ATT AGT AGA GCA 89535 Gly Asp Ile Arg Gln Ala His Cys Asn Ile Ser Arg Ala
290 295
CAA TGG AAT AAG ACT TTA GAA AAG GTA GTT GAC AAA TTA 934
Gln Trp Asn Lys Thr Leu Glu Lys Val Val Asp Lys Leu
300 305 31040 AGA AAA CAA TTT GGG GAT AAT ACA ACA ATA GCT TTT AAT 973
Arg Lys Gln Phe Gly Asp Asn Thr Thr Ile Ala Phe Asn
315 320
CGA TCC TCA GGA GGG GAC CCA GAA ATT GTA ATG CAC ACT 1012
Arg Ser Ser Gly Gly Asp Pro Glu Ile Val Met His Thr45 325 330 335
TTT AAT TGT GGA GGG GAA TTT TTC TAC TGT AAT ACA ACA 1051
Phe Asn Cys GIy Gly Glu Phe Phe Tyr Cys Asn Thr Thr
340 345 350
CAA CTG TTT AAT AGT ACT TGG AAT AAT ACT TGG AAG GAT 109050 Gln Leu Phe Asn Ser Thr Trp Asn Asn Thr Trp Lys Asp
355 360
CCT AAC AGG AGT GAC AAT ATC ACA CTC CCA TGC AGA ATA 1129
Pro Asn Arg Ser Asp Asn Ile Thr Leu Pro Cys Arg Ile
365 370 37555 AAA CAA ATT ATA AAC ATG TGG CAG GAA GTA GGA AAA GCA 1168
Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Lys Ala
380 385
ATG TAC GCC CCT CCC ATC AGA GGG GAA ATT AGA TGT TCA 1207
Met Tyr Ala Pro Pro Ile Arg Gly Glu Ile Arg Cys Ser60 390 395 400
TCA AAT ATC ACA GGG CTG CTA CTA ACA AGA GAT GGT GGT 1246
Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly GIy
405 410 415
AAT GAC GAT GGT AAT GAC ACG ACC ACA AAC AGG ACC GAG 1285
Asn Asp Asp Gly Asn Asp Thr Thr Thr Asn Arg Thr Glu
420 425
ATC TTC AGA CCT GGA GGA GGA GAT ATG AGG GAC AAT TGG 1324
Ile Phe Arg Pro Gly GIy Gly Asp Met Arg Asp Asn Trp
430 435 440
AGA AGT GAA TTA TAT AGA TAT AAA GTA GTA AAA ATT GAA 1363
Arg Ser Glu Leu Tyr Arg Tyr Lys Val Val Lys Ile Glu
445 45010 CCA TTA GGA ATA GCA CCC ACC AGG GCA AAG AGA AGA GTG 1402
Pro Leu Gly Ile Ala Pro Thr Arg Ala Lys Arg Arg Val
455 4G0 465
GTG CAG AGA GAA AAA AGA GCA GTA GGA CTA GGA GCT TTG 1441
Val Gln Arg Glu Lys Arg Ala Val Gly Leu Gly Ala Leu15 470 475 480
TTC CTT GGG T TCTTAGGAG CATAAAGCTT CTAGA 1475
Phe Leu Gly
48320 克隆 C10.7
G GTA CTT GTG TGG AAA GAA GCA AAC ACA ACT CTA TTT 37
Val Pro Val Trp Lys Glu Ala Asn Thr Thr Leu Phe
1 5 10
TGT GCA TCA GAT GCT AAA GCA TAT GAT AGA GAA GTA CAT 7625 Cys Ala Ser Asp Ala Lys Ala Tyr Asp Arg Glu Val His
15 20 25
AAT GTT TGG GCA ACA CAT GCC TGT GTA CCC ACA GAC CCC 115
Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro
30 3530 AAC CCA CAA GAA ATA GTA TTG GGA AAT GTG ACA GAA AAT 154
Asn Pro Gln Glu Ile Val Leu Gly Asn Val Thr Glu Asn
40 45 50
TTT AAC ATG TGG AAA AAT AAC ATG GTA GAA CAA ATG CAT 193
Phe Asn Met Trp Lys Asn Asn Met Val Glu Gln Met His35 55 60
GAG GAT ATA ATC AAT TTA TGG GAT CAA AGC TTA AAG CCA 232
Glu Asp Ile Ile Asn Leu Trp Asp Gln Ser Leu Lys Pro
65 70 75
TGT GTA AAG TTA ACT CCA CTC TGT GTT ACT TTA AAG TGC 27140 Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Lys Cys
80 85 90
AAG GAT CTG GAG AGG AAT ACT ACC TAT AAT AGC ACT ATT 310
Lys Asp Leu Glu Arg Asn Thr Thr Tyr Asn Ser Thr Ile
95 10045 ACC AAT AAT AGT AGT TTG GAG GGA CTA AGA GAA CAA ATG 349
Thr Asn Asn Ser Ser Leu Glu Gly Leu Arg Glu Gln Met
105 110 115
ACA AAC TGC TCT TTC AAC ATC ACC ACA AGT ATA AGA GAT 388
Thr Asn Cys Ser Phe Asn Ile Thr Thr Ser Ile Arg Asp50 120 125
AAG GTG CAG AAA GAA TAT GCA CTT TTG TAT AAA CTT GAT 427
Lys Val Gln Lys Glu Tyr Ala Leu Leu Tyr Lys Leu Asp
130 135 140
GTA GTA CCA ATA GAA GAA GAT GAC AAT ACT AGC TAT AGA 46655 Val Val Pro Ile Glu Glu Asp Asp Asn Thr Ser Tyr Arg
145 150 155
TTG ATA AGT TGT AAC ACC TCA GTC ATT ACA CAG GCT TGT 505
Leu Ile Ser Cys Asn Thr Ser Val Ile Thr Gln Ala Cys
160 16560 CCA AAG ACA TCC TTT GAG CCA ATT CCC ATA CAT TAT TGT 544
Pro Lys Thr Ser Phe Glu Pro Ile Pro Ile His Tyr Cys
170 175 180
GCC CCG GCT GGT TTT GCG ATT CTA AAG TGT AAT GAT AAG 583
Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys Asn Asp Lys65 185 190
AAG TTC AAT GGA ACA GGA CCA TGT AAA AAT GTC AGC ACA 622
Lys Phe Asn Gly Thr Gly Pro Cys Lys Ash Val Ser Thr
195 200 205
GTA CAA TGT ACA CAT GGA ATT AGG CCA GTA GTA TCA ACT 6615 Val Gln Cys Thr His Gly Ile Arg Pro Val Val Ser Thr
210 215 220
CAA CTG TTG TTA AAT GGC AGT CTA GCA GAA GAA GAG GTA 700
Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Val
225 23010 GTA ATC AGA TCT GCC AAT TTC ACA GAC AAT GCT AAA ACC 739
Val Ile Arg Ser Ala Asn Phe Thr Asp Ash Ala Lys Thr
235 240 245
ATA ATA GTA CAT CTA AAT GAA ACT GTA AAA ATT AAT TGT 778
Ile Ile Val His Leu Asn Glu Thr Val Lys Ile Asn Cys15 250 256
ACA AGA CTT GGC AAC AAT ACA AGA AAA AGT ATA AAT ATA 817
Thr Arg Leu Gly Asn Asn Thr Arg Lys Ser Ile Asn Ile
260 265 270
GGA CCA GGG AGA GTA CTC TAT GCA ACA GGA GAA ATA ATA 85620 Gly Pro Gly Arg Val Leu Tyr Ala Thr Gly Glu Ile Ile
275 280 285
GGA GAC ATA AGA CAA GCA CAT TGT AAC ATT AGT AGA GCA 895
Gly Asp Ile Arg Gln Ala His Cys Asn Ile Ser Arg Ala
290 29525 CAA TGG AAT AAG ACT TTA GAA AAG GTA GTT GAC AAG TTA 934
Gln Trp Asn Lys Thr Leu Glu Lys Val Val Asp Lys Leu
300 305 310
AGA AAA CAA TTT GGG GAT AAT ACA ACA ATA GCT TTT AAT 973
Arg Lys Gln Phe Gly Asp Asn Thr Thr Ile Ala Phe Asn30 315 320
CGA TCC TCA GGA GGG GAC CCA GAA ATT GTA ATG CAC ACT 1012
Arg Ser Ser Gly Gly Asp Pro Glu Ile Val Met His Thr
325 330 335
TTT AAT TGT GGA GGG GAA TTT TTC TAC TGT AAT ACA ACA 105135 Phe Asn Cys Gly Gly Glu Phe Phe Tyr Cys Asn Thr Thr
340 345 350
CAA CTG TTT AAT AGT ACT TGG AAT AAT ACT TGG AAG GAT 1090
Gln Leu Phe Asn Ser Thr Trp Asn Asn Thr Trp Lys Asp
355 36040 CCT AAC AGG AGT GAC AAT ATC ACA CTC CCA TGC AGA ATA 1129
Pro Asn Arg Ser Asp Asn Ile Thr Leu Pro Cys Arg Ile
365 370 375
AAA CAA ATT ATA AAC ATG TGG CAG GAA GTA GGA AAA GCA 1168
Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Lys Ala45 380 385
ATG TAC GCC CCT CCC ATC AGA GGG GAA ATT AGA TGT TCA 1207
Met Tyr Ala Pro Pro Ile Arg Gly Glu Ile Arg Cys Ser
390 395 400
TCA AAT ATC ACA GGG CTG CTA CTA ACA AGA GAT GGT GGT 124650 Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly
405 410 415
AAT GAC GAT GGT AAT GAC ACG ACC ACA AAC AGG ACC GAG 1285
Asn Asp Asp Gly Asn Asp Thr Thr Thr Asn Arg Thr Glu
420 42555 ATC TTC AGA CCT GGA GGA GGA GAT ATG AGG GAC AAT TGG 1324
Ile Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp
430 435 440
AGA AGT GAA TTA TAT AGA TAT AAA GTA GTA AAA ATT GAA 1363
Arg Ser Glu Leu Tyr Arg Tyr Lys Val Val Lys Ile Glu60 445 450
CCA TTA GGA ATA GCA CCC ACC AGG GCA AAG AGA AGA GTG 1402
Pro Leu Gly Ile Ala Pro Thr Arg Ala Lys Arg Arg Val
455 460 465
GTG CAG AGA GAA AAA AGA GCA GTA GGA CTA GGA GCT TTG 1441
Val Gln Arg Glu Lys Arg Ala Val Gly Leu Gly Ala Leu
470 475 480
TTC CTT GGG TTC TTG GGA GCA TAA AGC TTC TAG A 1475
Phe Leu GIy Phe Leu Gly Ala Xaa Ser Phe Xaa
485 490 491
克隆 C17.1
CTC GAG GTA CCT GTG TGG AAA GAA GCA ACC ACC ACT 3610 Leu Glu Val Pro Val Trp Lys Glu Ala Thr Thr Thr
1 5 10
CTA TTT TGT GCA TCA GAT GCT AAA GCA TAT GAT TCA GAG 75
Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp Ser Glu
15 20 2515 GCA CAT AAT GTT TGG GCC ACA CAT GCC TGT GTA CCC ACA 114
Ala His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr
30 35
GAC CCC AAC CCA CAA GAA GTA GAA TTG GAA AAT GTG ACA 153
Asp Pro Asn Pro Gln Glu Val Glu Leu Glu Asn Val Thr20 40 45 50
GAA AAT TTT AAC ATG TGG AAA AAT AAC ATG GTA GAA CAG 192
Glu Asn Phe Asn Met Trp Lys Asn Asn Met Val Glu Gln
55 60
ATG CAT GGG GAT ATA ATT AGT TTA TGG GAT CAA AGC CTA 23125 Met His Gly Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu
65 70 75
AAG CCA TGT GTA AAA TTA ACC CCA CTC TGT GTT ACG TTA 270
Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
80 85 9030 AAT TGC ACT GAC CCA AAT GTT ACT AAT AGC GAG AGA ACG 309
Asn Cys Thr Asp Pro Asn Val Thr Asn Ser Glu Arg Thr
95 100
ATA GAG GGG GGA GAA ATA AAA AAT TGC TCT TTC AAT ATC 348
Ile Glu Gly Gly Glu Ile Lys Asn Cys Ser Phe Asn lle35 105 110 115
ACC ACA AAC ATA AGA GAT AGG TTT CAG AAA GAA TAT GCA 387
Thr Thr Asn Ile Arg Asp Arg Phe Gln Lys Glu Tyr Ala
120 125
CTT TTT TAT AAA CTT GAT GTA ATA CCA TTA GGT AAT GAT 42640 Leu Phe Tyr Lys Leu Asp Val Ile Pro Leu Gly Asn Asp
130 135 140
AAT ACT AGC TAT AGG TTG ATA AGT TGT AAC ACC TCA GTC 465
Asn Thr Ser Tyr Arg Leu Ile Ser Cys Asn Thr Ser Val
145 150 15545 ATT ACA CAG GCC TGT CCA AAG GTA TCC TTT GAG CCA ATT 504
Ile Thr Gln Ala Cys Pro Lys Val Ser Phe Glu Pro Ile
160 165
CCC ATA CAT TAT TGT GCC CCG GCT GGT TTT GCG ATT CTA 543
Pro Ile His Tyr Cys Ala Pro Ala Gly Phe Ala Ile Leu50 170 175 180
AAG TGT AAA GAT AAG AAG TTC AAT GGA ACA GGA CCA TGT 582
Lys Cys Lys Asp Lys Lys Phe Aso Gly Thr Gly Pro Cys
185 190
ACA AAT GTC AGC ACA GTA CAA TGT ACA CAT GGA ATT AAG 62155 Thr Asn Val Ser Thr Val Gln Cys Thr His Gly Ile Lys
195 200 205
CCA GTA GTA TCA ACT CAA CTG TTG TTA AAT GGC AGT CTA 660
Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu
210 215 22060 GCA GAA GAA GAC ATA GTA ATT AGA TCC GCC AAT CTC ACA 699
Ala Glu Glu Asp I1e Val Ile Arg Ser Ala Asn Leu Thr
225 230
GAC AAT GCT AAA AAC ATA ATA GTA CAG CTG AAT GAA TCT 738
Asp Asn Ala Lys Asn Ile Ile Val Gln Leu Asn Glu Ser65 235 240 245
GTA ACA ATG AAT TGT ACA AGA CCC AAC AAC AAT ACA ATG 777
Val Thr Met Asn Cys Thr Arg Pro Asn Asn Asn Thr Met
250 255
AAA AGT ATA CAT ATA GGA CCA GGC AGA GCA TTT TAT GCA 8165 Lys Ser Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Ala
260 265 270
ACA GGA AAC ATA ATA GGA GAT ATA AGA CAA GCA CAT TGT 855
Thr Gly Asn Ile Ile Gly Asp Ile Arg Gln Ala His Cys
275 280 28510 AAC ATT AGT GGA ACA AAA TGG AAT GAC ACT TTG AAA AAG 894
Asn Ile Ser Gly Thr Lys Trp Asn Asp Thr Leu Lys Lys
290 295
ATA GCT ATA AAA TTA AGA GAA CAA TTT AAT AAG ACA ATA 933
Ile Ala Ile Lys Leu Arg Glu Gln Phe Asn Lys Thr Ile15 300 305 310
GTC TTT AAT CAA TCC TCA GGA GGG GAC CCA GAA ATT GCA 972
Val Phe Asn Gln Ser Ser Gly Gly Asp Pro Glu Ile Ala
315 320
ACG CTC AGT TTT AAT TGT GGA GGG GAA TTT TTC TAC TGT 101120 Thr Leu Ser Phe Asn Cys Gly Gly Glu Phe Phe Tyr Cys
325 330 335
AAT TCA ACA CAA CTG TTT AAT AGT ACT TGG AAT AGT ACT 1050
Asn Ser Thr Gln Leu Phe Asn Ser Thr Trp Asn Ser Thr
340 345 35025 GGG TCA AAT AAC ACT AAA GGA AAT GAC ACA ATC ACA CTC 1089
Gly Ser Asn Asn Thr Lys Gly Asn Asp Thr Ile Thr Leu
355 360
CCA TGC AGA ATA AGA CAA ATT ATA AAC ATG TGG CAG AAA 1128
Pro Cys Arg Ile Arg Gln Ils Ile Asn Met Trp Gln Lys30 365 370 375
ATA GGA AAA GCA ATG TAT GCC CCT CCC ATC AAA GGG CAA 1167
Ile Gly Lys Ala Met Tyr Ala Pro Pro Ile Lys Gly Gln
380 385
ATT AGA TGT TCA TCA AAT ATT ACA GGG CTA ATA TTA ACA 120635 Ile Arg Cys Ser Ser Asn Ile Thr Gly Leu Ile Leu Thr
390 395 400
AGA GAT GGT GGT AAC AAC AAC ATG AGC AAG ACC ACC GAG 1245
Arg Asp Gly Gly Asn Asn Asn Met Ser Lys Thr Thr Glu
405 410 41540 ACC TTC AGA CCT GGA GGA GGA GAT ATG AGG GAC AAT TGG 1284
Thr Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp
420 425
AGA AGT GAA TTA TAT AAA TAT AAA GTA GTA AAA ATT GAA 1323
Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile Glu45 430 435 440
CCA TTA GGA GTA GCA CCC ACC AGG GCA AAG AGA AGA GTG 1362
Pro Leu Gly Val Ala Pro Thr Arg Ala Lys Arg Arg Val
445 450
GTG CAG AGA GAA AAA AGA GCA GTG GGA ATA GGA GCT GTG 140150 Val Gln Arg Glu Lys Arg Ala Val Gly Ile Gly Ala Val
455 460 465
TTC CTT GGG TTC TTG GGA GCA TAA AGC TTC TAG A 1435
Phe Leu Gly Phe Leu Gly Ala Xaa Ser Phe Xaa
470 475 47855 克隆 C17.3
CTC GAG GTA CCT GTG TGG AAA GAA GCA ACC ACC ACT 36
Leu Glu Val Pro Val Trp Lys Glu Ala Thr Thr Thr
1 5 1060 CTA TTT TGT GCA TCA GAT GCT AAA GCA TAT GAT TCA GAG 75
Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp Ser Glu
15 20 25
GCA CAT AAT GTT TGG GCC ACA CAT GCC TGT GTA CCC ACA 114
Ala His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr65 30 35
GAC CCC AAC CCA CAA GAA GTA GAA TTG GAA AAT GTG ACA 153
Asp Pro Asn Pro Gln Glu Val Glu Leu Glu Asn Val Thr
40 45 50
GAA AAT TTT AAC ATG TGG AAA AAT AAC ATG GTA GAA CAG 1925 Glu Asn Phe Asn Met Trp Lys Asn Asn Mer Val Glu Gln
55 60
ATG CAT GGG GAT ATA ATT AGT TTA TGG GAT CAA AGC CTA 231
Met His Gly Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu
65 70 7510 AAG CCA TGT GTA AAA TTA ACC CCA CTC TGT GTT ACG TTA 270
Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
80 85 90
AAT TGC ACT GAC CCA AAT GTT ACT AAT AGC GAG AGA ACG 309
Asn Cys Thr Asp Pro Asn Val Thr Asn Ser Glu Arg Thr15 95 100
ATA GAG GGG GGA GAA ATA AAA AAT TGC TCT TTC AAT ATC 348
Ile Glu Gly Gly Glu Ile Lys Asn Cys Ser Phe Asn Ile
105 110 115
ACC ACA AAC ATA AGA GAT AGG TTT CAG AAA GAA TAT GCA 3S720 Thr Thr Asn Ile Arg Asp Arg Phe Gln Lys Glu Tyr Ala
120 125
CTT TTT TAT AAA CTT GAT GTA ATA CCA TTA GGT AAT GAT 426
Leu Phe Tyr Lys Leu Asp Val Ile Pro Leu Gly Asn Asp
130 135 14025 AAT ACT AGC TAT AGG TTG ATA AGT TGT AAC ACC TCA GTC 465
Asn Thr Ser Tyr Arg Leu Ile Ser Cys Asn Thr Ser Val
145 150 155
ATT ACA CAG GCC TGT CCA AAG GTA TCC TTT GAG CCA ATT 504
Ile Thr Gln Ala Cys Pro Lys Val Ser Phe Glu Pro Ile30 160 165
CCC ATA CAT TAT TGT GCC CCG GCT GGT TTT GCG ATT CTA 543
Pro Ile His Tyr Cys Ala Pro Ala Gly Phe Ala Ile Leu
170 175 180
AAG TGT AAA GAT AAG AAG TTC AAT GGA ACA GGA CCA TGT 55235 Lys Cys Lys Asp Lys Lys Phe Asn Gly Thr Gly Pro Cys
185 190
ACA AAT GTC AGC ACA GTA CAA TGT ACA CAT GGA ATT AAG 621
Thr Asn Val Ser Thr Val Gln Cys Thr His Gly Ile Lys
195 200 20540 CCA GTA GTA TCA ACT CAA CTG TTG TTA AAT GGC AGT CTA 660
Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu
210 215 220
GCA GAA GAA GAC ATA GTA ATT AGA TCC GCC AAT CTC ACA 699
Ala Glu Glu Asp Ile Val Ile Arg Ser Ala Asn Leu Thr45 225 230
GAC AAT GCT AAA AAC ATA ATA GTA CAG CTG AAT GAA TCT 738
Asp Asn Ala Lys Asn Ile Ile Val Gln Leu Asn Glu Ser
235 240 245
GTA ACA ATG AAT TGT ACA AGA CCC AAC AAC AAT ACA ATG 77750 Val Thr Met Asn Cys Thr Arg Pro Asn Asn Asn Thr Met
250 255
AAA AGT ATA CAT ATA GGA CCA GGC AGA GCA TTT TAT GCA 815
Lys Ser Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Ala
260 265 27055 ACA GGA AAC ATA ATA GGA GAT ATA AGA CAA GCA CAT TGT 855
Thr Gly Asn Ile Ile Gly Asp Ile Arg Gln Ala His Cys
275 280 285
AAC ATT AGT GGA ACA AAA TGG AAT GAC ACT TTG AAA AAG 894
Asn Ile Ser Gly Thr Lys Trp Asn Asp Thr Leu Lys Lys60 290 295
ATA GCT ATA AAA TTA AGA GAA CAA TTT AAT AAG ACA ATA 933
Ile Ala Ile Lys Leu Arg Glu Gln Phe Asn Lys Thr Ile
300 305 310
GTC TTT AAT CAA TCC TCA GGA GGG GAC CCA GAA ATT GCA 972
Val Phe Asn Gln Ser Ser Gly Gly Asp Pro Glu Ile Ala
315 320
ACG CTC AGT TTT AAT TGT GGA GGG GAA TTT TTC TAC TGT 10115 Thr Leu Ser Phe Asn Cys Gly Gly Glu Phe Phe Tyr Cys
325 330 335
AAT TCA ACA CAA CTG TTT AAT AGT ACT TGG AAT AGT ACT 1050
Asn Ser Thr Gln Leu Phe Asn Ser Thr Trp Asn Ser Thr
340 345 35010 GGG TCA AAT AAC ACT AAA GGA AAT GAC ACA ATC ACA CTC 1089
Gly Ser Asn Asn Thr Lys Gly Asn Asp Thr Ile Thr Leu
355 360
CCA TGC AGA ATA AGA CAA ATT ATA AAC ATG TGG CAG AAA l128
Pro Cys Arg Ile Arg Gln Ile Ile Asn Met Trp Gln Lys15 365 370 375
ATA GGA AAA GCA ATG TAT GCC CCT CCC ATC AAA GGG CAA 1167
Ile Gly Lys Ala Met Tyr Ala Pro Pro Ile Lys Gly Gln
380 385
ATT AGA TGT TCA TCA AAT ATT ACA GGG CTA ATA TTA ACA 120620 Ile Arg Cys Ser Ser Asn Ile Thr Gly Leu Ile Leu Thr
390 395 400
AGA GAT GGT GGT AAC AAC AAC ATG AGC AAG ACC ACC GAG 1245
Arg Asp Gly Gly Asn Asn Asn Met Ser Lys Thr Thr Glu
405 410 41525 ACC TTC AGA CCT GGA GGA GGA GAT ATG AGG GAC AAT TGG 1284
Thr Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp
420 425
AGA AGT GAA TTA TAT AAA TAT AAA GTA GTA AAA ATT GAA 1323
Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile Glu30 430 435 440
CCA TTA GGA GTA GCA CCC ACC AGG GCA AAG AGA AGA GTG 1362
Pro Leu Gly Val Ala Pro Thr Arg Ala Lys Arg Arg Val
445 450
GTG CAG AGA GAA AAA AGA GCA GTG GGA ATA GGA GCT GTG 140135 Val Gln Arg Glu Lys Arg Ala Val Gly Ile Gly Ala Val
455 460 465
TTC CTT GGG TTC TTG GGA GCA TAA AGC TTC TAG A 1435
Phe Leu Gly Phe Leu Gly Ala Xaa Ser Phe Xaa
470 475 478
除了表1中所列出的，图3显示七个分离物各自克隆的氨基酸序列的序列对比。方框内显示各克隆所对应的残基。在图中，将该氨基酸序列与MN-rgp120(SEQ.ID.NO.29)进行序列对比。
在一个实施方案中，本发明的gp120多肽与逃逸分离物之一的序列具有相同的氨基酸序列。在另一个实施方案中，如下文详述，氨基酸序列是截短的。另一个实施方案中，本发明的gp120多肽序列在逃逸分离物的序列中，含有一种或多种氨基酸的取代，插入或缺失(改变)。通常，除了不位于截短的氨基酸序列的氨基酸序列和消除表位外，本发明的gp120多肽将包括在逃逸分离物中的氨基酸序列中的改变，这些改变不改变多肽具有的与该分离物的氨基酸序列相同的诱导中和抗体的能力。
一般来说，本发明的gp120多肽的氨基酸序列中的取代是保守取代，尤其是gp120的V2,V3，及C4结构域中的氨基酸残基，这些结构域中含有中和表位。然而，非保守取代位于特别是不含中和表位的的结构域中。
保守取代以类似大小和特性的氨基酸取代另一氨基酸。例如，疏水残基或亲水残基分别被另一个疏水残基或亲水残基所代替。氨基酸可分成下列组：带正电荷的的残基(K,R和H)；带负电荷的残基(D和E)；酰胺类(N和Q)；芳香类(F,Y和W)；疏水残基(P,G,V,L,I,和M)；和不带电荷的残基(S和T)。通常，在小组内的残基可被该小组另一成员所代替。
在一个实施方案中，在gp120的V2,V3及C4结构域中的临界氨基酸残基与逃逸分离物序列所对应的残基是完全相同的。gp120的V2,V3，及C4结构域中的临界氨基酸残基在实验部分得以描述。在另一实施方案中，gp120的V2,V3，及C4结构域中的所有氨基酸残基与逃逸分离物序列所对应的残基是完全相同的。来源于逃逸分离物的编码gp120的寡核苷酸
本发明也提供了来源于逃逸分离物的编码gp120的新寡核苷酸(其可用于表达gp120)。本发明的寡核苷酸编码本发明的多肽。寡核苷酸可以是DNA或RNA，通常是DNA。虽然由于基因密码子的简并性，许多核苷酸序列能编码相同的氨基酸，但简而言之，本发明的寡核苷酸包括表1中所说明的逃逸分离物的核苷酸序列(SEQ ID No.2,4,6,8,10,12,14,16,18,20,22,24,26和28)。通常，本发明的寡核苷酸小于约5千碱基(kb)，优选为小于约3kb。
为了表达所编码的氨基酸序列，可将寡核苷酸插入到转录单位中。而转录单位可插入到用于细胞系的制备的质粒中，或插入到病毒中(例如；疫苗)或直接用作为疫苗DNA。合适的用于疫苗蛋白质生产的转录单位为大家所熟知。优选的表达载体，命名为psvI685，在SEQID NO.32中说明。载体包括连接到连接序列上的HSV-1gD1信号序列。将要表达的gp120核苷酸序列始于基因的Kpn I位点。由于所有gp120或gp160序列含有这一位点，任何gp120核苷酸序列均可类似地插入到载体中，并且被表达。载体从SV40开始以polyA尾结束。
除了对本发明的多肽序列的表达有用之外，本发明的寡核苷酸也可用于对HIV分离物检测的诊断学上。例如，编码中和表位的寡核苷酸或其部分可用于支链DNA诊断学上或在原位杂交研究中做探针。疫苗的制备
利用在合适载体中的本发明的gp120多肽(其来源于所选择的逃逸分离物)来制备亚单位疫苗。多肽可单独使用，但通常与多价疫苗一起施用，这种亚单位疫苗包括gp120MN。除了本发明的一种或多种gp120多肽之外，一般地疫苗包括MN多肽(在下文中为MN-rgp120)。疫苗通常包括大约3至5个不同的gp120多肽，但有30个或者更多的不同的gp120多肽可加以利用。
用于疫苗的gp120多肽的制备方法为大家所熟知，并在下文中得以描述。除了所选择的HTV分离物的利用外，该方法中所制备的gp120亚单位疫苗不同于现有技术的gp120亚单位疫苗。
如同现有技术的gp120亚单位疫苗，在可引起抗体形成所要求的纯度和足够的浓度下，将gp120与生理上可接受的载体相混合。生理上可接受载体在疫苗中所使用的剂量与浓度对接受者无毒。一般地，疫苗配制成注射剂，通常用于肌内或皮下注射。用于注射的合适载体包括无菌水，但是优选为生理盐溶液，如正常的盐水或缓冲的含盐溶液，如磷酸缓冲盐水或环乳酸。疫苗一般地含有佐剂。有用的佐剂包括QS21(皂树肥皂草，由剑桥Biotech,Worcester,MA提供)，它能刺激细胞毒性T-细胞，以及明矾(铝氢氧化物佐剂)。也利用不同的能提高细胞的或局部免疫性的佐剂。尤其是，在疫苗中可包括免疫加强因子如细胞因子。合适的加强免疫的细胞因子的例子包括白细胞介素，如白细胞介素(IL-2)和白细胞介素-12(IL-12)，以及肿瘤坏死因子-α(TNF-α)
存在于疫苗中的附加赋形剂包括低分子量的多肽(少于约10个残基)，蛋白质，氨基酸，碳水化合物其包括葡萄糖或葡聚糖，螯合剂如EDTA，及其它赋形剂，这些物质能稳定蛋白质或阻止微生物生长。
疫苗也可含有其它HIV蛋白质。尤其是，gp41或gp41的胞外部分或HIV-1核心蛋白质如P24,P17，和P55可存在于疫苗中。虽然gp41的氨基酸序列比gp120的更保守，但gp41含有中和表位。优选地，疫苗中存在的任何gp41来自疫苗中存在的HIV分离物。用于疫苗中的来自分离物的gp160可代替疫苗中的gp120或与来自分离物的gp120一起使用。此外，来自不同分离物的gp160与疫苗中的那些相比，可另外存在于疫苗中。
按照本发明的疫苗也可含有与工程病毒组合的一种或多种可溶性gp120多肽序列或其片段，其中所说的病毒特异性地用于表达具有引起细胞毒性T-细胞效应能力的蛋白质。合适的工程病毒来源于例如，金丝雀痘病毒，疫苗病毒，稀释的疱疹病毒(如，疱疹单纯病毒)，和水痘带状疱疹。如上述，那些典型的工程病毒修饰得表达任何HIV蛋白质(其能诱导细胞毒性T-细胞效应)。通常，在用gp120/人工病毒疫苗进行免疫后，施用一剂量或多剂量的gp120多肽序列促进免疫应答。若需要，病毒可人工做成表达一种或多种本发明的gp120多肽序列，或其片段，并与可溶性gp120多肽序列一起或单独用于疫苗中。
一般地，疫苗制剂包括在约1.0ml载体内的总共大约为300-600μg的gp120。优选疫苗制剂包括在两倍600μg明矾中利用两倍重量的gp120多肽。然而，也利用更小量的疫苗制剂(例如；每剂量50μg)，一般地与明矾或其它佐剂一起使用。疫苗中任何分离物的gp120的量根据gp120的免疫原性发生相应变化。例如，来自一些HIV菌株的gp120比来自MN菌株的gp120(SEQ ID NO.29)免疫原性要低一些。如果混合使用具有不同免疫原性的两种菌株，对每种病毒的量进行根据经验的滴定以测定疫苗中每一菌株的百分比。对于具有类似免疫原性的分离物，在疫苗中将采用大约相等量的每种分离物的gp120。例如，在一优选实施方案中，疫苗包括来源于MN和本发明的一种菌株的gp120，其在约1.0ml的载体中，且浓度为每菌株约300μg。当疫苗包括来自30个分离物的gp120时，从约10μg到约50μg的分离物均可加以利用。在多价疫苗中测定免疫原性蛋白质的相对量的方法为大家所熟知，并用来，例如，进行检测在多价小儿麻痹症疫苗中的各种分离物的相对比例。
本发明的疫苗以与现有技术HIV gp120亚单位施用方法相同的方式进行施用。尤其是，根据方案，通常在0,1，及6,8或12月施用疫苗。一个优选的方案包括在0,1,6和12月施用疫苗。在免疫处理后，可进行年度或双年度的增强处理。然而，在免疫过程期间和此后，可以分析中和抗体水平并相应调整方案。
对未感染的个体施用疫苗。此外，可对血清反应阳性的个体施用疫苗，如同用现有技术HIV疫苗，以加强对病毒的免疫应答。目前也在探索：将编码用于疫苗的gp120菌株的DNA利用合适载体进行施用，以使其在宿主中得以表达。按这一方法，除去重复免疫的需要，gp120可由受感染的宿主产生。下文描述gp120表达载体的制备。
如上述，虽然本文所描述gp120分离物可用作为疫苗，但该氨基酸序列也可单独或与制剂中相同类型的氨基酸序列组合使用而作为免疫原，以引起识别存在免疫原中的种种分离物的抗体。免疫原以与病毒相同的方式进行配制，且其包括相同的赋形剂等。由这些免疫原诱导的抗体可用于诊断中以检测免疫原中的HIV菌株或亲和纯化菌株。gp120多肽序列和趋化因子受体
若CD4是HIV-1的初级细胞内受体，它不足以满足HIV-1进入细胞内。已确定出协同CD4所需要的协同受体。这些协同受体是七个跨膜G-蛋白偶联受体家族的趋化因子的成员。根据氨基端半胱氨酸的间距，将趋化因子超家族亚分成两个组。CXC趋化因子主要涉及中性白细胞介导的炎症，CC趋化因子易涉及慢性炎症。已确定了至少五个CC趋化因子受体，命名为CC-CKR1-5的趋化因子受体(本领域也称为CCR1-5)，以及至少四个CXC趋化因子受体，命名为CXC-CKR1-4的趋化因子受体(本领域也称为CXCR-1-4)。
CXC-CKR4(CXCR-4)(其也称为α-趋化因子受体fusin)是T-细胞-毒性的HIV-1菌株进入的协同因子。CC-CKR-5(CC-R5)(其也称为β-趋化因子受体)与其相关家族的成员如CC-CKR-2b和CC-CKR3一起充当巨噬细胞-毒性的HIV-1菌株进入的协同因子。T-细胞-毒性的菌株可感染原始T-细胞和T-细胞系，但不是巨噬细胞，而巨噬细胞-毒性的菌株可感染巨噬细胞和原始T-细胞，但不是T-细胞系。在Deng等自然381:661-666(1996)中更充分地讨论了T-细胞-和巨噬细胞-毒性的菌株，本文以其整体一并参考。T-细胞-毒性的菌株的例子包括实验室分离物，如ⅢB和MN。巨噬细胞-毒性的菌株包括原始分离物，这些分离物包括但不限于来源于用基于gp120的疫苗进行免疫的被接种者的A244,GNE6,GNE8，以及逃逸病毒。二元-毒性的菌株可利用协同受体的两种类型，该菌株经CXC-CKR-4或经一种或多种CC-CKR家族的成员，优选为CC-CKR-5,CC-CKR-2b，或CC-CKR-3进入细胞。虽然本发明不被任何理论约束或限制，但认为T-细胞-毒性和巨噬细胞-毒性的HIV-1菌株的进入提供了一个统一的对各病毒菌株间的细胞趋性的不同，及对许多CD4-转染的非灵长类细胞的抗HIV-1感染的抗性，以及对人类群体中的部分个体的抗HIV-1-感染抗性的解释。
因此，一个实施方案是包含(1)第一gp120多肽序列或其片段(其来自巨噬细胞-毒性的HIV-1菌株)和/或第二gp120多肽序列或其片段(其来自T-细胞毒性菌株)，和(2)逃逸分离物HIV gp120多肽序列或其片段(其来自用第一/或第二HIV gp120多肽序列接种的被接种者)相组合的一种疫苗。优选地，疫苗包括至少两种结合在不同趋化因子受体上的gp120多肽序列。在一个实施方案中，疫苗包含结合在不同趋化因子受体上的第一和第二gp120多肽序列。此外，与被第一和第二gp120多肽序列的二者之一或两者结合的趋化因子受体相比，逃逸分离物gp120多肽序列可结合不同的趋化因子受体。
一种优选的T-细胞毒性菌株是实验室分离物，最优选为MN。用于本发明的优选巨噬细胞-毒性病毒是GNE6和GNE8，它们是本文所揭示的逃逸病毒的代表物，且由于它们的gp120诱导产生能识别gp120序列(例如，V3结构域)的抗体则不同于MN，其中所说的gp120序列涉及与CC趋化因子受体如CXC-CKR-5的结合。
如上述，在一个实施方案中，在疫苗中可通过施用一种或多种趋化因子受体结合的gp120多肽序列或其片段(其含有合适的趋化因子受体结合的结构域)以阻止HIV感染。优选地，疫苗也包含一种或多种CD4-结合的gp120多肽序列或其适当的片段。这些疫苗可诱导抗HIV的抗体，它们能抑制病毒gp120-趋化因子受体或-CD4的结合过程。此外，这些gp120多肽可通过与HIV感染有关的一种或多种协同受体(如CD4或趋化因子受体)相结合直接阻止HIV感染，这样为治疗HIV感染提供了预防和治疗作用。优选地，这一方面有用的gp120多肽序列含有T-细胞结合(TCB)的结构域。
趋化因子受体-结合性gp120多肽的各种运用及关于CC趋化因子受体家族的讨论如下。然而，本领域技术人员将发现：这一讨论同样适用于在HIV感染中充当协同因子的CXC趋化因子受体。
如用作疫苗或免疫原所描述的，gp120多肽可用作含有一种或多种gp120多肽的组合物。对于可能被感染或需要这种治疗(如利用本文所描述的施用剂量和途径及方法进行治疗)的患者而言，可预防性地或治疗性地施用该组合物。然而，优选慢性施用且因此调整剂量。据记载在体内施用也可诱导能结合病毒gp120且进一步抑制病毒与CC-CKR的结合的抗体。
gp120多肽也可用于筛选试验以确定CC-CKR的拮抗剂。例如，由于候选拮抗剂能抑制gp120与CC-CKR CC-CKR受体的结合因而可筛选出候选拮抗剂，其中所说的受体是分离的并附着在物体表面上(例如，塑料培养皿)或经重组或天然地表达在细胞的表面上。拮抗剂也可结合gp120或结合受体。理想的候选拮抗剂包括能结合受体的gp120化合物，gp120小肽(长度为5-20个氨基酸，优选为7-10个氨基酸)或gp120的肽模拟物(peptidomimetics)，和结合gp120的单克隆抗体，以及能结合gp120或受体的有机小分子。
由gp120多肽诱导的抗体也可用来诱导能结合CC趋化因子的抗自生类型抗体。这些抗自生类型的抗体可通过其与抗gp120多肽抗体的结合且其能抑制gp120与CC-CKR受体的结合而进行筛选。这些抗自生类型抗体通过结合CC-CKR受体上而模拟gp120。这样的抗体，优选人类抗体，可由许多方法获得，如来自于复合文库(例如，Burton等，免疫学进展(1994)57:191-280)的人类抗体。现在有可能制备转基因动物(例如，小鼠)，在免疫方面，这些转基因动物在缺乏内源性免疫球蛋白产物的情况下能够产生所有的人类抗体。例如，嵌合的和胚系突变体小鼠中的抗体重链连接区(JH)的基因发生纯合缺失，则可完全抑制内源性抗体的产生。如Jakobovitis等，美国国家科学院院报90:2551(1993)；Jakobovits等，自然362:255-258(1993)；Bruggermann等，年度免疫学7:33(1993)所描述的，将人胚系免疫球蛋白的基因排列转移到这样的胚系突变体小鼠中，则可导致挑战抗原的人类抗体的产生。
此外，可利用McCafferty等，自然348:552-553(1990)所描述的噬菌体显示技术，在体外由未接受免疫的供体提供的免疫球蛋白可变(V)结构域全部基因来制备人类抗体和抗体片段。根据这一技术，阅读框中的任何的抗体V结构域基因被关闭成丝状噬菌体的主要或次要的外被蛋白质基因，如M13或fd，并且在噬菌体微粒的表面作为功能抗体片段。因为丝状微粒含有噬菌体基因组的单链DNA拷贝，基于抗体的功能性质的选择导致编码具有那些性质的抗体的基因的选择。如Johnson等，结构生物学的当前观点3:564-571(1993)所综述的，可以各种形式进行噬菌体显示操作。
V-基因片断的几种来源均可用于噬菌体显示操作。Clackson等，自然352:624-628(1991)从来源于免疫小鼠脾的V-基因小型随机复合文库中分离出抗oxazolone抗体的多样化的排列基因。可构建来源于未免疫的人供体(或早期细胞)的全部V基因组。目前已有阐明，对应于多样化排列的抗原(包括自体抗原)的抗体可通过按照Marks等，分子生物学杂志222:581-537(1991)，或Griffith等，EMBO J.12:725-734(1993)中所描述的技术进行分离。
在天然的免疫应答中，抗体基因以高速率积累突变(体细胞高变)。一些引起更高亲和性的变化以及具有高亲和性表面的免疫球蛋白的B细胞，在尔后的抗原攻击期间，优选复制并得以分化。这一自然过程可通过利用被称为的＂链重组＂技术(Marks等，生物技术10:779-783[19921])进行模拟。在这一方法中，通过噬菌体显示技术所获得的＂原始＂人类抗体的亲和性可通过用V结构域基因(其来源于未免疫供体)的自然发生的变体(全部)的全部基因依次取代重链和轻链的V结构域的基因得以提高。这一技术使得可在nM范围内产生具有亲和性的的抗体和抗体片段。用于制备大噬菌体抗体全体的策略见Waterhouse等，核酸研究21:2265-2266(1993)。
因此，如同上述的利用gp120单克隆抗体(其抑制gp120结合在受体上)，在复合文库或其他系统中结合CC-CKR的抗体可通过筛选在噬菌体表面表达的抗体或其片段获得。
除利用gp-120抗体筛选抗体之外，随机或复合肽文库也可利用任何本发明的gp120抗体或gp120化合物进行筛选。有效的方法可从含有1百万至十亿种不同序列的收集大量肽的文库中确定出肽配体，其中所说的不同序列可利用单克隆抗体或靶分子进行筛选。这一技术的功效来自于与文库中大序列所偶联的氨基酸的化学多样性。参见实施例，Scott等，Cur.Open.生物技术5(1):40-8(1994)；Kenan等，生物化学科学潮流(1994)19(2):57-64。因此，如本文讨论产生的单克隆抗体(优选为人类单克隆或其片段)对于抑制或治疗HIV感染或疾病，及确定附加药物的筛选试验有利用价值。gp120的制备
如同现有技术的HIVgp120亚单位疫苗，用于疫苗的gp120可用任何合适的方法进行制备。重组制备的或化学合成的gp120，出于安全考虑优选从HIV直接分离的gp120。用于制备gp120重组体的方法描述如下。
编码来源于逃逸分离物的gp120和能够表达gp120的寡核苷酸可由常规方法制备。例如，可合成核苷酸序列。此外，编码gp120的另一个HIV核苷酸序列可用作骨架，并且如同通过定点诱变改变可改变任何不同的残基。定点诱变的描述见Kunkel等，美国国家科学院院报82:488-492(1985)和Zoller等，核酸研究10:6487-6500(1982)，且其为大家所熟知。
在一个优选实施方案中，核苷酸序列存在于含有编码gp120并在所编码蛋白质的表达启动子的转录和翻译控制之下的DNA的表达构建体中。在哺乳动物的细胞中，启动子可以是用于表达的真核启动子。若人们希望扩充启动子或在原核宿主中产生gp120，启动子可是原核启动子。通常，利用强启动子以提供高水平的转录和表达。
表达构建体可以是载体的一部分，其在适当的细胞宿主中能在染色体外稳定存在或整合到宿主基因组中。通常，为表达构建体提供标记，这便于对含有构建体的宿主的选择。标记可位于相同或不同的DNA分子上，合乎需要的为相同的DNA分子。
可将表达构建体连接到为所需宿主细胞识别的复制系统上。各种复制系统包括病毒复制系统诸如来源于逆转录病毒，猴病毒，牛乳头瘤病毒，或类似的那些系统。此外，构建体可连接到扩增基因上，例如DHFR基因，那么可产生gp120 DNA若干拷贝。将构建体导入到宿主内随构建体而发生变化，且可采用任何方便的方法来完成。为表达蛋白质可采用许多原核与真核宿主。
优选地，gp120在哺乳动物细胞中表达，因为这些细胞提供了与天然gp120相同的糖基化和二硫键。gp120和gp120片段(其作为与单纯疱疹病毒1(HSV-1)的糖蛋白D(gD-1)的N端序列相结合的融合蛋白)在哺乳动物中的表达分别见Lasky L.A.等1986所描述的(被重组体包膜糖蛋白的抗体中和的爱滋病逆转录病毒)科学233:209-212和Haffar,O.K.等，1991(HIV-1gp160的胞质尾区含有与细胞膜相连的区域)病毒学180:439-441。用于表达gp120的优选方法见实施例的描述。在实施例中，异源信号序列便于蛋白质的表达。然而，也可利用天然信号序列表达蛋白质。
通过常规的方法可产生具有一种表1中所说明的氨基酸序列的分离的，纯化的gp120多肽。例如，这些可化学合成蛋白质。在一个优选的实施方案中，利用本发明的表达构建体，在哺乳动物细胞中表达蛋白质。用常规方法可纯化被表达的蛋白质。一个优选的纯化方法见实施例中的描述。gp120片段
本发明也提供了适于诱导用于疫苗的抗体的的gp120片段。如本文所使用的，一种截断的gp120没有完整的gp120序列的部分(其始于gp120的氨基或羧基末端的任一端)。本发明的截短gp120序列没有C5结构域。gp120的C5结构域是分子的一个主要的免疫原性位点。然而，对该区的抗体不中和病毒。因此，从诱导用于血清分类的抗体的免疫原中消除gp120的这一部分是有利的。
在另一个实施方案中，截短的gp120序列还没有gp120V5结构域，从羧基末端区至约453个氨基酸残基。保持在序列中的V5结构域部分为制备表达构建体的便利的限制酶切位点。然而，没有整个gp120V5结构域的截短gp120也适于用于诱导抗体。
此外，也可从截短的gp120序列中除去gp120的氨基末端部分。尤其是，截短的gp120序列可没有gp120信号序列。截短的gp120序列可没有gp120C1结构域，从由羧基末端至第111个氨基酸残基，且除去了大多数C1结构域但是保存一个方便的限制酶切位点。然而，经过V2半胱氨酸残基(其形成一个二硫键)的C1结构域部分可另外被除去，那么截短的gp120序列从gp120C1结构域的羧基末端至第117个氨基酸残基。在一个优选实施方案中，截短的gp120序列从gp120氨基末端至C1结构域的第111个残基和第453个残基至gp120的羧基末端。
如上述，可由重组工程制备截短的gp120序列。方便地，将编码截短的gp120序列的DNA连接到编码信号序列的异源DNA序列上。
人们认为，在本文的教导下，对于本发明的内容在具体问题或情况中的应用在本领域普通技术人员的能力之内。本发明的产品和其分离、使用及制造的代表性方法的实施例如下，但是本发明不限于这些。本文所引用的所有文献在此一并作为参考。
实施例材料和方法
收集自志愿者的样品。血液样品从MN-rgp120免疫个体收集，这些个体在参加国家卫生协会(NIH)发起的HIV-1疫苗Ⅰ期(NIH方案AVEG016)和Ⅱ期(NIH方案AVEG201)试验时，受到HIV-1的感染。研究过程中的受试验者人口统计以及研究方法设计由McElrath(生物癌症讨论会，6:1-11,1995)和McElrath等(爱滋病的国家协同疫苗发展组织的第八年度会议摘要，Bethseda,MD216,1996)进行了描述。按照参与机构协会考察委员会批准的一个讨论通过方案获得样品。试验阶段，HIV-1的感染时间根据NIH艾滋病疫苗评估网提供的数据具体确定，试验中PCR和/或血清分析用于检测HIV-1的感染。
用于克隆HIV-1包膜糖蛋白的样品的制备。通过FICOLL-HYPAQUE梯度离心法，从肝素化静脉血液制备HIV-1感染疫苗的外周血液单核细胞(PBMCs)。确定细胞数量和生存力。分离后，在磷酸盐缓冲盐水中洗涤PBMCs两次，并以6x106细胞/ml的密度悬浮于PCR溶解缓冲液(50mM KCl,10mM Tris(PH8.4),2.5mM MgCl2,0.1mg/ml明胶(Sigma),0.45％NONIDET p40清洗剂，0.45％TWEEN20清洗剂(两种清洗剂都可从美国生化公司买到)和溶解细胞的0.06mg/ml的蛋白酶K(Gibco BRL))中。在50-60℃条件下培养溶解物1小时，其后在95℃条件下灭活蛋白酶10分钟。转移和冻结溶解产物，在-70℃条件下储存以备使用。
聚合酶链式反应(PCR)扩增。利用下述的嵌合引物对样品进行两轮的PCR扩增反应。在第一轮反应中，将25μl的PBMC溶解产物等分试样(包含大约1μg的基因组DNA)与等量的PCR反应混合物(包含400μM的每种dNTP、200Cμg/ml BSA(Sigma化学公司，RIA级)以及在50mM KCl、20mM Tris(pH8.4)和3mM MgCl2中的大约100pmole的每种引物)混合。95℃条件下变性步骤开始10分钟之后，在55℃的浸透步骤中加入5个单位的标记聚合酶(AMPLITAQ,PekinElmer Cetus)，并用矿物油覆盖样品。
PCR流程如下：2个55℃下1分钟、72℃下2.5分钟和94℃下1分钟的循环，随后是28个55℃下30秒、72℃下45秒和94℃下2.5分钟的循环，以及一个72℃下5分钟的延伸步骤。
利用以上或PCR优化试剂盒(Invitrogen)中描述的试剂和流程，在最后100μl的反应量中用合适的嵌合引物再扩增第一轮反应物的10μl等分试样。用QIAQUICK-旋转体(Riagen公司)纯化PCR反应物。第一轮反应中使用的引物对是正向的120.os.F(在HIVPV22 6248-6270位置的同源序列5′-gggaattcggatccAGAGCAGAAGACAGTGGCAATGA)(SEQ.ID.NO.34)或者JM11A(在6048-6074位置的5′-ctcgag-CTCCTGAAGACAGTCAGACTCATCAAG)(SEQ.ID.NO.35)[Kusumi等；病毒学杂志66:875(1992)]与反向的120.os.R(在7836-7859位置的5′-ggtctagaagctttaGC CCATAGTGCTTCCTGCTGC)(SEQ.ID.NO.36)组合。内部的嵌合引物是在6389-6410位置的120.BX.F(5′-gggcggatcctcgaGGTACCTGTRTGGAAAGAAGCA.R:A或G)(SEQ.ID.NO.37)和120.is.R(在7819-7841位置的5′-ggtctagaagctttaTGCTC CYAAGAACCCAAGGAA；Y:T或C)(SEQ.ID.NO.38)。异源引物序列以小写字母表示。
PCR产物的亚克隆和作为融合蛋白的重组包膜糖蛋白的表达。HIV-1包膜糖蛋白gp120序列作为嵌合的基因和融合蛋白被克隆和表达，其中与成熟gp120序列的氨基酸13相对应，来自单纯疱疹病毒类型1(HSV-1)成熟N端的信号序列和27个氨基酸与gp120基因的N端序列融合。通过人工引入异源PCR引物末端的限制位点和人工引入HSV-1gD的N端序列的XhoI位点组合，将包含逃逸样品gp120序列的PCR产物作为嵌合基因克隆进pRKS表达质粒。
用测序酶和dGTP试剂盒(美国生化公司)对所得的双链DNA进行测序。来自糖蛋白D的序列用来加强表达并为方便的蛋白质分析提供标记表位，如以下文章中所描述的：Berman等；病毒学杂志.7:4464-9(1932)；Nakamura等；艾滋病和人类逆转录病毒：1875-85(1992)；以及Nakamura等；病毒学杂志67:6179-91(1993)。
简言之，通过PCR反应所产生的分离DNA片段连接进入一质粒(pRK.gD-5,pRKgDstop)，在读框中，该质粒用来将gp120片段融合于1型单纯疱疹病毒(gD-1)的糖蛋白D(gD)基因5′序列并朝向翻译终止密码子的3′端。gD-1基因片段编码成熟形式HSV-1蛋白质的信号序列和25位氨基酸。为了能够实现在哺乳动物细胞中的表达，嵌合的基因片段经克隆进入pRKS表达质粒(Eaten等，生物化学291:8343-8347(1986))，该质粒包含一具有克隆位点和翻译终止密码子的多接头，克隆位点和翻译终止密码子位于巨细胞病毒促进剂和猴病毒40病毒聚腺苷酸化位点之间。
利用磷酸钙技术(Graham等，病毒学52:456-467(1973))，将所得的质粒转染到293s早期人类肾细胞系(Graham等，基因病毒杂志36:59-77(1977)。转染48小时后，收集生长调节细胞培养物介质，通过ELISA方法或特定的放射性免疫沉淀法检测可溶性蛋白质。放射性免疫沉淀法，是将细胞培养上清液中的代谢标记蛋白进行十二烷基硫酸钠聚丙烯酰胺凝胶电泳(PAGE)分离，并通过如Berman(病毒学杂志63:3489-3498(1989))和Laemmli(自然，227:680-685(1970))描述的放射自显影术使其显现。
血清测定。利用Berman等(病毒学杂志7:4464-9(1992))、Nakamura等(爱滋病和人类逆转录病毒8:1875-85(1992))和Nakamura等(病毒学杂志67:6179-91(1993))描述的测定方法进行血清测定，目的是检测rgp120抗体，与gp120V3结构域序列对应的合成gp120V3结构域肽抗体，以及能够阻断MN-rgp120结合到细胞表面CD4的抗体。利用连续三倍稀释的血清液确定与gp120和V3肽结合的抗体的终点滴度。定义终点稀释液滴度为：比产生1∶50稀释的、集合的正常人类血清光密度值高两倍的光密度值。抗体滴度由计算机程序计算，这种程序在抗体稀释液之间进行插值运算。阳性对照标准血清的变异的中间测定(inter-assay)系数是35％。
单克隆抗体从逃逸病毒结合到rgp120。一种类似于Moore等(爱滋病3:155-63(1989))描述的ELISA用来测量把各种单克隆抗体(MAbs)从逃逸病毒结合到rgp120s上。简言之，在Nunc-免疫平板(Maxisorp，鉴定过的)上涂上(100μg,4℃条件下在5μg/ml PBS中放置过夜)一层亲和纯化的抗在gp120(D7324，国际酶，Fallbrook，加拿大)C末端上的肽的绵羊多克隆抗血清。在用PBS-0.05％TWEEN-20的清洗剂洗涤一次之后，在室温下用PBS-1.0％BSA封阻平板30-60分钟。将293s细胞的细胞培养上清液稀释以便含有等量的gD-rgp120融合蛋白，加入到平板上并在室温下培养2小时，随后用PBS-0.05％TWEEN-20清洗剂洗涤三次。将各种MAbs在PBS-1.0％BSA中稀释，将稀释的MAbs加到每孔中并在室温下培养1小时。
洗涤平板3次，在室温下用辣根过氧化物酶轭和物(山羊抗鼠类或者抗人类IgG,Cappel)第二抗体培养1小时。洗涤3次之后展开平板，在平板读数计中读出OD492(492nm处的光密度)。通过稀释标准化生长调节的细胞培养上清液，稀释方法以MAb5B6与HSV-1糖蛋白D融合蛋白的特异性结合为基础。
病毒中和测定。在细胞病变测定中测定疫苗血清通过HIV-1MN抑制MT4细胞感染的能力，测定中用一种测热指示剂染料定量细胞生存力，如Robertson等所描述的方法(病毒学方法杂志20:195-202(1988))。简言之，以澄清的上清液从慢性传染的H9/HIV-1细胞培养液制备HIV-1MN的病毒贮存液(从Dr.Michael Norcross，美国食品与药品管理署获得)。离心受HIV-1MN慢性感染的H9细胞并重悬于十分之一的原体积量培养物中。正如Wrin等(病毒学杂志69:39-48(1995))描述的快速旋转细胞方法，通过机械剪切作用释放出细胞关联病毒。
将足以确保在7天中完全溶解杀死细胞的数量的病毒与试验抗血清的三倍连续稀释液一起培养，随后用于在10％的FCS/RPMI-1640细胞培养介质中攻击MT4T-淋巴细胞。培养物在37℃、5％CO2条件下培养7天，然后用MTT染色检测细胞生存力，如Robertson等所描述的方法(病毒学杂志methods20:195-202(1988))。通过测定570-650nm处的OD值定量化病毒中和终点，然后计算终点滴度作为抗血清稀释倍数的倒数，该抗血清稀释液给出具有未保护的(杀灭的)细胞的对照信号两倍以上的信号。典型地，这些滴度是50％保护条件下计算值的两倍。
结果
受感染者的免疫历史。自1992以来，有499个成年人接受了MN-rgp120免疫处理，第Ⅰ期试验中是在低等或中等风险个体中进行，第Ⅱ期临床试验中包括中等到高等危险个体。这里谈及的研究过程，即对九个个体中头七个的遗传和免疫特征的跟踪，这些个体在试验期间通过高危行为成为HIV-1的感染体。表2A给出了一系列试验处理结果和概括了被接种者状态，表2B给出了一系列疫苗分析结果。
表2A对用MN-rgp120免疫后受HIV-1感染的被接种者的描述研究号 病例号 *风险群体 #抗原剂量/佐剂016 C6 M/H 300/QS21016 C8 M/H 600/QS21016 C15 M/H 300/QS21201 C7 M/H 600/Alum201 C11 M/H 600/Alum201 C10 M/IDU 600/Alum201 C17 M/IDU 600/Alum
*M/H表示男性同性恋者；M/IDU表示男性静脉内用毒者。
#数字表示每次免疫处理注入的MN-rgp120以微克表示的剂量QS21表示配制在QS21佐剂中的抗原；Alum表示配制在氢氧化铝中的MN-rgp120。
表2B对用MN-rgp120免疫后受HIV-1感染的被接种者的描述病例号 注射进程 HIV-1+前 HIV-1+的 □HIV-1+(月) 注射次数 时间(月) 间隔(月)C6 0,1,10,5 2 4.00 2.00C8 0,1 2 4.00 3.00C15 0,1,2 3 6.25 4.00C7 0,1,6,12 3 9.25 3.00C11 0,1,6,12 4 19.50 6.75C10 0,1,6,19 3 19.50 13.50C17 0,1,6,18 4 24.75 6.25
表示最后一次免疫与检测到HIV-1感染之间的间隔
3个感染出现在Ⅰ期试验(NIH方案AVEG201)中，该试验比较配制在两种不同佐剂(alum和QS21)中的MN-rgp120的安全性与免疫原性。4个感染出现在Ⅱ期试验中，该试验的目的是在各种高危人群(静脉用药者，同性恋者和两性男性者，HIV-1感染个体的性伙伴)中建立MN-rgp120安全性和免疫原性。
在研究的7个感染(表3)中，两个(C4和C8)在两次注射之后出现，三个(C7,C10和C15)在三次注射之后出现，两个(C11和C17)在接受四次预定的注射之后出现。接受最后一次免疫与形成感染之间的间隔在2到13.5个月之间。
表3感染HIV-1的被接种者中峰值后加强MN-rgp120抗体滴度注射 C6 C8 C15 C7 C11 C10 C171 ＜50 2185 79 ＜50 1890 na na2 21539 10125 na 413 32696 7771 70563 # # 4460 9707 34728 11627 184134 R # # # # # 11340
#因受HIV-1感染未分析样本。
na表示不能用于检测的样品。
黑体表示非常低的抗体滴度。
免疫个体中对gp120的抗体反应。对所有接受了免疫过程的感染个体，通过ELISA法测定其对MN-rgp120的抗体反应的大小与特异性(图1)。七个受测验者中五个显示正常的抗体反应动力学过程，其包括一种小的但具有再现性的初次反应(1∶100-1∶2,000)和一种强烈的二次反应(加强)效应(滴度范围1∶7,000-1∶32,000)，以及跟随第三和第四次注射的抗体反应，这两次反应类似于或者稍强于第二次免疫后的反应(图1，表3)。
在C7(图1C)中观察到的抗体反应不寻常，因为在第一次注射后检测不到抗体，且在第二次注射后检测的滴度仅为1∶350。这样似乎是C7对首次免疫无反应，在第二次注射之后获得的抗体反应代表初次免疫反应。与这一假说相一致，第三次注射仅仅产生1∶9,707的滴度，例外于那些通常在两次免疫之后观察到的滴度。
从受测验者C15(图1G)也观察到一种非典型抗体反应，其接受免疫过程根据一个加速的免疫进度表(0、1以及2个月)来进行。正如所料，从该受试验者观察到的抗体滴度(1∶4,460)，位于两次免疫后观察到的滴度范围的低值一端，并且远低于三次免疫后的正常值。C15的第三次免疫后缺乏有效的加强反应并不奇怪，因为前面的研究过程在狒狒体内进行加速的0、1、2月免疫进程[Anderson等，211传染病学杂志.160:960-9(1989)]，类似于延长了第二次反应以及不能引起有效的第三次加强反应。
后来对受试验者C6(图1A)和C8(图1B)的血清和血浆分析结果表明，他们在第二次和第三次免疫之间的某点被HIV-1感染。gp120抗体测定中HIV-1感染的血清证明十分明显，在第二次注射后两周滴度未减少，相反形成一非特性的高滴度峰值(图1A和1B)。在第三次注射后MN-rgp120滴度中出现类似的峰值，表明受试验者C7在36周左右，即大约在接受第三次注射(图1C)后16周受到感染。在gp120滴度中，受试验者C10(图1E)、C11(图1D)、C15(图1G)以及C17(图1F)在第三次或者第四次免疫后均出现未预料到的增值，以HIV-1感染最为典型。所获得的数据显示用于MN-rgp120抗体反应的免疫引发不足以提供免受HIV-1感染的普遍保护。
抗V3结构域的抗体滴度。为了进一步说明抗gp120的抗体反应的特征，对一包含主要中和决定簇(PND)的MN-rgp120，测定其合成V3结构域肽的抗体滴度。七个受试验者中五个在第二次免疫后呈现好的V3滴度(1∶400到1∶4000)，然而另外两个受试验者(C7和C15)却在出现有效滴度(图1C和1G)前需要进行第三次免疫。如前面所观察到的(C11)，一些个体(例如C11、C10、C17)的V3滴度峰值似乎随着每一连续的免疫过程而下降(图1D、1E和1F)。在HIV-1感染之后，可观察到两种V3反应模式。三个受试验者(C6、C7和C10)的V3结构域肽(图1A、1C和1E)滴度呈现较大幅度的增加，而C8(图1B)显示较大幅度的减少。在分析的时候，数据不足以得出结论：认为对受试验者C11、C15和C17的试验中，V3滴度的变化是对HIV-1感染的反应。
所获得的结果表明：先于HIV-1感染在各时间点以V3结构域形成抗体反应的能力，不是一种有效相关的抵抗所有HIV-1菌株的保护免疫性。
CD4阻断滴度。阻断gp120结合CD4的抗体代表异种类别病毒中和抗体。已知其中一些能够结合gp120的C4结构域[Nakamura等；病毒学杂志67:6179-91(1993)；Anderson等；传染病杂志.160:960-9((1983)]，另外一些能够识别不连续表位决定的构象[Berman等；病毒学杂志7:4464-9(1932)；Nakamura等；病毒学杂志67:6179-91(1933)；McKeating等；爱滋病研究和人类逆转录病毒8:451-9(1992)；Ho等；病毒学杂志。65:489-93(1991)；Barbas等；美国国家科学院院报91:3809-13(1994)]。
检测两种类型表位抗体的方法，是测定被接种者血清阻断[125I]-标记gp120结合到细胞表面CD4的能力[[Nakamura等；爱滋病和人逆转录病毒81875-85(1992)；Nakamura等；病毒学杂志67:6179-91(1993)]。在感染(图2)之前，测定所有七位被接种者的CD4阻断滴度，其滴度峰值范围为1∶10-1∶300。在感染前的最后一时间点上，七个被接种者中五个的CD4滴度很低(1∶30或者更少)。然而一个被接种者(C17)却在感染(图2F)之前具有大约1∶300的CD4阻断滴度。这样，缺乏阻断MN-rgp120结合到CD4的抗体不能说明所有感染过程。在受HIV-1感染之后，从七个受试验者的五个中可观察到其CD4阻断滴度(1∶100-1∶1,000)有较大幅度的增加。这五个被接种者包括C6、C7、C8、C10和C11。这些结果显示由MN-rgp120引起的CD4阻断滴度低于天然感染引起的CD4阻断滴度。]
病毒中和活性。利用一种比色分析法测定MN-rgp120免疫受试验者抗血清的病毒中和活性，即测定抗体(用病毒处理过)培育后的MT4细胞的生存力。由于不知道任一逃逸感染者的实际受感染日期，同时也不经常地收集血清样品，所以也不知道任一被接种者在受感染时抗体中和效应的大小。
在检验的七个受感染体中，最靠近感染时间的血清样品是从C7获得的样品，在检测到受HIV-1感染之前，其对HIV-1MN的中和滴度1∶15存在了三周(表4)。然而，在其它情况中，最后一次注射和感染时间之间的间隔是10到25周。
表4HIV-1感染的被接种者的血清的中和活性
周 C6 C8 C15 C7 C11 C10 C17
0 ＜10＊ ＜10＊ ＜10＊ ＜10＊ ＜10＊ ＜10＊ ＜10＊
2 ＜10 ＜10 ＜10 - - - -
4 ＜10＊ ＜10＊ nd＊ ＜10＊ ＜10＊ ＜10＊ ＜10＊
6 10 80 - ＜10 30 150 150
8 - - nd＊ - - - -
10 - - 35 - - - -
15 - - - ＜10 - - -
16 150# 250# - - 30 10 ＜10
24 150# ＜10＊ 20＊ ＜10＊ ＜10＊
26 70 500 200 400
30 - - 40 100
33 15 - - -
35 - 100 - -
36 30# - 10 40
52 30＊ ＜10 ＜10
54 250 - -
57 100 - -
63 90 - -
64 - - ＜10
77 40# - -
78 500# 10＊
80 100
84 60
90 150
104 150#
*表示免疫。
#表示HIV-1阳性。
nd表示未试验。
-表示不能获得样品。
检验两个早期受感染个体的血清(表4)，发现一个个体(C6)在先于HIV-1感染检测的十周内具有的中和滴度峰值为1∶10，而另一个体(C8)在先于HIV-1感染检测的十周内具有的中和滴度峰值为1∶80。受试验者C15，其接受的免疫过程是根据一个加速进度表进行的，在先于HIV-1感染检测的14周，第三次注射后其中和滴度为1∶35。受试验者C10，其在第三次免疫后(第24周)具有的中和滴度峰值为1∶200，在52周，先于第一次指示HIV-1感染的六个月时(第78周)没有任何可检测的滴度。
受试验者C11在先于HIV-1的检测的十四周具有中和滴度1∶90，和第三次免疫后的滴度峰值1∶500。类似地，被接种者C17在先于HIV-1的检测的十四周具有中和滴度1∶150，和第三次免疫后两周的滴度峰值1∶400。
基于gp120效应的衰变速率约两个月时间[Belshe等；JAMA272(6):475-80(1994)]，十周内从被接种者C10和C17观察的中和滴度从1∶150衰减为1∶10，在最后的感染前血清样品和HIV-1检测时间间隔之间，在C8、C15、C11以及C17中的滴度似乎可以衰减到1∶10或更少。
这些研究结果显示了所有的被接种者均在先于HIV-1感染的某些时间发展一定水平的病毒中和抗体，并且中和效应在感染时有可能很小。一般来说，在受HIV-1感染个体中观察到的病毒中和效应的大小，与未受感染个体中观察到的病毒中和效应大小相差不大(Belshe等，JAMA272(6):475-80(1994))。
病毒的序列。确定来自所有七种逃逸病毒的gp120核苷酸序列，是为了评价具有疫苗抗原的逃逸病毒的相似性。利用聚合酶链式反应，扩增来自原病毒DNA的包膜糖蛋白基因。通过直接扩增梯度纯化的淋巴细胞溶菌产物的DNA来获得序列，这些淋巴细胞直接从患者血液中获得，没有任何中间的培养或者扩增步骤。
图3中列出了完整的gp120序列(每个样品两个克隆)。所有七种包膜糖蛋白都具有亚类(clade)B病毒的典型序列。与MN-rgp120的全部同源性的大小为69％-80％(表5)。
表5MN-rgp120序列与得自感染的被接种者的序列的比较MN C6.1 C8.3 C7.2 C11.5 C10.5 C17.1 C15.2MN 100 79 78 70 75 69 80 72C6.1 100 78 70 81 75 90 79C8.3 100 68 80 76 84 83C7.2 100 80 73 76 73C11.5 100 75 70 80C10.5 100 70 72C17.1 100 87C15.1 100
*数据表示百分等同性。
有趣的是，逃逸病毒不同于MN-rgp120的高百分比(七个中四个)为25-30％[Myers等；逆转录病毒和爱滋病数据库，Los Alamos国家实验室(1992和1995)]。历史上这种程度的序列变异是亚型间(intra-clade)而非亚型内变异的典型，预期亚型内变异程度在10-20％内[Myers等；逆转录病毒和艾滋病数据库，Los Alamos国家实验室(1992和1995)]。与MN-rgp120有最大相似性的病毒中，两个(c6和C8)在完全免疫之前作为早期感染发生，一个(C17)作为一种后期感染发生。
在V3结构域中的多态性。特别令人感兴趣的是，在已知结构域多形态中包含有由病毒中和抗体识别的表位。最具有特征的中和表位，即主要中和决定簇(PND)，发生在V3环的尖端。在亚型8病毒中，以与HIV-1原型MN菌株等同性为基础，大约60％具有MN血清型定义的特征序列，IGPGRAF(SEQ.ID.NO.39)[Berman等；病毒学杂志7:4464-9(1992)；Myers等；逆转录病毒和爱滋病数据库，Los Alamos国家实验室(1992和1995)；La Rosa等；科学249:932-5(1990)]。
三种病毒(C6、C8和C17)具有MN血清型特征序列(图3)。相对地，四种病毒在PND中具有带氨基酸取代基的序列[IGPGRAW(C7),LGPGSTF(C11),IGPGRVL(C10)以及IGPGSAF(C15)](分别为SEQ.ID.NO.40-43)，因此将其分类为＂无MN类似＂病毒。要注意的是，四种＂无MN类似＂序列的每一种都属稀有序列(表6)，并且其不是亚型B病毒最普通＂无MN＂变体的典型[Myers等；逆转录病毒和爱滋病数据库，Los Alamos国家实验室(1992和1995)]。
表6以MN-rgp120免疫的HIV-1感染个体中主要中和决定簇的形态变化频率V3序列 观察值 数据集合频率GNE LANL LANL.1 La Rosa序列 n 频率 (n=52) (n=519) (n=160) (n=245)GPGRAF 3 0.42 0.67 0.57 0.66 0.60GPGRAW 1 0.14 0.03 0.013 0.06 0.010GPGRVL 1 0.14 ＜0.02 0.004 ＜0.006 ＜0.008GPGSTF**1 0.14 ＜0.02 ＜0.002 ＜0.006 ＜0.004GPGSAF 1 0.14 0.02 0.011 ＜0.006 ＜0.004
*数据集合GNE指一组在1992年收集的52个不相关的分离物；数据集合LANL指Myers等(逆转录病毒和爱滋病数据库，LosAlamos国家实验室1992和1995)报道的一组519种序列；LANL.1指B.Korber(个人通讯)提供的一组160个流行病学非相关个体；数据集合La Rosa指由La Rosa等(科学249:932-5(1990))报道的序列数据。
**在所检验的数据组中不存在的序列。
在Los Alamos国家实验室搜集的519种亚型B序列中，与逃逸病毒匹配的具有PND序列的病毒传播范围从最高的1.3％(C7)到最低的0.2％(C11)[Myers等；逆转录病毒和爱滋病数据库，Los Alamos国家实验室(1992和1995)]。同样地，从其它三个独立衍生数据组中可观察到低频(表6)。这些序列的出现与1985年以前收集的数据组间和1992收集的数据组间无大的差别[La Rosa；科学，249:932-5(1990)]，或者不显著差别于160个流行病学非相关个体组(B.Korber，私人通信)。所有四组数据都说明具类似MN PND序列病毒的传播范围为60％。基于这一数据，确定七种逃逸感染中四种由位于病毒光谱范围以外的病毒引起，所说的疫苗预期抑制该病毒。
逃逸病毒V3结构域的其它特性。象MN-rgp120一样，所有逃逸病毒的V3结构域长为36个氨基酸。然而，所有七种病毒在糖基化位点数量方面和合胞体诱导(SI)特征序列方面不同于MN-rgp120。
MN-rgp120的序列因在V3结构域中306位置处缺乏N-连接糖基化位点而有些不寻常[Myers等；逆转录病毒和爱滋病数据库，LosAlamos国家实验室(1932和1935)]。已知MN-rgp120的抗血清能中和各种在该位置上包含糖基化位点的病毒(例如SF-2,DU6587-5,DU4489-5,CC)，故缺乏这一糖基化位点似乎并不是抗原性上重要的[Berman等；病毒学杂志7:4464-9(1992)]。
此外，MN-rgp120的V3结构域具有合胞体诱导病毒的典型序列多形态(R在位置311处，K在位置324处，K在位置328处)[Fouchier等；病毒学杂志66:3183-87(1992)]，而所有七种逃逸病毒都具有与非合胞体诱导相关的序列。
合胞体诱导病毒与急性疾病的发展[Tersmette等；病毒学杂志62:2026-32(1988)]和T细胞嗜性有关[O′Brien等；自然(伦敦)348:69-73(1990)；Shioda等；自然(伦敦)349:167-9(1991)]。迄今，具有这些性质的病毒没有从MN-rgp120免疫的志愿者回收到。
在V1,V2和C4结构域中的多态性。前面的研究确定了gp120的V1,V2以及C4结构域中的附加中和表位[Nakamura等；病毒学杂志67:6179-91(1993)；McKeating等；爱滋病研究和人逆转录病毒8:451-9(1992)；Ho等；病毒学杂志65:489-93(1991)；Barbas等；美国国家科学院院报91:3809-13(1994)；McKeating等；病毒学杂志67:433244(1993)；Moore等；病毒学杂志67:6136-6151(1993)；Davis等；J.Gen.Virol.74:2609-17(1993)]。
这些中和表位最具有特色部分在C4结构域内，它引起人们的特别关注，因为已了解到结合到这一区域的抗体要阻断gp120结合到CD4上[Moore等；爱滋病3:155-63(1989)；McKeating等；爱滋病研究和人逆转录病毒8:451-9(1992)]。因为表位位于保守(C)结构域内，故天然存在的多种形态，在该区域中的远比其它中和表位中的有限。Nakamura等(病毒学杂志67:6179-91(1993))报道：一些中和MAbs的结合依赖于位置429处的K。
比较MN-rgp120序列和HIV-1的其它菌株，显示在该位置发生一次普通的同质异晶过程，包括E取代为K。确实，相同分离病毒的附属菌株在这一位置上经常显示同质异晶现象。HIV-1LAI的HXB2附属菌株在位置429处含有K，而HIV-1LAI的BH10,HIB和LAV附属菌株在该位置处含有E[Nakamura等；病毒学杂志67:6179-91(1993)]。同样地，HIV-1的1984分离菌株在这一位置显示E，而用以产生MN-rgp120的HIV-1的1990分离菌株，在这一位置具有K。
检验受感染疫苗接受者的序列时(图3)，发现来自受试验者C17的病毒，如MN-rgp120一样在位置429处含有K，而不同于疫苗免疫原的六种其它病毒在这一位置具有E。这些结果显示七种逃逸病毒中的六种，在gp120的C4结构域中的CD4-阻断的中和表位方面不同于疫苗免疫原。
用单克隆抗体进行的研究限定了gp120的V1与V2结构域中的中和表位[McKeating等；病毒学杂志67:4932-44(1993)；Moore等；病毒学杂志67:613-6151(1993)；Davis等；J.Gen.Virol.74:2609-17(1993)]。如发生在C4结构域的多态性一样，V2结构域显示七种普通的多态性，其影响到病毒中和抗体的结合。发生在位置171处的多态性对鼠科动物MAb 1025的结合至关重要，而残基187对几个由1088表现的MAbs的MAb结合来说很重要。
检验V2结构域序列(图3)，发现所有受感染的被接种者病毒均不同于MN-rgp120，因在其位置171处R取代G和在位置187处I或V取代E。在MN-rgp120的V2结构域中识别这些邻近位点的抗体，不希望它们中和在这些位置上具有附加氨基酸取代基的病毒。这样，所有七种逃逸病毒在gp120的V2结构域中的中和表位上区别于MN-rgp120。
有关人士报道了gp120V1结构域中的其它中和表位[O′Brien等；自然(伦敦)348:69-73(1990)；McKeating等；病毒学杂志67:4932-44(1993)]。虽然未鉴定在MN-rgp120的V1结构域中的中和表位，但在逃逸病毒该区域观察到的多态性令人感兴趣。特别惊人的是(图3)该区域长度范围从20氨基酸(C17)到45个氨基酸(C6),N-连接糖基化位点的数量范围2至6。相对地，MN-rgp120的V1结构域长度为31个氨基酸并编码三个N-连接糖基化位点。
尽管对序列数据库的检验结果表明，在V2结构域中的变异可与V1结构域中的变异相比较，但逃逸病毒的V2结构域仍显示了比预期更少的变异。具体地说，V2结构域的长度从36个氨基酸(C7)到39个氨基酸，同时七种病毒的六种在该结构域中包含三个N-连接糖基化位点。在V4结构域中发现了高度多态性，其中序列长度范围从26(C10)到33(C15,C7)个氨基酸，并包含4个或者5个N-连接糖基化位点。
来自逃逸病毒的包膜糖蛋白抗原性。为了确定序列变异对糖蛋白抗原性的重要性，从所有七个受感染的被接种者的病毒制备重组gp120(图4)。在这一研究过程中，集合了一系列MAbs，并且其与MN-rgp120的结合，可与通过ELTSA方法从被接种者分离物获得的rgp120相比较(表7)。
表7与对MN-rgp120的结合比较，MAb对来自受感染试验者的rgp120的结合的相对反应性V3 不连续 C8 V2gp120 1034 50.1 1.5E 1025 1024 1088MN 1.0 1.00 1.00 1.00 1.00 1.00C6.1 0.37 0.37 0.17 0.00 0.00 0.00C6.5 0.33 0.33 0.75 0.00 0.00 0.00C8.3 0.11 0.37 0.38 0.00 0.00 0.00C8.6 0.14 0.34 0.29 0.00 0.00 0.00C7.2 0.47 0.60 0.71 0.00 0.00 0.00C11.5 0.00 0.00 0.17 0.00 0.00 0.00C11.7 0.00 0.00 0.17 0.00 0.00 0.00C10.5 0.33 0.40 0.46 0.24 0.03 0.04C10.7 0.42 0.48 0.50 0.29 0.07 0.09C17.1 0.33 0.52 0.33 0.00 0.30 0.07C17.3 0.37 0.56 0.33 0.00 0.38 0.06C15.2 0.00 0.47 0.92 0.00 0.00 0.00C15.3 0.00 0.37 0.63 0.00 0.00 0.00
*相对反应性值表示MAb浓度2μg/ml时，患者分离物的rgp120光密度值与MN-rgp120光密度值的比值。
对照实验中，MAb5BG的结合(其特定用于与所有rgp120蛋白质N末端融合的HSV gD-1标记表位)用来标准化来自每一分离物的gp120数量(图5A)。研究结果显示该分析测定应在微量滴定板孔截留了等量rgp120s的条件下进行。
利用1034MAb(分离自用如Nakamura等(病毒学杂志67:6179-91,1993)描述的MN-rgp120免疫的鼠体)和50.1 MAb(从用如Rini等(美国科学院学报，90:6325-9,1993)描述的合成V3结构域肽免疫的鼠体中制得)检验V3结构域的抗原结构。已知两MAbs都显示出有力的病毒中和活性。当检验MAb与重组体蛋白质的结合时，同与任何逃逸病毒包膜蛋白质的结合相比，MAb与MN-rgp120的结合至少要大10倍(图5B和C)。令人惊奇地是，来自三个患者分离物(C8、C6和C17)的rgp120在它们的MAb结合活性方面是相互变化的，其中这三个患者分离物具有MN血清型限定的序列IGPGRAF(SEQ.ID.NO.39)。因此，Mab1034和MAb50.1与来自C17的rgp120的结合大大地大于与来自C6和C8的rgp120s的结合。
在为这些MAbs所识别的表位方面的差异是明显的，这是由于C6-rgp120和C8-rgp120和50.1的结合不相上下，而同与C8-衍生的蛋白质的结合相比，1034更好地与C6-衍生的蛋白质结合。最差的MAb反应性是与来自C11和C15的rgp120s的反应。这一结果与序列分析的结果一致，序列分析显示这两种病毒都在V3结构域中的第18位置上具有取代R的S自由基。令人惊奇地是，这两种MAbs都显示出比预期更好的与来自C7和C10病毒的rgp120的结合。如同MN-rgp120一样，两种蛋白质在V3环中都包含五-肽、IGPGR序列(SEQ.ID.NO.44)，但它们与MN-rgp120是不同的，在MN-rgp120中V和L在gp120中的第319和320位取代A和F，并且W在来自C7的gp120中的第320位置取代F。这些结果表明在318位置上的R对这两种MAb的结合来说是十分重要的，并且在319和320位置上的疏水取代并不完全破坏1034和50.1所识别的表位。
正如通过序列数据所预测的一样，如果利用指向MN-rgp120的V2结构域的Mabs(1088和1025)进行与逃逸病毒rgp120s的任何结合，那么几乎没有结合。也与序列数据一致的是观察结果：指向MN-rgp120的C4结构域的MAb1024具有与C17-rgp120(如同在429位置包含K的MN-rgp120一样)之间的一定反应性，但是不具有与其它的分离物(在429残基上包含E)的任何反应性。
同时，这些研究表明所有七种逃逸病毒的抗原结构不同于在三孔上具有中和表位特征的疫苗免疫原。
观察到一种模式完全不同的与人杂交瘤的反应性，正如Ho等(病毒学杂志65:489-93,1991)描述的，该MAb15e由受HIV-1感染的个体制备。对于这一MAb，可达到与MN-rgp120和来自C7的rgp120的最大结合，同时观测到与来自C11的rgp120的两个克隆的最差的反应性。中等条件下，观测到与得自C10和C17的rgp120s的不相上下的反应性。
这些结果显示15e表位是多形的，并且表位在MN-rgp120和得自C7的rgp120上是保守的，但在得自C11的rgp120s上丢失。令人感兴趣的是，得自C6的gp120的两种不同克隆给出极为不同的抗体结合模式。因此，得自克隆C6.5的rgp120显示出与这一抗体的强反应性，而得自克隆C6.1的rgp120显示出与这一MAb的极弱的反应性。序列数据(图3)的比较表明两个C6克隆在6个氨基酸位置上是不同的。基于结合到已知序列的其它病毒蛋白质上的比较，似乎在Kgp120的C3结构域中的351位取代Ⅰ说明了在结合活性方面的区别。这一结果也与C11的两克隆的结果一致，该C11在这一位置同样包含带正电的K，并且也具有与这一MAb的弱反应性。此外，T在C4结构域中的439位上对Ⅰ的取代能够说明在C6.1和C6.5之间的15e结合方面的区别。虽然在C4结构域中的这一位置上的多态性不能解释为什么上述两种C11克隆不能结合到15e上，但是可以通过邻近的T在434位置上对M的取代来影响这一结合。
讨论
在这些研究中，在九个疫苗之七个中的病毒和免疫应答得到测定，其中的九个疫苗在参与MN-rgp120(一种候选HIV-1疫苗)的1期和2期试验的同时，均已通过高风险的活性感染了HIV-1。期待这样的感染将因下列两个理由之一而发生：1)在感染期间缺乏足够的免疫应答；或者2)用落在抗原光谱(期待为疫苗免疫原所覆盖)之外的病毒进行感染。数据表明对于所观测到的感染，两种解释都可以包括(表8)。
表8逃逸感染的总结与MN-rgp120同源病例号 充分免疫 MN-rgp120 V3 C4 V2同源性(％) PND 表位 表位C6 - 79 + - -C8 - 78 + - -C15 - 72 - - -C7 - 70 - - -C11 + 75 - - -C10 + 69 - - -C17 + 80 + + -
在接受没有最小的三剂量疫苗的个体中发生两个感染，其中所谓的最小剂量是用蛋白质亚单位疫苗(例如在如由Francis等(Ann.Int.Med.97:302-6,1982)描述的明矾佐剂中的乙型肝炎病毒)诱导保护免疫性所典型地需要的。两种附加的逃逸感染发生于有弱或者不能检测到的初次(C7)和加强(C15)反应的疫苗中。在三个在接收三次或多次生产性免疫(C10、C11和C17)之后而感染HIV-1的个体中，至少两个，并且有可能所有三个，似乎在接收他们最后免疫之后的六个月以上才受到感染。因为对MN-rgp120的抗体滴度典型地以2至2.5个月的半衰期衰变[Belshe等；JAMA272(6):475-80(1994)；Berman等；爱滋病，8:591-601(1994)]，所以期待抗体滴度以至少八倍以及在感染期间有可能高达六十倍来衰变。因此，在感染期间的足够免疫应答的缺乏为七种逃逸感染的至少六个提供了一种可能的解释。
研究受到HIV-1激发的gp160免疫黑猩猩[McElrath等；在201方案AVEG第Ⅱ期中的中的纵向疫苗诱导免疫性和研究参与者风险行为。包括于：国家爱滋病疫苗协同发展组织第八次年度会议文摘。Bethseda,MD1996:216]和受到嵌合SIV/HIV-1病毒(SHIV)激发的9p120-免疫猕猴短尾猴的疫苗功效，结果数据表明感染时间的中和抗体反应的大小与保护免疫性具有重要关系。如果证明了保持中和抗体滴度与人类保护免疫性有效相关，那么要实现长期持久的保护，就要求设计有用来最大化抗体反应的方式(例如新的佐剂)或免疫制度(频繁推进)。每六个月使用一次激发剂可能有好处。
对于后期感染的其它可能的解释是，疫苗抗原和逃逸病毒包膜糖蛋白抗原之间的区别。这一解释得到观察结果的支持，七种逃逸病毒的四种具有在氨基酸水平上有25-30％不同于MN-rgp120的包膜糖蛋白。该区别的大小历史性地[Myers等；逆转录病毒和爱滋病数据库，Los Alamos国家的实验室(1992和1995)]与内亚型变异相关，并且远超过预期的相同亚型内病毒变异的平均值10-20％。尽管对包膜糖蛋白许多结构域中序列变异的生物重要性还不清楚，但在中和表位的多态性的确是影响疫苗功效的一个重要因子。以前的研究[Salmon-Ceron等；爱滋病研究人类逆转录病毒11:1479-86(1995)；Javaherian等；科学250:1590-3(1930)]已经证明能由HIV-1包膜衍生疫苗引起的中和活性宽度，关键依赖于在V3结构域中的表位序列(例如；PND)。这样，基于HIV-1的LAI菌株的供选疫苗(原型＂非MN类似＂亚型B病毒)，显示极小或没有与亚型B病毒的交叉中和活性，而包含＂MN类似＂PND序列(IGPGRAF)(SEQ.ID.NO.44)的疫苗显示广泛的交叉中和活性。七种逃逸病毒中，具有PND中带氨基酸取代基的包膜糖蛋白的四种，符合这样一种解释，即抗原结构的区别与某些这样的感染有关。
在最近几年，＂类MN＂病毒发生在PND表位之外的多态性逐渐变得清楚。最好的例子是发生在C4结构域中的多态性，其中两个抗原明显变体因在位置429处存在K或E而有所区别[Moore等；爱滋病3:155-63(1989)]。因为七种逃逸病毒的六种不同于疫苗菌株，因此它们在位置429处包含E而非K，对MN-rgp120的C4结构域产生的抗体不可能中和在七个被接种者的六个中感染的病毒。
已知在gp120的V1与V2结构域中存在着其它中和表位。虽然这些结构域因为插入和缺失而高度可变，McKeating等仍描述了其中和表位(McKeating等；病毒学杂志67:4932-44(1993)；Moore等；病毒学杂志67:6136-6151(1993)；和Davis等；J.Gen.Virol.74:2609-17(1993))。如C4表位一样，已知其序列变异发生在由相同双亲分离体衍生而来的不同亚菌株之间。因为所有七种逃逸病毒的疫苗抗原内存在RDK序列而非GDK序列，故其不同于MN-rgp120，对MN-rgp120的V2结构域的中和抗体，将不能如预期的那样中和任一从以MN-rgp120免疫的被接种者回收的病毒。
虽然中和表位的多态性可以解释大多数感染中的保护性缺乏，但看来似乎不能解释被接种者C17的感染，其受到在V3与C4结构域中配合MN-rgp120的病毒的感染。如果序列差异是在这种情况下引起保护性缺乏的原因，那么关键性的差异就可能与该逃逸病毒gp120的V1结构域中不寻常的序列有关。几项研究结果表明V1结构域具有通过病毒中和单克隆抗体识别的表位[McKeating等；病毒学杂志67:4932-44(1993)；Davis等；J.Gen.Virol.74:2609-17(1993)；Kayman等；病毒学杂志68:400-410(1994)]。
虽然我们对V1表位的了解相对于其它中和位点来说还很少，V1表位似乎是依赖于构象的，并由来自HIV-1感染个体的抗血清在V1与V2结构域中识别的表位[McKeating等；病毒学杂志67:4932-44(1993)；Kayman等；病毒学杂志68:400-410(1994)]。来自C17的病毒的V1序列很值得注意，因为它比MN-rgp120或者其它任何逃逸病毒都要小并且含有较少的N-连接糖基化位点。基于同样的理由，来自C11和C6的包膜糖蛋白也值得注意，因为它们比MN-rgp120或者其它的逃逸病毒更大并含有更多的糖基化位点。
氨基酸序列的差异可以为抗原结构差异提供线索，而这种多态性的后果只有通过对抗体结合的研究方可得到证明。为了确定序列差异与抗原结构差异的相关性，表达来自所有七种逃逸病毒每一种两个克隆的gp120，同时用单克隆抗体板检验克隆的抗原性。正如从序列数据预测的一样，对MN-rgp120的V2结构域没有逃逸病毒包膜糖蛋白与中和MAbs进行反应。检验对C4结构域的MAbs时，仅有C17包膜糖蛋白(其关于K429配合MN-rgp120)显示虽然较弱但很重要的结合。令人惊奇的是，三种包含亚型B PND共有序列IGPGRAF(SEQ.ID.NO.!!)的逃逸包膜糖蛋白，尽管它们具有的PND序列与疫苗免疫原密切有关，但其与所有三种PND的指向MAbs反应微弱。这样，所有三个携带疫苗分离物似乎都具有受MAb结合干扰的识别位点之外的变化。
许多年来人们已经知道：抗体外中和作用的抗性是由于在远程序列方面的突变所致，该远程序列改变中和表位的构象，并且通过病毒中和抗体来干扰识别[Nara等；病毒学杂志64:3773-91(1990)；cordonnier等；自然，340:571-4(1989)]。同时，这些结果表明：从逃逸病毒回收的包膜糖蛋白的抗原结构极为不同于疫苗抗原的结构。
新结果是残基在C3结构域中的定位，该C3结构域似乎影响结合病毒中和人MAb,15e的结合。已知这一MAb识别不连续表位，阻断CD4结合，以及中和HIV-1的各种实验室和初级分离物[Ho等；病毒学杂志65:489-93(1991)；Thali等；病毒学杂志66:5635-5641(1992)；Moore等；AIDS研究.人类逆转录病毒9:1179-1187(1993)]。
逃逸病毒与包膜糖蛋白的结合的比较表明：这一抗体的识别关键取决于gp120的C3或者C4结构域中的残基。在C3结构域中的351位的带正电荷的K的唯一存在为HIV-1的C11.5、C11.7和C6.1菌株不能与15e结合的现象提供了一种普通的解释。此外，可能的是，不同的氨基酸在不同位置的取代说明15e不能与得自C6和C11克隆的rgp120s结合。发生这一类型取代的唯一明显位置是在C4结构域中，其中T在434(C11)取代M以及T在439取代I。
本研究表明：MN-rgp120的当前制剂抗HIV-1感染的有效性不到100％。基于以前的用MN-rgp120进行的体外和体内研究，期待防止天然HIV-1在人类中感染的保护取决于病毒中和抗体的域值浓度，以及疫苗免疫原和激发病毒之间的抗原相似性。
在这一点上，七种逃逸感染(C17)中只有一种是未预料到的。这一个体接收全程的免疫，也在至少两个的重要中和表位(V3和C4结构域)上感染有类似于MN-rgp120的病毒。这一感染可能与感染期间抗体应答的大小有关，或者与逃逸病毒和疫苗菌株之间的抗原差别有关，或者与在这一方案中得到监控的感染环境(例如溃疡性的损害，由具有急性感染或严重病毒血症的供体引起的感染)有关。此外，这一个体可以代表一个真正的疫苗无效，而无需明确的解释。
在平衡方面，本文所描述的逃逸感染的分析并没有揭示任何数据，该数据使作为抑制HIV-1感染的疫苗的MN-rgp120的继续发展受挫。上述结果支持如下推测：提高疫苗免疫原性(如通过附加的加强免疫)可能是需要的，以便保持长期的保护免疫性，并且得自除MN-rgp120之外的病毒的其它抗原不同的菌株的rgp120的加入对于扩展保护的宽度是有用的。
得自逃逸感染的病毒和病毒糖蛋白的可利用性可以提供一种使鉴定新抗原(包埋在多价疫苗中)的过程合理化的重要方法。按照定义，由逃逸病毒制备的重组病毒糖蛋白具有与MN-rgp120极为不同的抗原结构，并且当前所传递的病毒的代表。因此，把逃逸病毒的rgp120与MN-rgp120相结合是有效的补充方法，并且极大地扩展了抗原复杂度和增加了交叉中和活性的宽度。
序列表(1)一般信息：
(ⅰ)申请人：Berman,Phillip W.
(ⅱ)发明名称：HIV包膜多肽和疫苗
(ⅲ)序列数：44个
(ⅳ)通讯地址：
(A)收信人：SKJERVEN,MORRILL,MACPHERSON等.
(B)街道：25Metro Drive,Suite700
(C)城市：San Jose
(D)州：加利福尼亚
(E)国家：美国
(F)ZIP:95110
(ⅴ)计算机可读形式：
(A)介质类型：3.5英寸，1.44Mb软盘
(B)计算机：IBMPC兼容机
(C)操作系统：PC-DOS/MS-DOS
(D)软件：WinPatin(Genentech)
(ⅵ)当前的申请数据：
(A)申请号：
(B)申请日：
(C)分类号：
(ⅷ)律师/代理人信息：
(A)姓名：Terlizzi,Laura
(B)登记号：31,307
(C)证书号：M-3897US
(ⅸ)电讯信息：
(A)电话：(408)4539200
(B)传真：(408)4537979(2)SEQ ID NO:1的信息：
(ⅰ)序列特征：
(A)长度：1503个碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ IDNO:1:
GGG GTA CCT GTG TGG AAG GAA GCA ACC ACC ACT CTA 36
Gly Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu
1 5 10TTT TGT GCA TCA GAT GCT AAA GCA TAT GAC ACA GAG GTG 75Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp Thr Glu Val
15 20 25CAT AAT GTT TGG GCC ACA CAT GCT TGT GTA CCC ACA GAC 114His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp
30 35CCA AAC CCA CAA GAA ATG GTA TTG GAA AAT GTG ACA GAA 153Pro Asn Pro Gln Glu Met Val Leu Glu Asn Val Thr Glu
40 45 50GAT TTT AAC ATG TGG AAA AAT GAC ATG GTA GAA CAG ATG 192Asp Phe Asn Met Trp Lys Asn Asp Met Val Glu Gln Met
55 60CAT GAG GAT ATA ATC AGT TTA TGG GAT CAA AGC CTA AAA 231His Glu Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu Lys65 70 75CCA TGT GTA AAA TTA ACC CCA CTC TGT ATT ACT TTA AAT 27CPro Cys Val Lys Leu Thr Pro Leu Cys Ile Thr Leu Asn
80 85 90TGC ACC AAT TGG AAG AAG AAT GAT ACT AAA ACT AAT AGT 309Cys Thr Asn Trp Lys Lys Asn Asp Thr Lys Thr Asn Ser
95 100AGT AGT ACT ACA ACT AAT AAT AGT AGT GCT ACA GCT AAT 348Ser Ser Thr Thr Thr Asn Asn Ser Ser Ala Thr Ala Asn
105 110 115AGT AGT AGT ACT ACA ACT AAT AGT AGT TGG GGA GAG ATA 387Ser Ser ser Thr Thr Thr Asn Ser Ser Trp Gly Glu Ile
120 125AAG GAG GGA GAA ATA AAG AAC TGC TCT TTC AAT ATC ACC 426Lys Glu Gly Glu Ile Lys Asn Cys Ser Phe Asn Ile Thr130 135 140ACA AGC ATA AGA GAC AAG GTG AAG AAA GAA TAT GCA CTT 465Thr Ser Ile Arg Asp Lys Val Lys Lys Glu Tyr Ala Leu
145 150 155TTT TAT AGC CTT GAT GTA GTA CCA ATA GAA AAT GAT AAT 504Phe Tyr Ser Leu Asp Val Val Pro Ile Glu Asn Asp Asn
160 165ACT AGC TAT AGG TTG AGA AGT TGT AAC ACC TCA GTC ATT 543Thr Ser Tyr Arg Leu Arg Ser Cys Asn Thr Ser Val Ile
170 175 180ACA CAA GCC TGT CCA AAG GTA ACT TTT GAG CCA ATT CCC 582Thr Gln Ala Cys Pro Lys Val Thr Phe Glu Pro Ile Pro
185 190ATA CAT TAT TGT ACC CCG GCT GGT TTT GCG ATT CTG AAG 621Ile His Tyr Cys Thr Pro Ala Gly Phe Ala Ile Leu Lys195 200 205TGT AGA GAT AAA AAG TTC AAT GGA ACA GGA CCA TGC AAA 660Cys Arg Asp Lys Lys Phe Asn Gly Thr Gly Pro Cys Lys
210 215 220AAT GTT AGC ACA GTA CAA TGT GCA CAT GGA ATT AAG CCA 699Asn Val Ser Thr Val Gln Cys Ala His Gly Ile Lys Pro
225 230GTA GTG TCA ACT CAA CTG CTG TTA AAT GGC AGC CTA GCA 738Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala
235 240 245GAA GAA GAG GTA ATA ATT AGA TCT GCC AAT TTC TCA AAC 777Glu Glu Glu Val Ile Ile Arg Ser Ala Asn Phe Ser Asn
250 255AAT GCT AAA ATC ATA ATA GTA CAG TTG AGG GAA CCT GTA 816Asn Ala Lys Ile Ile Ile Val Gln Leu Arg Glu Pro Val260 265 270GAA ATT AAT TGT ACA AGA CCC AGC AAC AAT ACA ATA AAA 855Glu Ile Asn Cys Thr Arg Pro Ser Asn Asn Thr Ile Lys
275 280 285GGT ATA CAC ATA GGA CCA GGG AGA GCA TTT TAT GCA ACA 894Gly Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Ala Thr
290 295GGA GAC ATA CGA GGA GAT ATA AGA CAA GCA CAT TGT AAC 933Gly Asp Ile Arg Gly Asp Ile Arg Gln AlaHis Cys Asn
300 305 310ATT AGT GGA GCA AAA TGG AAT AAC ACT TTA AAG AAG GTA 972Ile Ser Gly Ala Lys Trp Asn Asn Thr Leu Lys Lys Val
315 320GTT AAA AAA TTA AAA GAA CAA TTT CCA AAT AAA ACA ATA 1011Val Lys Lys Leu Lys Glu Gln Phe Pro Asn Lys Thr Ile325 330 335GTC TTT AAC CAT TCC TCA GCA GGG GAC CCA GAA ATT GTA 1050Val Phe Asn His Ser Ser Gly Gly Asp Pro Glu Ile Val
340 345 350ATG CAC AGT TTT AAT TGT CAA GGG GAA TTT TTC TAC TGT 1089Met His Ser Phe Asn Cys Gln Gly Glu Phe Phe Tyr Cys
355 360AAT ACA ACA AAG CTG TTT AAT AGT ACT TGG AAT GAT ACT 1128Asn Thr Thr Lys Leu Phe Asn Ser Thr Trp Asn Asp Thr
365 370 375ACA GAG TCA AAT AAC AAT GAT AGT ACT ATT ACA CTC CCA 1167Thr Glu Ser Asn Asn Asn Asp Ser Thr Ile Thr Leu Pro
380 385TGC AGA ATA AAA CAA ATT ATA AAC ATG TGG CAG GAA ATA 1206Cys Arg Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Ile390 395 400GGA AAA GCA ATG TAT GCC CCT CCC ACC AGA GGA GAA ATT 1245Gly Lys Ala Met Tyr Ala Pro Pro Thr Arg Gly Glu Ile
405 410 415AAA TGT TCA TCA AAT ATT ACA GGA CTA CTG TTA ATA AGA 1284Lys Cys Ser Ser Asn Ile Thr Gly Leu Leu Leu Ile Arg
420 425GAT GGT GGT ATT AAC ACT AGC GAT GCC ACC GAG ACC TTC 1323Asp Gly Gly Ile Asn Thr Ser Asp Ala Thr Glu Thr Phe
430 435 440AGA CCG GGA GGA GGA GAT ATG AGG GAC AAT TGG AGA AGT 1362Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp Arg Ser
445 450GAA TTA TAT AAA TAT AAA GTA GTG AAA ATT GAG CCA TTA 1401Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile Glu Pro Leu455 460 465GGA GTA GCA CCC ACC AAG GCA AAG AGA AGA GTG GTG CAG 1440Gly Val Ala Pro Thr Lys Ala Lys Ar9 Ar9 Val Val Gln
470 475 480AGA GAA AAA AGA GCA GTA ACA CTA GGA GCT ATG TTC CTT 1479Arg Glu Lys Arg Ala Val Thr Leu Gly Ala Met Phe Leu
485 490GGG TTC TTA GGA GCA TAA AGC TTC 1503Gly Phe Leu Gly Ala Xaa Ser Phe
495 500 501(2)SEQ ID NO:2的信息：
(ⅰ)序列特征：
(A)长度：501个氨基酸
(B)类型：氨基酸
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:2:Gly Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu Phe Cys Ala1 5 10 15Ser Asp Ala Lys Ala Tyr Asp Thr Glu Val His Asn Val Trp Ala
20 25 30Thr His Ala Cys Val Pro Thr Asp Pro Asn Pro Gln Glu Met Val
35 40 45Leu Glu Asn Val Thr Glu Asp Phe Asn Met Trp Lys Asn Asp Met
50 55 60Val Glu Gln Met His Glu Asp Ile Ile Ser Leu Trp Asp Gln Ser
65 70 75Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Ile Thr Leu Asn
80 85 90Cys Thr Asn Trp Lys Lys Asn Asp Thr Lys Thr Asn Ser Ser Ser
95 100 105Thr Thr Thr Asn Asn Ser Ser Ala Thr Ala Asn Ser Ser Ser Thr
110 115 120Thr Thr Asn Ser Ser Trp Gly Glu Ile Lys Glu Gly Glu Ile Lys
125 130 135Asn Cys Ser Phe Asn Ile Thr Thr Ser Ile Arg Asp Lys Val Lys
140 145 150Lys Glu Tyr Ala Leu Phe Tyr Ser Leu Asp Val Val Pro Ile Glu
155 160 165Asn Asp Asn Thr Ser Tyr Arg Leu Arg Ser Cys Asn Thr Ser Val
170 175 180Ile Thr Gln Ala Cys Pro Lys Val Thr Phe Glu Pro Ile Pro Ile
185 190 195His Tyr Cys Thr Pro Ala Gly Phe Ala Ile Leu Lys Cys Arg Asp
200 205 210Lys Lys Phe Asn Gly Thr Gly Pro Cys Lys Asn Val Ser Thr Val
215 220 225Gln Cys Ala His Gly Ile Lys Pro Val Val Ser Thr Gln Leu Leu
230 235 240Leu Asn Gly Ser Leu Ala Glu Glu Glu Val Ile Ile Arg Ser Ala
245 250 255Asn Phe Ser Asn Asn Ala Lys Ile Ile Ile Val Gln Leu Arg Glu
260 265 270Pro Val Glu Ile Asn Cys Thr Arg Pro Ser Asn Asn Thr Ile Lys
275 280 285Gly Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Ala Thr Gly Asp
290 295 300Ile Arg Gly Asp Ile Arg Gln Ala His Cys Asn Ile Ser Gly Ala
305 310 315Lys Trp Asn Asn Thr Leu Lys Lys Val Val Lys Lys Leu Lys Glu
320 325 330Gln Phe Pro Asn Lys Thr Ile Val Phe Asn His Ser Ser Gly Gly
335 340 345Asp Pro Glu Ile Val Met His Ser Phe Asn Cys Gln Gly Glu Phe
350 355 360Phe Tyr Cys Asn Thr Thr Lys Leu Phe Asn Ser Thr Trp Asn Asp
365 370 375Thr Thr Glu Ser Asn Asn Asn Asp Ser Thr Ile Thr Leu Pro Cys
380 385 390Arg Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Ile Gly Lys Ala
395 400 405Met Tyr Ala Pro Pro Thr Arg Gly Glu Ile Lys Cys Ser Ser Asn
410 415 420Ile Thr Gly Leu Leu Leu Ile Arg Asp Gly Gly Ile Asn Thr Ser
425 430 435Asp Ala Thr Glu Thr Phe Arg Pro Gly Gly Gly Asp Met Arg Asp
440 445 450Asn Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile Glu
455 460 465Pro Leu Gly Val Ala Pro Thr Lys Ala Lys Arg Arg Val Val Gln
470 475 480Arg Glu Lys Arg Ala Val Thr Leu Gly Ala Met Phe Leu Gly Phe
485 490 495Leu Gly Ala Xaa Ser Phe
500 501(2)SEQIDNO:3的信息：
(ⅰ)序列特征：
(A)长度：1503个碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:3:
GGG GTA CCT GTA TGG AAA GAA GCA ACC ACC ACT CTA 36
Gly Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu
1 5 10TTT TGT GCA TCA GAT GCT AAA GCA TAT GAC ACA GAG GTG 75Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp Thr Glu Val
15 20 25CAT AAT GTT TGG GCC ACA CAT GCT TGT GTA CCC ACA GAC 114His Asn Val Trp Ala Thr Mis Ala Cys Val Pro Thr Asp
30 35CCA AAC CCA CAA GAA ATG GTA TTG GAA AAT GTG ACA GAA 153Pro Asn Pro Gln Glu Met Val Leu Glu Asn Val Thr Glu
40 45 50GAT TTT AAC ATG TGG AAA AAT GAC ATG GTA GAA CAG ATG 192Asp Phe Asn Met Trp Lys Asn Asp Met Val Glu Gln Met
55 60CAT GAG ANT ATA ATC AGT TTA TGG GAT CAA AGC CTA AAA 231His Glu Xaa Ile Ile Ser Leu Trp Asp Gln Ser Leu Lys65 70 75CCA TGT GTA AAA TTA ACC CCA CTC TGT ATT ACT TTA AAT 270Pro Cys Val Lys Leu Thr Pro Leu Cys Ile Thr Leu Asn
80 85 90TGC ACC AAT TGG AAG GAG AAT GAT ACT AAA ACT AAT AGT 309Cys Thr Asn Trp Lys Glu Ash Asp Thr Lys Thr Asn Ser
95 100AGT AGT ACT ACA ACT AAT AAT AGT AGT GCT ACA GCT AAT 348Ser Ser Thr Thr Thr Asn Asn Ser Ser Ala Thr Ala Asn
105 110 115AGT AGT AGT ACT ACA ACT AAT AGT AGT TGG GGA GAG ATA 387Ser Ser Ser Thr Thr Thr Asn Ser Ser Trp Gly Glu Ile
120 125AAG GAG GGA GAA ATA AAG AAC TGC TCT TTC AAT ATC ACC 426Lys Glu Gly Glu Ile Lys Asn Cys Ser Phe Asn Ile Thr130 135 140ACA GGC ATA AGA GAC AAG GTG AAG AAA GAA TAT GCA CTT 465Thr Gly Ile Arg Asp Lys Val Lys Lys Glu Tyr Ala Leu
145 150 155TTT TAT AGC CTT GAT GTA GTA CCA ATA GAA AAT GAT AAT 504Phe Tyr Ser Leu Asp Val Val Pro Ile Glu Asn Asp Asn
160 165ACT AGC TAT AGG TTG AGA AGT TGT AAC ACC TCA GTC ATT 543Thr Ser Tyr Arg Leu Arg Ser Cys Asn Thr Ser Val Ile
170 175 180ACA CAA GCC TGT CCA AAG GTA ACT TTT GAG CCA ATT CCC 582Thr Gln Ala Cys Pro Lys Val Thr Phe Glu Pro Ile Pro
185 190ATA CAT TAT TGT ACC CCG GCT GGT TTT GCG ATT CTG AAG 621Ile His Tyr Cys Thr Pro Ala Gly Phe Ala Ile Leu Lys195 200 205TGT AAA GAT AAA AAG TTC AAT GGA ACA GGA CCA TGC AAA 660Cys Lys Asp Lys Lys Phe Asn Gly Thr Gly Pro Cys Lys
210 215 220AAT GTT AGC ACA GTA CAA TGT ACA CAT GGA ATT AAG CCA 699Asn Val Ser Thr Val Gln Cys Thr His Gly Ile Lys Pro
225 230GTA GTG TCA ACT CAA CTG CTG TTA AAT GGC AGC CTA GCA 738Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala
235 240 245GAA GAA GAG GTA ATA ATT AGA TCT GCC AAT TTC TCA AAC 777Glu Glu Glu Val Ile Ile Arg Ser Ala Asn Phe Ser Asn
250 255AAT GCT AAA ATC ATA ATA GTA CAG TTG AAG GAA CCT GTA 816Asn Ala Lys Ile Ile Ile Val Gln Leu Lys Glu Pro Val260 265 270GAA ATT AAT TGT ACA AGA CCC AGC AAC AAT ACA ATA AAA 855Glu Ile Asn Cys Thr Arg Pro Ser Asn Asn Thr Ile Lys
275 280 285GGT ATA CAC ATA GGA CCA GGG AGA GCA TTT TAT GCA ACA 894Gly Ils His Ile Gly Pro Gly Arg Ala Phe Tyr Ala Thr
290 295GGA GAC ATA CGA GGA GAT ATA AGA CAA GCA CAT TGT AAC 933Gly Asp Ile Arg Gly Asp Ile Arg Gln Ala His Cys Asn
300 305 310ATT AGT GGA GCA AAA TGG AAT AAC ACT TTA AAG AAG GTA 972Ile Ser Gly Ala Lys Trp Asn Asn Thr Leu Lys Lys Val
315 320CTT ATA AAA TTA AAA GAA CAA TTT CCA AAT AAA ACA ATA 1011Val Ile Lys Leu Lys Glu Gln Phe Pro Asn Lys Thr Ile325 330 335GTC TTT AAC CAT TCC TCA GGA GGG GAC CCA GAA ATT GTA 1050Val Phe Asn His Ser Ser Gly Gly Asp Pro Glu Ile Val
340 345 350ATG CAC AGT TTT AAT TGT CAA GGG GAA TTT TTC TAC TGT 1089Met His Ser Phe Asn Cys Gln Gly Glu Phe Phe Tyr Cys
355 360AAT ACA ACG AAG CTG TTT AAT AGT ACT TGG AAT GAT ACT 1128Asn Thr Thr Lys Leu Phe Asn Ser Thr Trp Asn Asp Thr
365 370 375ACA GAG TCA AAT AAC AAT GAT AGT ACT ATT ACA CTC CCA 1167Thr Glu Ser Asn Asn Asn Asp Ser Thr Ile Thr Leu Pro
380 385TGC AGA ATA AAA CAA ATT ATA AAC ATG TGG CAG GAA GTA 1206Cys Arg Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val390 395 400GGA AAA GCA ATG TAT GCC CCT CCC ATC AGA GGA GAA ATT 1245Gly Lys Ala Met Tyr Ala Pro Pro Ile Arg Gly Glu Ile
405 410 415AAA TGT TCA TCA AAT ATT ACA GGA CTA CTG TTA ACA AGA 1284Lys Cys Ser Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg
420 425GAT GGT GGT ATT AAC ACT AGC GAT GCC ACC GAG ACC TTC 1323Asp Gly Gly Ile Asn Thr Ser Asp Ala Thr Glu Thr Phe
430 435 440AGA CCG GGA GGA GGA GAT ATG AGG GAC AAT TG6 AGA AGT 1362Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp Arg Ser
445 450GAA TTA TAT AAA TAT AAA GTA GTG AAA ATT GAG CCA TTA 1401Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile Glu Pro Leu455 460 465GGA GTA GCA CCC ACC AAG GCA AAG AGA AGA GTC GTG CAG 1440Gly Val Ala Pro Thr Lys Ala Lys Arg Arg Val Val Gln
470 475 480AGA GAA AAA AGA GCA GTA ACA CTA GGA GCT ATG TTC CTT 1479Arg Glu Lys Arg Ala Val Thr Leu Gly Ala Met Phe Leu
485 490GGG TTC TTG GGA GCA TAA AGC TTC 1503Gly Phe Leu Gly Ala Xaa Ser Phe
495 500 501(2)SEQ ID NO:4的信息：
(ⅰ)序列特征：
(A)长度：501个氨基酸
(B)类型：氨基酸
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:4:Gly Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu Phe Cys Ala1 5 10 15Ser Asp Ala Lys Ala Tyr Asp Thr Glu Val His Asn Val Trp Ala
20 25 30Thr His Ala Cys Val Pro Thr Asp Pro Asn Pro Gln Glu Met Val
35 40 45Leu Glu Asn Val Thr Glu Asp Phe Asn Met Trp Lys Asn Asp Met
50 55 60Val Glu Gln Met His Glu Xaa Ile Ile Ser Leu Trp Asp Gln Ser
65 70 75Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Ile Thr Leu Asn
80 85 90Cys Thr Asn Trp Lys Glu Asn Asp Thr Lys Thr Asn Ser Ser Ser
95 100 105Thr Thr Thr Asn Asn Ser Ser Ala Thr Ala Asn Ser Ser Ser Thr
110 115 120Thr Thr Asn Ser Ser Trp Gly Glu Ile Lys Glu Gly Glu Ile Lys
125 130 135Asn Cys Ser Phe Asn Ile Thr Thr Gly Ile Arg Asp Lys Val Lys
140 145 150Lys Glu Tyr Ala Leu Phe Tyr Ser Leu Asp Val Val Pro Ile Glu
155 160 165Asn Asp Asn Thr Ser Tyr Arg Leu Arg Ser Cys Asn Thr Ser Val
170 175 180Ile Thr Gln Ala Cys Pro Lys Val Thr Phe Glu Pro Ile Pro Ile
185 190 195His Tyr Cys Thr Pro Ala Gly Phe Ala Ile Leu Lys Cys Lys Asp
200 205 210Lys Lys Phe Asn Gly Thr Gly Pro Cys Lys Asn Val Ser Thr Val
215 220 225Gln Cys Thr Mis Gly Ile Lys Pro Val Val Ser Thr Gln Leu Leu
230 235 240Leu Asn Gly Ser Leu Ala Glu Glu Glu Val Ile Ile Arg Ser Ala
245 250 255Asn Phe Ser Asn Asn Ala Lys Ile Ile Ile Val Gln Leu Lys Glu
260 265 270Pro Val Glu Ile Asn Cys Thr Arg Pro Ser Asn Asn Thr Ile Lys
275 280 285Gly Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Ala Thr Gly Asp
290 295 300Ile Arg Gly Asp Ile Arg Gln Ala His Cys Asn Ile Ser Gly Ala
305 310 315Lys Trp Asn Asn Thr Leu Lys Lys Val Val Ile Lys Leu Lys Glu
320 325 330Gln Phe Pro Asn Lys Thr Ile Val Phe Asn His Ser Ser Gly Gly
335 340 345Asp Pro Glu Ile Val Met His Ser Phe Asn Cys Gln Gly Glu Phe
350 355 360Phe Tyr Cys Asn Thr Thr Lys Leu Phe Asn Ser Thr Trp Asn Asp
365 370 375Thr Thr Glu Ser Asn Asn Asn Asp Ser Thr Ile Thr Leu Pro Cys
380 385 390Arg Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Lys Ala
395 400 405Met Tyr Ala Pro Pro Ile Arg Gly Glu Ile Lys Cys Ser Ser Asn
410 415 420Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly Ile Asn Thr Ser
425 430 435Asp Ala Thr Glu Thr Phe Arg Pro Gly Gly Gly Asp Met Arg Asp
440 445 450Asn Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile Glu
455 460 465Pro Leu Gly Val Ala Pro Thr Lys Ala Lys Arg Arg Val Val Gln
470 475 480Arg Glu Lys Arg Ala Val Thr Leu Gly Ala Met Phe Leu Gly Phe
485 490 495Leu Gly Ala Xaa Ser Phe
500 501(2)SEQ ID NO:5的信息：
(ⅰ)序列特征：
(A)长度：1461个碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:5:G GTA CCT GTA TGG AAA GAA GCA ACC ACC ACT CTA TTT 37
Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu Phe
1 5 10TGT GCA TCA GAT GCT AAA GCA TAT GAT ACA GAG GTA CAT 76Cys Ala Ser Asp Ala Lys Ala Tyr Asp Thr Glu Val His
15 20 25AAT GTT TGG GCT ACA CAT GCC TGT GTA CCC ACA GAC CCC 115Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro
30 35AAC CCA CAA GAA GTA GTA TTG GAA AAT GTA ACA GAA AAT 154Asn Pro Gln Glu Val Val Leu Glu Asn Val Thr Glu Asn
40 45 50TTT AAC ATG TGG AAA AAT AAC ATG GTA GAA CAG ATG CAT 193Phe Asn Met Trp Lys Asn Asn Met Val Glu Gln Met His
55 60GAG GAT ATA ATC AGT TTA TGG GAT CAA AGT CTA AAG CCA 232Glu Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu Lys Pro65 70 75TGT GTA AAA TTA ACC CCA CTC TGT GTT ACT TTA AAT TGC 271Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Asn Cys
80 85 90ACT AAT TTG GAG AAT GCT AAT AAT ACC GAG AAT GCT AAT 310Thr Asn Leu Glu Asn Ala Asn Asn Thr Glu Asn Ala Asn
95 100AAT ACC AAT AAT TAT ACC TTG GGG ATG GAG AGA GGT GAA 349Asn Thr Asn Asn Tyr Thr Leu Gly Met Glu Arg Gly Glu
105 110 115ATA AAA AAC TGC TCT TTC AAT ATC ACC ACA AGC TTA AGA 388Ile Lys Asn Cys Ser Phe Asn Ile Thr Thr Ser Leu Arg
120 125GAT AAG GTG AAA AAA GAA TAT GCA TTG TTT TAT AAA CTT 427Asp Lys Val Lys Lys Glu Tyr Ala Leu Phe Tyr Lys Leu130 135 140GAT GTA GTA CAA ATA GAT AAT AGT ACC AAC TAT AGG CTG 466Asp Val Val Gln Ile Asp Asn Ser Thr Asn Tyr Arg Leu
145 150 155ATA AGT TGT AAT ACC TCA GTC ATT ACA CAG GCC TGT CCA 505Ile Ser Cys Asn Thr Ser Val Ile Thr Gln Ala Cys Pro
160 165AAG GTA TCC TTT GAG CTA ATT CCC ATA CAT TAT TGT GCC 544Lys Val Ser Phe Glu Leu Ile Pro Ile His Tyr Cys Ala
170 175 180CCG GCT GGT TTT GCG ATT CTA AAG TGT AAA GAT AAG AAG 583Pro Ala Gly Phe Ala Ile Leu Lys Cys Lys Asp Lys Lys
185 190TTC AAT GGA ACA GGA CCA TGT AAA AAT GTC AGC ACA GTA 622Phe Asn Gly Thr Gly Pro Cys Lys Asn Val Ser Thr Val195 200 205CAA TGT ACA CAT GGA ATT AGA CCA GTA GTA TCA ACT CAA 661Gln Cys Thr His Gly Ile Arg Pro Val Val Ser Thr Gln
210 215 220CTA CTG TTA AAT GGC AGT CTA GCA GAA GAA GAG ATA GTA 700Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Ile Val
225 230ATT AGA TCT GAA AAT ATC ACA GAC AAT GCT AAA ACC ATA 739Ile Arg Ser Glu Asn Ile Thr Asp Asn Ala Lys Thr Ile
235 240 245ATA GTG CAG CTA AAT GAA TCT ATA GTG ATT AAT TGT ACA 778Ile Val Gln Leu Asn Glu Ser Ile Val Ile Asn Cys Thr
250 255AGA CCC AAT AAC AAC ACA AGA AAA AGT ATA AAT ATA GGA 817Arg Pro Asn Asn Asn Thr Arg Lys Ser Ile Asn Ile Gly260 265 270CCA GGG AGA GCA TTC TAT ACA ACA GGA GAC ATA ATA GGA 856Pro Gly Arg Ala Phe Tyr Thr Thr Gly Asp Ile Ile Gly
275 280 285GAT ATA AGA CAA GCA CAT TGT AAC CTT AGT AAA ACA CAA 895Asp Ile Arg Gln Ala His Cys Asn Leu Ser Lys Thr Gln
290 295TGG GAA AAA ACG TTA AGA CAG ATA GCT ATA AAA TTA GAA 934Trp Glu Lys Thr Leu Arg Gln Ile Ala Ile Lys Leu Glu
300 305 310GAA AAA TTT AAG AAT AAA ACA ATA GCC TTT AAT AAA TCC 973Glu Lys Phe Lys Asn Lys Thr Ile Ala Phe Asn Lys Ser
315 320TCA GGA GGG GAC CCA GAA ATT GTA ATG CAC AGT TTT AAT 1012Ser Gly Gly Asp Pro Glu Ile Val Met His Ser Phe Asn325 330 335TGT GGA GGG GAA TTT TTC TAC TGT AAT ACA ACA AAA CTG 1051Cys Gly Gly Glu Phe Phe Tyr Cys Asn Thr Thr Lys Leu
340 345 350TTT AAT AGT ACC TGG AAT TTA ACA CAA CCG TTT AGT AAT 1090Phe Asn Ser Thr Trp Asn Leu Thr Gln Pro Phe Ser Asn
355 360ACC GGG AAT CGT ACT GAA GAG TTA AAT ATT ACA CTC CCA 1129Thr Gly Asn Arg Thr Glu Glu Leu Asn Ile Thr Leu Pro
365 370 375TGC AGA ATA AAA CAA ATC ATA AAC TTG TGG CAG GAA GTA 1168Cys Arg Ile Lys Gln Ile Ile Asn Leu Trp Gln Glu Val
380 385GGC AAA GCA ATG TAT GCC CCT CCC ATC AGA GGA CAA ATT 1207Gly Lys Ala Met Tyr Ala Pro Pro Ile Arg Gly Gln Ile390 395 400AGA TGT TCA TCA AAT ATT ACA GGG CTA CTA TTA ACA AGA 1246Arg Cys Ser Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg
405 410 415GAT GGT GGA AGT AAC ACC GGT GAC AAC AGG ACT GAG ACC 1285Asp Gly Gly Ser Asn Thr Gly Asp Asn Arg Thr Glu Thr
420 425TTT AGA CCT GGA GGA GGA GAT ATG AGG GAC AAT TGG AGA 1324Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp Arg
430 435 440AGT GAA TTA TAT AAA TAT AAA GTA GTA AGA ATT GAA CCA 1363Ser Glu Leu Tyr Lys Tyr Lys Val Val Arg Ile Glu Pro
445 450TTA GGA GTA GCA CCC ACC CAG GCA AAG AGA AGA GTG GTG 1402Leu Gly Val Ala Pro Thr Gln Ala Lys Arg Arg Val Val45 460 465CAA AGA GAA AAA AGA GCA GTG GGG ATA GGA GCT ATG TTC 1441Gln Arg Glu Lys Arg Ala Val Gly Ile Gly Ala Met Phe
470 475 480CTT GGG TTC TTG GGA GAT AA 1461Leu Gly Phe Leu Gly Asp
485 486(2)SEQ ID NO:6的信息：
(ⅰ)序列特征：
(A)长度：486个氨基酸
(B)类型：氨基酸
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:6:Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu Phe Cys Ala Ser1 5 10 15Asp Ala Lys Ala Tyr Asp Thr Glu Val His Asn Val Trp Ala Thr
20 25 30His Ala Cys Val Pro Thr Asp Pro Asn Pro Gln Glu Val Val Leu
35 40 45Glu Asn Val Thr Glu Asn Phe Asn Met Trp Lys Asn Asn Met Val
50 55 60Glu Gln Met His Glu Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu
65 70 75Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Asn Cys
80 85 90Thr Asn Leu Glu Asn Ala Asn Asn Thr Glu Asn Ala Asn Asn Thr
95 100 105Asn Asn Tyr Thr Leu Gly Met Glu Arg Gly Glu Ile Lys Asn Cys
110 115 120Ser Phe Asn Ile Thr Thr Ser Leu Arg Asp Lys Val Lys Lys Glu
125 130 135Tyr Ala Leu Phe Tyr Lys Leu Asp Val Val Gln Ile Asp Asn Ser
140 145 150Thr Asn Tyr Arg Leu Ile Ser Cys Asn Thr Ser Val Ile Thr Gln
155 160 165Ala Cys Pro Lys Val Ser Phe Glu Leu Ile Pro Ile His Tyr Cys
170 175 180Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys Lys Asp Lys Lys Phe
185 190 195Asn Gly Thr Gly Pro Cys Lys Asn Val Ser Thr Val Gln Cys Thr
200 205 210His Gly Ile Arg Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly
215 220 225Ser Leu Ala Clu Glu Glu Ile Val Ile Arg Ser Glu Asn Ile Thr
230 235 240Asp Asn Ala Lys Thr Ile Ile Val Gln Leu Asn Glu Ser Ile Val
245 250 255Ile Asn Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys Ser Ile Asn
260 265 270Ile Gly Pro Gly Arg Ala Phe Tyr Thr Thr Gly Asp Ile Ile Gly
275 280 285Asp Ile Arg Gln Ala His Cys Asn Leu Ser Lys Thr Gln Trp Glu
290 295 300Lys Thr Leu Arg Gln Ile Ala Ile Lys Leu Glu Glu Lys Phe Lys
305 310 315Asn Lys Thr Ile Ala Phe Asn Lys Ser Ser Gly Gly Asp Pro Glu
320 325 330Ile Val Met His Ser Phe Asn Cys Gly Gly Glu Phe Phe Tyr Cys
335 340 345Asn Thr Thr Lys Leu Phe Asn Ser Thr Trp Asn Leu Thr Gln Pro
350 355 360Phe Ser Asn Thr Gly Asn Arg Thr Glu Glu Leu Asn Ile Thr Leu
365 370 375Pro Cys Arg Ile Lys Gln Ile lle Asn Leu Trp Gln Glu Val Gly
380 385 390Lys Ala Met Tyr Ala Pro Pro Ile Arg Gly Gln Ile Arg Cys Ser
395 400 405Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly Ser Asn
410 415 420Thr Gly Asp Asn Arg Thr Glu Thr Phe Arg Pro Gly Gly Gly Asp
425 430 435Met Arg Asp Asn Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val
440 445 450Arg Ile Glu Pro Leu Gly Val Ala Pro Thr Gln Ala Lys Arg Arg
455 460 465Val Val Gln Arg Glu Lys Arg Ala Val Gly Ile Gly Ala Met Phe
470 475 480Leu Gly Phe Leu Gly Asp
485 486(2)SEQ ID NO:7的信息：
(ⅰ)序列特征：
(A)长度：1474个碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:7G GTA CCT GTG TGG AAA GAA GCA ACC ACC ACT CTA TTT 37
Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu Phe
1 5 10TGT GCA TCA GAT GCT AAA GCA TAT GAT ACA GAG GTA CAT 76Cys Ala Ser Asp Ala Lys Ala Tyr Asp Thr Glu Val His
15 20 25AAT GTT TGG GCT ACA CAT GCC TGT GTA CCC ACA GAC CCC 115Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro
30 35AAC CCA CAA GAA GTA GTA TTG GAA AAT GTA ACA GAA AAT 154Asn Pro Gln Glu Val Val Leu Glu Asn Val Thr Glu Asn
40 45 50TTT AAC ATG TGG AAA AAT AAC ATG GTA GAA CAG ATG CAT 193Phe Asn Met Trp Lys Asn Asn Met Val Glu Gln Met His
55 60GAG GAT ATA ATC AGT TTA TGG GAT CAA AGT CTA AAG CCA 232Glu Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu Lys Pro65 70 75TGT GTA AAA TTA ACC CCA CTC TGT GTT ACT TTA AAT TGC 271Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Asn Cys
80 85 90ACT AAT TTG GAG AAT GCT AAT AAT ACC GAG AAT GCT AAT 310Thr Asn Leu Glu Asn Ala Asn Asn Thr Glu Asn Ala Asn
95 100AAT ACC AAT AAT TAT ACC TTG GGG ATG GAG AGA GGT GAA 349Asn Thr Asn Asn Tyr Thr Leu Gly Met Glu Arg Gly Glu
105 110 115AGA AAA AAC TGC TCT TTC AAT ATC ACC ACA AGC TTA AGA 388Arg Lys Asn Cys Ser Phe Asn Ile Thr Thr Ser Leu Arg
120 125GAT AAG GGG AAA AAA GAA TAT GCA TTG TTT TAT AAA CTT 427Asp Lys Gly Lys Lys Glu Tyr Ala Leu Phe Tyr Lys Leu130 135 140GAT GTA GTA CAA ATA GAT AAT AGT ACC AAC TAT AGG CTG 466Asp Val Val Gln Ile Asp Asn Ser Thr Asn Tyr Arg Leu
145 150 155ATA AGT TGT AAT ACC TCA GTC ATT ACA CAG GCC TGT CCA 505Ile Ser Cys Asn Thr Ser Val Ile Thr Gln Ala Cys Pro
160 165AAG GTA TCC TTT GAG CCA ATT CCC ATA CAT TAT TGT GCC 544Lys Val Ser Phe Glu Pro Ile Pro Ile His Tyr Cys Ala
170 175 180CCG GCT GGT TTT GCG ATT CTA AAG TGT AAA GAT AAG AAG 583Pro Ala Gly Phe Ala Ile Leu Lys Cys Lys Asp Lys Lys
185 190TTC AAT GGA ACA GGA CCA TGT AAA AAT GTC AGG ACA GTA 622Phe Asn Gly Thr Gly Pro Cys Lys Asn Val Arg Thr Val195 200 205CAA TGT ACA CAT GGA ATT AGA CCA GTA GTA TCA ACT CAA 661Gln Cys Thr His Gly Ile Arg Pro Val Val Ser Thr Gln
210 215 220CTA CTG TTA AAT GGC AGT CTA GCA GAA GAA GAG ATA GTA 700Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Ile Val
225 230ATT AGA TCT GAA AAT ATC ACA GAC AAT GCT AAA ACC ATA 739Ile Arg Ser Glu Asn Ile Thr Asp Asn Ala Lys Thr Ile
235 240 245ATA GTG CAG CTA AAT GAA TCT ATA GTG ATT AAT TGT ACA 778Ile Val Gln Leu Asn Glu Ser Ile Val Ile Asn Cys Thr
250 255AGA CCC AAT AAC AAC ACA AGA AAA AGT ATA AAT ATA GGA 817Arg Pro Asn Asn Asn Thr Arg Lys Ser Ile Asn Ile Gly260 265 270CCA GGG AGA GCA TTC TAT ACA ACA GGA GAC ATA ATA GGA 856Pro Gly Arg Ala Phe Tyr Thr Thr Gly Asp Ile Ile Gly
275 280 285GAT ATA AGA CAA GCA CAT TGT AAC CTT AGT AAA ACA CAA 895Asp Ile Arg Gln Ala His Cys Asn Leu Ser Lys Thr Gln
290 295TGG GAA AAA ACG TTA AGA CAG ATA GCT ATA AAA TTA GAA 934Trp Glu Lys Thr Leu Arg Gln Ile Ala Ile Lys Leu Glu
300 305 310GAA AAA TTT AAG AAT AAA ACA ATA GCC TTT AAT AAA TCC 973Glu Lys Phe Lys Asn Lys Thr Ile Ala Phe Asn Lys Ser
315 320TCA GGA GGG GAC CCA GAA ATT GTA ATG CAC AGT TTT AAT 1012Ser Gly Gly Asp Pro Glu Ile Val Met His Ser Phe Asn325 330 335TGT GGA GGG GGA TTT TTC TAC TGT AGT ACG AGA AAA CTG 1051Cys Gly Gly Gly Phe Phe Tyr Cys Ser Thr Arg Lys Leu
340 345 350TTT AAT AGT ACC TGG AAT TTA ACA CAA CCG TTT AGT AAT 1090Phe Asn Ser Thr Trp Asn Leu Thr Gln Pro Phe Ser Asn
355 360ACC GGG GAT CGT ACT GAA GAG TTA AAT ATT ACA CTC CCA 1129Thr Gly Asp Arg Thr Glu Glu Leu Asn Ile Thr Leu Pro
365 370 375TGC AGA ATA AAA CAA ATC ATA AAC TTG TGG CAG GAA GTA 1168Cys Arg Ile Lys Gln Ile Ile Asn Leu Trp Gln Glu Val
380 385GGC AAA GCA ATG TAT GCC CCT CCC ATC AGA GGA CAA ATT 1207Gly Lys Ala Met Tyr Ala Pro Pro Ile Arg Gly Gln Ile390 395 400AGA TGT TCA TCA AAT ATT ACA GGG CTA CTA TTA AGG AGA 1246Arg Cys Ser Ser Asn Ile Thr Gly Leu Leu Leu Arg Arg
405 410 415GAT GGT GGA AGT AAC ACC AGT GAC AAC CAG ACT GAG ACC 1285Asp Gly Gly Ser Asn Thr Ser Asp Asn Gln Thr Glu Thr
420 425TTT AGA CCT GGG GGA GGA GAT ATG AGG GAC AAG TGG AGA 1324Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Lys Trp Arg
430 435 440AGT GAA TTA TAT AAA TAT AAA GTA GTA AGA ATT GAA CCA 1363Ser Glu Leu Tyr Lys Tyr Lys Val Val Arg Ile Glu Pro
445 450TTA GGA GTA GCA CCC ACC CAG GCA AAG AGA AGA GTG GTG 1402Leu Gly Val Ala Pro Thr Gln Ala Lys Arg Arg Val Val455 460 465CAA AGA GAA AAA AGA GCA GTG GGG ATA GGA GCT ATG TTC 1441Gln Arg Glu Lys Arg Ala Val Gly Ile Gly Ala Met Phe
470 475 480CTT AGG TTC TTA GGA GAT AAA GCT TCT AGA GTC 1474Leu Arg Phe Leu Gly Asp Lys Ala Ser Arg Val
485 490 491(2)SEQ ID NO:8的信息：
(ⅰ)序列特征：
(A)长度：491个氨基酸
(B)类型：氨基酸
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:8:Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu Phe Cys Ala Ser1 5 10 15Asp Ala Lys Ala Tyr Asp Thr Glu Val His Asn Val Trp Ala Thr
20 25 30His Ala Cys Val Pro Thr Asp Pro Asn Pro Gln Glu Val Val Leu
35 40 45Glu Asn Val Thr Glu Asn Phe Asn Met Trp Ly5 Asn Asn Met Val
50 55 60Glu Gln Met His Glu Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu
65 70 75Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Asn Cys
80 85 90Thr Asn Leu Glu Asn Ala Asn Asn Thr Glu Asn Ala Asn Asn Thr
95 100 105Asn Asn Tyr Thr Leu Gly Met Glu Arg Gly Glu Arg Lys Asn Cys
110 115 120Ser Phe Asn Ile Thr Thr Ser Leu Arg Asp Lys Gly Lys Lys Glu
125 130 135Tyr Ala Leu Phe Tyr Lys Leu Asp Val Val Gln lle Asp Asn Ser
140 145 150Thr Asn Tyr Arg Leu Ile Ser Cys Asn Thr Ser Val Ile Thr Gln
155 160 165Ala Cys Pro Lys Val Ser Phe Glu Pro Ile Pro Ile His Tyr Cys
170 175 180Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys Lys Asp Lys Lys Phe
185 190 195Asn Gly Thr Gly Pro Cys Lys Asn Val Arg Thr Val Gln Cys Thr
200 205 210His Gly Ile Ar9 Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly
215 220 225Ser Leu Ala Glu Glu Glu Ile Val Ile Arg Ser Glu Asn Ile Thr
230 235 240Asp Asn Ala Lys Thr Ile Ile Val Gln Leu Asn Glu Ser Ile Val
245 250 255Ile Asn Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys Ser Ile Asn
260 265 270Ile Gly Pro Gly Arg Ala Phe Tyr Thr Thr Gly Asp Ile Ile Gly
275 280 285Asp Ile Arg Gln Ala His Cys Asn Leu Ser Lys Thr Gln Trp Glu
290 295 300Lys Thr Leu Arg Gln Ile Ala Ile Lys Leu Glu Glu Lys Phe Lys
305 310 315Asn Lys Thr Ile Ala Phe Asn Lys Ser Ser Gly Gly Asp Pro Glu
320 325 330Ile Val Met His Ser Phe Asn Cys Gly Gly Gly Phe Phe Tyr Cys
335 340 345Ser Thr Arg Lys Leu Phe Asn Ser Thr Trp Asn Leu Thr Gln Pro
350 355 360Phe Ser Asn Thr Gly Asp Arg Thr Glu Glu Leu Asn Ile Thr Leu
365 370 375Pro Cys Arg Ile Lys Gln Ile Ile Asn Leu Trp Gln Glu Val Gly
380 385 390Lys Ala Met Tyr Ala Pro Pro Ile Ar9 Gly Gln Ile Arg Cys Ser
395 400 405Ser Asn Ile Thr Gly Leu Leu Leu Arg Arg Asp Gly Gly Ser Asn
410 415 420Thr Ser Asp Asn Gln Thr Glu Thr Phe Arg Pro Gly Gly Gly Asp
425 430 435Met Arg Asp Lys Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val
440 445 450Arg Ile Glu Pro Leu Gly Val Ala Pro Thr Gln Ala Lys Arg Arg
455 460 465Val Val Gln Arg Glu Lys Arg Ala Val Gly Ile Gly Ala Met Phe
470 475 480Leu Arg Phe Leu Gly Asp Lys Ala Ser Arg Val
485 490 491(2)SEQ ID NO:9的信息：
(ⅰ)序列特征：
(A)长度：1512个碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:9:
CTC GAG GTA CCT GTA TGG AAA GAA GCA ACT ACC ACT 36
Leu Glu Val Pro Val Trp Lys Glu Ala Thr Thr Thr
1 5 10CTA TTT TGT GCA TCA GAT GCT AAA GCA TAT AAT ACA GAG 75Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asn Thr Glu
15 20 25AAA CAT AAT GTT TGG GCC ACA CAC GCC TGT GTA CCC ACA 114Lys His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr
30 35GAT CCC AAC CCA CAA GAA GTA GTA TTG GGA AAT GTG ACA 153Asp Pro Asn Pro Gln Glu Val Val Leu Gly Asn Val Thr
40 45 50GAA AAT TTT AAC ATG TGG AAA AAT AAC ATG GTA GAA CAA 192Glu Asn Phe Asn Met Trp Lys Asn Asn Met Val Glu Gln
55 60ATG CAT GAA GAT ATA ATC AGT TTA TGG GAT CAA AGT CTA 231Met His Glu Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu65 70 75AAG CCA TGT GTA AAA TTA ACC CCA CTC TGT GTT ACT TTA 270Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
80 85 90AAT TGC ACT GAT GAT TTA GGG AAT GCT ACT AAT ACC AAT 309Asn Cys Thr Asp Asp Leu Gly Asn Ala Thr Asn Thr Asn
95 100AGT AGT GCC ACT ACC AAT AGT AGT AGT TGG GAA GAA ATG 348Ser Ser Ala Thr Thr Asn Ser Ser Ser Trp Glu Glu Met
105 110 115AAG GGG GAA ATG AAA AGA TGC TCT TTC AAT ATC ACC ACA 387Lys Gly Glu Met Lys Arg Cy5 Ser Phe Asn Ile Thr Thr
120 125AGC ATA AGA GAT AAG ATT AAG AAA GAA CAT GCA CTT TTC 426Ser Ile Arg Asp Lys Ile Lys Lys Glu His Ala Leu Phe130 135 140TAT AGA CTT GAT GTA GTA CCA ATA GAT AAT GAT AAT ACC 465Tyr Arg Leu Asp Val Val Pro Ile Asp Asn Asp Asn Thr
145 150 155ACA TAT AGG TTG ATA AAT TGT AAT ACC TCA GTC ATT ACA 504Thr Tyr Arg Leu Ile Asn Cys Asn Thr Ser Val Ile Thr
160 165CAG GCC TGT CCA AAG GTA TCA TTT GAG CCA ATT CCC ATA 543Gln Ala Cys Pro Lys Val Ser Phe Glu Pro Ile Pro Ile
170 175 180CAT TTT TGT GCC CCG GCT GGT TTT GCG ATT CTA AAG TGT 582His Phe Cys Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys
185 190AAT AAT AAG ACG TTC GAG GGA AAA GGA CCA TGT AAA AAT 621Asn Asn Lys Thr Phe Glu Gly Lys Gly Pro Cys Lys Asn195 200 205GTC AGT ACA GTA CAA TGC ACA CAT GGA ATT AGG CCA GTA 660Val Ser Thr Val Gln Cys Thr His Gly Ile Arg Pro Val
210 215 220GTG TCA ACT CAA CTG CTG TTA AAT GGC AGT CTA GCA GAA 699Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu
225 230GAA GAG GTA ATA ATT AGA TCT GAC AAT ATC ACA GAC AAT 738Glu Glu Val Ile Ile Arg Ser Asp Asn Ile Thr Asp Asn
235 240 245ACT AAA ACC ATT ATA GTA CAG CTA AAC GAA TCT GTA GTA 777Thr Lys Thr Ile Ile Val Gln Leu Asn Glu Ser Val Val
250 255ATT AAT TGT ACA AGA CCC AAC AAC AAT ACA AGA AAA AGT 816Ile Asn Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys Ser260 265 270ATA CAT ATA GGA CCA GGG AGT GCA TTT TTT GCA ACA GGA 855Ile His Ile Gly Pro Gly Ser Ala Phe Phe Ala Thr Gly
275 280 285GAA ATA ATA GGA GAT ATA AGA CAA GCA CAC TGT AAC CTT 894Glu Ile Ile Gly Asp Ile Arg Gln Ala His Cys Asn Leu
290 295AGT AGA ACA CAA TGG AAT AAC ACT TTA GGA AAG ATA GTC 933Ser Arg Thr Gln Trp Asn Asn Thr Leu Gly Lys Ile Val
300 305 310ATA AAA TTA AGA GAA CAA TTT AGA AAA CAA TTT GGA GAA 972Ile Lys Leu Arg Glu Gln Phe Arg Lys Gln Phe Gly Glu
315 320AAA ACA ATA GTC TTT AAT CGA TCC TCA GGA GGG GAC CCG 1011Lys Thr Ile Val Phe Asn Arg Ser Ser Gly Gly Asp Pro325 330 335GAA ATT GCA ATG CAC AGT TTT AAT TGT GGA GGG GAA TTT 1050Glu Ile Ala Met His Ser Phe Asn Cys Gly Gly Glu Phe
340 345 350TTC TAC TGT AAC ACA ACA GCA CTG TTT AAT AGT ACC TGG 1089Phe Tyr Cys Asn Thr Thr Ala Leu Phe Asn Ser Thr Trp
355 360AAT GTT ACT AAA GGG TTG AAT AAC ACT GAA GGA AAT AGC 1128Asn Val Thr Lys Gly Leu Asn Asn Thr Glu Gly Asn Ser
365 370 375ACA GGA GAT GAA AAT ATC ATA CTC CCA TGT AGA ATA AAA 1167Thr Gly Asp Glu Asn Ile Ile Leu Pro Cys Arg Ile Lys
380 385CAA ATT ATA AAC ATG TGG CAG GAA GTA GGA AAA GCA ATG 1206Gln Ile Ile Asn Met Trp Gln Glu Val Gly Lys Ala Met390 395 400TAT GCC CCT CCC ATC AGT GGA CAA ATT AGA TGT TCA TCA 1245Tyr Ala Pro Pro Ile Ser Gly Gln Ile Arg Cys Ser Ser
405 410 415AAC ATT ACA GGG CTG CTA CTA ACA AGA GAT GGT GGT AGT 1284Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly Ser
420 425AAG AAC GAG AGC ATC ACC ACC GAG GTC TTC AGA CCT GGA 1323Lys Asn Glu Ser Ile Thr Thr Glu Val Phe Ar9 Pro Gly
430 435 440GGA GGA GAT ATG AGG GAC AAT TGG AGA AGT GAA TTA TAT 1362Gly Gly Asp Met Arg Asp Asn Trp Arg Ser Glu Leu Tyr
445 450AAA TAT AAA GTA GTA AAA ATT GAA CCA TTA GGA GTA GCG 1401Lys Tyr Lys Val Val Lys Ile Glu Pro Leu Gly Val Ala455 460 465CCC ACC AAG GCA AAG AGA AGA GTG GTG CAG AGA GAA AAA 1440Pro Thr Lys Ala Lys Arg Arg Val Val Gln Arg Glu Lys
470 475 480AGA GCA GTG GGA ACA ATA GGA GCT ATG TTC CTT GGG TTC 1479Arg Ala Val Gly Thr Ile Gly Ala Met Phe Leu Gly Phe
485 490TTG GGA GCA TAA AGC TTC TAG AGT CGA CCT GCA 1512Leu Gly Ala Xaa Ser Phe Xaa Ser Arg Pro Ala
495 500 504(2)SEQ ID NO:10的信息：
(ⅰ)序列特征：
(A)长度：504个氨基酸
(B)类型：氨基酸
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:10:Leu Glu Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu Phe Cys1 5 10 15Ala Ser Asp Ala Lys Ala Tyr Asn Thr Glu Lys His Asn Val Trp
20 25 30Ala Thr His Ala Cys Val Pro Thr Asp Pro Asn Pro Gln Glu Val
35 40 45Val Leu Gly Asn Val Thr Glu Asn Phe Asn Met Trp Lys Asn Asn
50 55 60Met Val Glu Gln Met His Glu Asp Ile Ile Ser Leu Trp Asp Gln
65 70 75Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
80 85 90Asn Cys Thr Asp Asp Leu Gly Asn Ala Thr Asn Thr Asn Ser Ser
95 100 105Ala Thr Thr Asn Ser Ser Ser Trp Glu Glu Met Lys Gly Glu Met
110 115 120Lys Arg Cys Ser Phe Asn Ile Thr Thr Ser Ile Arg Asp Lys Ile
125 130 135Lys Lys Glu His Ala Leu Phe Tyr Arg Leu Asp Val Val Pro Ile
140 145 150Asp Asn Asp Asn Thr Thr Tyr Arg Leu Ile Asn Cys Asn Thr Ser
155 160 165Val Ile Thr Gln Ala Cys Pro Lys Val Ser Phe Glu Pro Ile Pro
170 175 180Ile His Phe Cys Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys Asn
185 190 195Asn Lys Thr Phe Glu Gly Lys Gly Pro Cys Lys Asn Val Ser Thr
200 205 210Val Gln Cys Thr His Gly Ile Arg Pro Val Val Ser Thr Gln Leu
215 220 225Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Val Ile Ile Arg Ser
230 235 240Asp Asn Ile Thr Asp Asn Thr Lys Thr Ile Ile Val Gln Leu Asn
245 250 255Glu Ser Val Val Ile Asn Cys Thr Arg Pro Asn Asn Asn Thr Arg
260 265 270Lys Ser Ile His Ile Gly Pro Gly Ser Ala Phe Phe Ala Thr Gly
275 280 285Glu Ile Ile Gly Asp Ile Arg Gln Ala His Cys Asn Leu Ser Arg
290 295 300Thr Gln Trp Asn Asn Thr Leu Gly Lys Ile Val Ile Lys Leu Arg
305 310 315Glu Gln Phe Arg Lys Gln Phe Gly Glu Lys Thr Ile Val Phe Asn
320 325 330Arg Ser Ser Gly Gly Asp Pro Glu Ile Ala Met His Ser Phe Asn
335 340 345Cys Gly Gly Glu Phe Phe Tyr Cys Asn Thr Thr Ala Leu Phe Asn
350 355 360Ser Thr Trp Asn Val Thr Lys Gly Leu Asn Asn Thr Glu Gly Asn
365 370 375Ser Thr Gly Asp Glu Asn Ile Ile Leu Pro Cys Arg Ile Lys Gln
380 385 390Ile Ile Asn Met Trp Gln Glu Val Gly Lys Ala Met Tyr Ala Pro
395 400 405Pro Ile Ser Gly Gln Ile Arg Cys Ser Ser Asn Ile Thr Gly Leu
410 415 420Leu Leu Thr Arg Asp Gly Gly Ser Lys Asn Glu Ser Ile Thr Thr
425 430 435Glu Val Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp Arg
440 445 450Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile Glu Pro Leu Gly
455 460 465Val Ala Pro Thr Lys Ala Lys Arg Arg Val Val Gln Arg Glu Lys
470 475 480Arg Ala Val Gly Thr Ile Gly Ala Met Phe Leu Gly Phe Leu Gly
485 490 495Ala Xaa Ser Phe Xaa Ser Arg Pro Ala
500 504(2)SEQ ID NO:11的信息：
(ⅰ)序列特征：
(A)长度：1501个碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQIDNO:11:
CTC GAG GTA CCT GTG TGG AAA GAA GCA ACT ACC ACT 36
Leu Glu Val Pro Val Trp Lys Glu Ala Thr Thr Thr
1 5 10CTA TTT TGT GCA TCA GAT GCT AAA GCA TAT AAT ACA GAG 75Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asn Thr Glu
15 20 25AAA CAT AAT GTT TGG GCC ACA CAC GCC TGT GTA CCC ACA 114Lys His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr
30 35GAT CCC AAC CCA CAA GAA GTA GTA TTG GGA AAT GTG ACA 153Asp Pro Asn Pro Gln Glu Val Val Leu Gly Asn Val Thr
40 45 50GAA AAT TTT AAC ATG TGG AAA AAT AAC ATG GTA GAA CAA 192Glu Asn Phe Asn Met Trp Lys Asn Asn Met Val Glu Gln
55 60ATG CAT GAA GAT ATA ATC AGT TTA TGG GAT CAA AGT CTA 231Met His Glu Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu65 70 75AAG CCA TGT GTA AAA TTA ACC CCA CTC TGT GTT ACT TTA 270Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
80 85 90AAT TGC ACT GAT GAT TTA GGG AAT GCT ACT AAT ACC AAT 309Asn Cys Thr Asp Asp Leu Gly Asn Ala Thr Asn Thr Asn
95 100AGC AGT GCC ACT ACC AAT AGT AGT AGT TGG GAA GAA ATG 348Ser Ser Ala Thr Thr Asn Ser Ser Ser Trp Glu Glu Met
105 110 115AAG GGG GAA ATG AAA AGG TGC TCT TTC AAT ATC ACC ACA 387Lys Gly Glu Met Lys Arg Cys Ser Phe Asn Ile Thr Thr
120 125AGC ATA AGA GAT AAG ATT AAG AAA GAA CAT GCA CTT TTC 426Ser Ile Arg Asp Lys Ile Lys Lys Glu His Ala Leu Phe130 135 140TAT AGA CTT GAT GTA GTA CCA ATA GAT AAT GAT AAT ACC 465Tyr Arg Leu Asp Val Val Pro Ile Asp Asn Asp Asn Thr
145 150 155ACA TAT AGG TTG ATA AAT TGT AAT ACC TCA GTC ATT ACA 504Thr Tyr Arg Leu Ile Asn Cys Asn Thr Ser Val Ile Thr
160 165CAG GCC TGT CCA AAG GTA TCA TTT GAG CCA ATT CCC ATA 543Gln Ala Cys Pro Lys Val Ser Phe Glu Pro Ile Pro Ile
170 175 180CAT TTT TGT GCC CCG GCT GGT TTT GCG ATT CTA AAG TGT 582His Phe Cys Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys
185 190AAT AAT AAG ACG TTC GAG GGA AAA GGA CCA TGT AAA AAT 621Asn Asn Lys Thr Phe Glu Gly Lys Gly Pro Cys Lys Asn195 200 205GTC AGT ACA GTA CAA TGC ACA CAT GGA ATT AGG CCA GTA 650Val Ser Thr Val Gln Cys Thr His Gly Ile Arg Pro Val
210 215 220GTG TCA ACT CAA CTG CTG TTA AAT GGC AGT CTA GCA GAA 699Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu
225 230GAA GAG GTA ATA ATT AGA TCT GGC AAT ATC ACA GAC AAT 738Glu Glu Val Ile Ile Arg Ser Gly Asn Ile Thr Asp Asn
235 240 245ACT AAA ACC ATT ATA GTA CAG CTA AAC GAA TCT GTA GTA 777Thr Lys Thr Ile Ile Val Gln Leu Asn Glu Ser Val Val
250 255ATT AAT TGT ACA AGA TCC AAC AAC AAT ACA AGA AAA AGT 816Ile Asn Cys Thr Arg Ser Asn Asn Asn Thr Arg Lys Ser260 265 270ATA CAT ATA GGA CCA GGG AGT GCA TTT TTT GCA ACA GGA 855Ile His Ile Gly Pro Gly Ser Ala Phe Phe Ala Thr Gly
275 280 285GAA ATA ATA GGA GAT ATA AGA CAA GCA CAC TGT AAC CTT 894Glu Ile Ile Gly Asp Ile Arg Gln Ala His Cys Asn Leu
290 295AGT AGA ACA CAA TGG AAT AAC ACT TTA GGA AAG ATA GTC 933Ser Arg Thr Gln Trp Asn Asn Thr Leu Gly Lys Ile Val
300 305 310ATA AAA TTA AGA GAA CAA TTT AGA AAA CAA TTT GGA GAA 972Ile Lys Leu Arg Glu Gln Phe Arg Lys Gln Phe Gly Glu
315 320AAA ACA ATA GTC TTT AAT CGA TCC TCA GGA GGG GAC CCG 1011Lys Thr Ile Val Phe Asn Arg Ser Ser Gly Gly Asp Pro325 330 335GAA ATT GCA ATG CAC AGT TTT AAT TGT GGA GGG GAA TTT 1050Glu Ile Ala Met His Ser Phe Asn Cys Gly Gly Glu Phe
340 345 350TTC TAC TGT AAC ACA ACA GCA CTG TTT AAT AGT ACC TGG 1089Phe Tyr Cys Asn Thr Thr Ala Leu Phe Asn Ser Thr Trp
355 360AAT GTT ACT AAA GGG TTG AAT AAC ACT GAA GGA AAT AGC 1128Asn Val Thr Lys Gly Leu Asn Asn Thr Glu Gly Asn Ser
365 370 375ACA GGG GAT GAA AAT ATC ATA CTC CCA TGT AGA ATA AAA 1167Thr Gly Asp Glu Asn Ile Ile Leu Pro Cys Arg Ile Lys
380 385CAA ATT ATA AAC ATG TGG CAG GAA GTA GGA AAA GCA ATG 1206Gln Ile Ile Asn Met Trp Gln Glu Val Gly Lys Ala Met390 395 400TAT GCC CCT CCC ATC AGT GGA CAA ATT AGA TGT TCA TCA 1245Tyr Ala Pro Pro Ile Ser Gly Gln Ile Arg Cys Ser Ser
405 410 415AAT ATT ACA GGG CTG CTA CTA ACA AGA GAT GGT GGT AGT 1284Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly ser
420 425AAG AAC GAG AGC ATC ACC ACC GAG GTC TTC AGA CCT GGA 1323Lys Asn Glu Ser Ile Thr Thr Glu Val Phe Arg Pro Gly
430 435 440GGA GGA GAT ATG AGG GAC AAT TGG AGA AGT GAA TTA TAT 1362Gly Gly Asp Met Arg Asp Asn Trp Arg Ser Glu Leu Tyr
445 450AAA TAT AAA GTA GTA AAA ATT GAA CCA TTA GGA GTA GCG 1401Lys Tyr Lys Val Val Lys Ile Glu Pro Leu Gly Val Ala455 460 465CCC ACC AAG GCA AAG AGA AGA GTG GTG CAG AGA GAA AAA 1440Pro Thr Lys Ala Lys Arg Arg Val Val Gln Arg Glu Lys
470 475 480AGA GCA GTG GGA ACA ATA GGA GCT ATG TTC CTT GGG TTC 1479Arg Ala Val Gly Thr Ile Gly Ala Met Phe Leu Gly Phe
485 490TTA GGA GCA TAA AGC TTC TAG A 1501Leu Gly Ala Xaa Ser Phe Xaa
495 500(2)SEQ ID NO:12的信息：
(ⅰ)序列特征：
(A)长度：500个氨基酸
(B)类型：氨基酸
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:12:Leu Glu Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu Phe Cys1 5 10 15Ala Ser Asp Ala Lys Ala Tyr Ash Thr Glu Lys His Ash Val Trp
20 25 30Ala Thr His Ala Cys Val Pro Thr Asp Pro Ash Pro Gln Glu Val
35 40 45Val Leu Gly Ash Val Thr Glu Asn Phe Asn Met Trp Lys Asn Asn
50 55 60Met Val Glu Gln Met His Glu Asp Ile Ile Ser Leu Trp Asp Gln
65 70 75Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
80 85 90Asn Cys Thr Asp Asp Leu Gly Asn Ala Thr Asn Thr Asn Ser Ser
95 100 105Ala Thr Thr Asn Ser Ser Ser Trp Glu Glu Met Lys Gly Glu Met
110 115 120Lys Arg Cys Ser Phe Asn Ile Thr Thr Ser Ile Arg Asp Lys Ile
125 130 135Lys Lys Glu His Ala Leu Phe Tyr Arg Leu Asp Val Val Pro Ile
140 145 150Asp Asn Asp Asn Thr Thr Tyr Arg Leu Ile Asn Cys Asn Thr Ser
155 160 165Val Ile Thr Gln Ala Cys Pro Lys Val Ser Phe Glu Pro Ile Pro
170 175 180Ile His Phe Cys Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys Asn
185 190 195Asn Lys Thr Phe Glu Gly Lys Gly Pro Cys Lys Asn Val Ser Thr
200 205 210Val Gln Cys Thr His Gly Ile Arg Pro Val Val Ser Thr Gln Leu
215 220 225Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Val Ile Ile Arg Ser
230 235 240Gly Asn Ile Thr Asp Asn Thr Lys Thr Ile Ile Val Gln Leu Asn
245 250 255Glu Ser Val Val Ile Asn Cys Thr Arg Ser Asn Asn Asn Thr Arg
260 265 270Lys Ser Ile His Ile Gly Pro Gly Ser Ala Phe Phe Ala Thr Gly
275 280 285Glu Ile Ile Gly Asp Ile Arg Gln Ala His Cys Asn Leu Ser Arg
290 295 300Thr Gln Trp Asn Asn Thr Leu Gly Lys Ile Val Ile Lys Leu Arg
305 310 315Glu Gln Phe Arg Lys Gln Phe Gly Glu Lys Thr Ile Val Phe Asn
320 325 330Arg Ser Ser Gly Gly Asp Pro Glu Ile Ala Met His Ser Phe Asn
335 340 345Cys Gly Gly Glu Phe Phe Tyr Cys Asn Thr Thr Ala Leu Phe Asn
350 355 360Ser Thr Trp Asn Val Thr Lys Gly Leu Asn Asn Thr Glu Gly Asn
365 370 375Ser Thr Gly Asp Glu Asn Ile Ile Leu Pro Cys Arg Ile Lys Gln
380 385 390Ile Ile Asn Met Trp Gln Glu Val Gly Lys Ala Met Tyr Ala Pro
395 400 405Pro Ile Ser Gly Gln Ile Arg Cys Ser Ser Asn Ile Thr Gly Leu
410 415 420Leu Leu Thr Arg Asp Gly Gly Ser Lys Asn Glu Ser Ile Thr Thr
425 430 435Glu Val Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp Arg
440 445 450Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile Glu Pro Leu Gly
455 460 465Val Ala Pro Thr Lys Ala Lys Arg Arg Val Val Gln Arg Glu Lys
470 475 480Arg Ala Val Gly Thr Ile Gly Ala Met Phe Leu Gly Phe Leu Gly
485 490 495Ala Xaa Ser Phe Xaa
500(2)SEQ ID NO:13的信息：
(ⅰ)序列特征：
(A)长度：1514个碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:13:GG GAA TTC GGA TCC GGG GTA CCT GTG TGG AAG GAA GCA 38
Glu Phe Gly Ser Gly Val Pro Val Trp Lys Glu Ala
1 5 10ACC ACC ACT CTA TTC TGT GCA TCA GAT GCT AGA GCA TAT 77Thr Thr Thr Leu Phe Cys Ala Ser Asp Ala Ar9 Ala Tyr
15 20 25GAC ACA GAG GTA CAT AAT GTT TGG GCC ACA CAT GCC TGT 116Asp Thr Glu Val His Asn Val Trp Ala Thr His Ala Cys
30 35GTA CCC ACA GAC CCT AGT CCA CAA GAA GTA GTT TTG GAA 155Val Pro Thr Asp Pro Ser Pro Gln Glu Val Val Leu Glu
40 45 50AAT GTG ACA GAA AAT TTT AAC ATG TGG AAA AAT AAC ATG 194Asn Val Thr Glu Asn Phe Asn Met Trp Lys Asn Asn Met
55 60GTA GAA CAA ATG CAT GAG GAT ATA ATT AGT TTA TGG GAT 233Val Glu Gln Met His Glu Asp Ile Ile Ser Leu Trp Asp65 70 75CAA AGC TTA AAG CCA TGT GTA AAA TTA ACC CCA CTC TGT 272Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys
80 85 90GTT ACT TTA AAT TGC AGT GAT TAT AGG AAT GCT ACT GAT 311Val Thr Leu Asn Cys Ser Asp Tyr Arg Asn Ala Thr Asp
95 100TAT AAG AAT GCT ACT GAT ACC ACT AGT AGT AAC GAG GGA 350Tyr Lys Asn Ala Thr Asp Thr Thr Ser Ser Asn Glu Gly
105 110 115AAG ATG GAG AGA GGA GAA ATA AAA AAC TGC TCT TTC AAT 389Lys Met Glu Arg Gly Glu Ile Lys Asn Cys Ser Phe Asn
120 125ATT ACC ACA AGC ATA AAA AAT AAG ATG CAG AAA GAA TAT 428Ile Thr Thr Ser Ile Lys Asn Lys Met Gln Lys Glu Tyr130 135 140GCA CTT TTC TAT AAA CTT GAT ATA GTA CCA ATA GAT AAT 467Ala Leu Phe Tyr Lys Leu Asp Ile Val Pro Ile Asp Asn
145 150 155ACA AGC TAT ACA TTG ATA AGT TGT AAC ACC TCA GTC ATT 506Thr Ser Tyr Thr Leu Ile Ser Cys Asn Thr Ser Val Ile
160 165ACA CAG GCC TGT CCA AAG GTA TCC TTT GAA CCA ACT CCC 545Thr Gln Ala Cys Pro Lys Val Ser Phe Glu Pro Thr Pro
170 175 180ATA CAT TAT TGT GCT CCG GCT GGT TTT GCG ATT CTA AAG 584Ile His Tyr Cys Ala Pro Ala Gly Phe Ala Ile Leu Lys
185 190TGT AAT GAT AAG AAG TTC AGT GGA AAA GGA GAA TGT AAA 623Cys Asn Asp Lys Lys Phe Ser GIy Lys Gly Glu Cys Lys195 200 205AAT GTC AGC ACA GTA CAA TGT ACA CAT GGA ATT AGG CCA 662Asn Val Ser Thr Val Gln Cys Thr His Gly Ile Arg Pro
210 215 220GTA GTA TCA ACT CAA CTG CTG TTA AAT GGC AGT CTA GCA 701Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala
225 230GAA GAA GAG GTG GTA ATT AGA TCT GAC AAT TTC ATA GAC 740Glu Glu Glu Val Val Ile Arg Ser Asp Asn Phe Ile Asp
235 240 245AAT ACT AAA ACC ATA ATA GTA CAG CTG AAA GAA TCT GTA 779Asn Thr Lys Thr Ile Ile Val Gln Leu Lys Glu Ser Val
250 255GAA ATT AAT TGT ATA AGA CCC AAC AAT AAT ACA AGA AAA 818Glu Ile Asn Cys Ile Arg Pro Asn Asn Asn Thr Arg Lys260 265 270GGT ATA CAT ATA GGA CCA GGG AGA GCA TGG TAT GCA ACA 857Gly Ile His Ile Gly Pro Gly Arg Ala Trp Tyr Ala Thr
275 280 285GGA GAA ATA GTA GGA GAT ATA AGA AAG GCA TAT TGT AAC 896Gly Glu Ile Val Gly Asp Ile Arg Lys Ala Tyr Cys Asn
290 295ATT AGT AGA ACA AAA TGG AAT AAC ACT TTA ATA CAG ATA 935Ile Ser Arg Thr Lys Trp Asn Asn Thr Leu Ile Gln Ile
300 305 310GCT AAC AAA TTA AAA GAA AAA TAT AAT ACA ACA ATA AGC 974Ala Asn Lys Leu Lys Glu Lys Tyr Asn Thr Thr Ile Ser
315 320TTT AAT CGA TCC TCA GGA GGG GAC CCA GAA ATT GTA ACG 1013Phe Asn Arg Ser Ser Gly Gly Asp Pro Glu Ile Val Thr325 330 335CAT AGT TTT AAT TGT GGA GGG GAG TTT TTC TAC TGT GAT 1052His Ser Phe Asn Cys Gly Gly Glu Phe Phe Tyr Cys Asp
340 345 350TCA ACA CAA CTG TTT AAT AGT ACT TGG AAT TTA AAT GGT 1091Ser Thr Gln Leu Phe Asn Ser Thr Trp Asn Leu Asn Gly
355 360ACT TGG AAT TTT ACT GCA GGG TCA AAT GAA ACT GAA GGC 1130Thr Trp Asn Phe Thr Ala Gly Ser Asn Glu Thr Glu GIy
365 370 375AAT ATC ACA CTC CCA TGC AGA ATA AAA CAA ATT ATA AAC 1169Asn Ile Thr Leu Pro Cys Arg Ile Lys Glln Ile Ile Asn
380 385AGG TGG CAG GAA GTA GGG AAA GCA ATG TAT GCC CCT CCC 1208Arg Trp Gln Glu Val Gly Lys Ala Met Tyr Ala Pro Pro390 395 400ATC AGT GGA CAA ATA AAA TGC TCA TCA AAC ATT ACA GGG 1247Ile Ser Gly Gln Ile Lys Cys Ser Ser Asn Ile Thr Gly
405 410 415ATG ATA TTA ACA AGG GAT GGT GGT AAC GAG AAC AAT AAT 1286Met Ile Leu Thr Arg Asp Gly Gly Asn Glu Asn Asn Asn
420 425GAG AGC AGT ACT ACT GAG ACC TTC AGA CCG GGA GGA GGA 1325Glu Ser Ser Thr Thr Glu Thr Phe Arg Pro Gly Gly Gly
430 435 440GAT ATG AGG AAC AAT TGG AGA AGT GAA TTA TAT AAA TAT 1364Asp Met Arg Asn Asn Trp Arg Ser Glu Leu Tyr Lys Tyr
445 450AAA GTA GTA AAA ATT GAA CCA TTA GGA GTA GCA CCC ACC 1403Lys Val Val Lys Ile Glu Pro Leu Gly Val Ala Pro Thr455 460 465AAG GCA AAG AGA AGA GTG GTG CAG AGA GAA AAA AGA GCA 1442Lys Ala Lys Arg Arg Val Val Gln Arg Glu Lys Arg Ala
470 475 480GTG GGA GCG CTA GGA GCT ATG TTC CTT GGG TTC TTA GGA 1481Val Gly Ala Leu Gly Ala Met Phe Leu Gly Phe Leu Gly
485 490GCA TAA AGC TTC TAG ACC GAC TCT AGA GGA TCC 1514Ala Xaa Ser Phe Xaa Thr Asp Ser Arg Gly Ser
495 500 504(2)SEQ ID NO:14的信息：
(ⅰ)序列特征：
(A)长度：504个氨基酸
(B)类型：氨基酸
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:14:Glu Phe Gly Ser Gly Val Pro Val Trp Lys Glu Ala Thr Thr Thr1 5 10 15Leu Phe Cys Ala Ser Asp Ala Arg Ala Tyr Asp Thr Glu Val His
20 25 30Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro Ser Pro
35 40 45Gln Glu Val Val Leu Glu Asn Val Thr Glu Asn Phe Asn Met Trp
50 55 60Lys Asn Asn Met Val Glu Gln Met His Glu Asp Ile Ile Ser Leu
65 70 75Trp Asp Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys
80 85 90Val Thr Leu Asn Cys Ser Asp Tyr Arg Asn Ala Thr Asp Tyr Lys
95 100 105Asn Ala Thr Asp Thr Thr Ser Ser Asn Glu Gly Lys Met Glu Arg
110 115 120Gly Glu Ile Lys Asn Cys Ser Phe Asn Ile Thr Thr Ser Ile Lys
125 130 135Asn Lys Met Gln Lys GLu Tyr Ala Leu Phe Tyr Lys Leu Asp Ile
140 145 150Val Pro Ile Asp Asn Thr Ser Tyr Thr Leu Ile Ser Cys Asn Thr
155 160 165Ser Val Ile Thr Gln Ala Cys Pro Lys Val Ser Phe Glu Pro Thr
170 175 180Pro Ile His Tyr Cys Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys
185 190 195Asn Asp Lys Lys Phe Ser Gly Lys Gly Glu Cys Lys Asn Val Ser
200 205 210Thr Val Gln Cys Thr His Gly Ile Arg Pro Val Val Ser Thr Gln
215 220 225Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Val Val Ile Arg
230 235 240Ser Asp Asn Phe Ile Asp Asn Thr Lys Thr Ile Ile Val Gln Leu
245 250 255Lys Glu Ser Val Glu Ile Asn Cys Ile Arg Pro Asn Asn Asn Thr
260 265 270Arg Lys Gly Ile His Ile Gly Pro Gly Arg Ala Trp Tyr Ala Thr
275 280 285Gly Glu Ile Val Gly Asp Ile Arg Lys Ala Tyr Cys Asn Ile Ser
290 295 300Arg Thr Lys Trp Asn Asn Thr Leu Ile Gln Ile Ala Asn Lys Leu
305 310 315Lys Glu Lys Tyr Asn Thr Thr Ile Ser Phe Asn Arg Ser Ser Gly
320 325 330Gly Asp Pro Glu Ile Val Thr His Ser Phe Asn Cys Gly Gly Glu
335 340 345Phe Phe Tyr Cys Asp Ser Thr Gln Leu Phe Asn Ser Thr Trp Asn
350 355 360Leu Asn Gly Thr Trp Asn Phe Thr Ala Gly Ser Asn Glu Thr Glu
365 370 375Gly Asn Ile Thr Leu Pro Cys Arg Ile Lys Gln Ile Ile Asn Arg
380 385 390Trp Gln Glu Val Gly Lys Ala Met Tyr Ala Pro Pro Ile Ser Gly
395 400 405Gln Ile Lys Cys Ser Ser Asn Ile Thr Gly Met Ile Leu Thr Arg
410 415 420Asp Gly Gly Asn Glu Asn Asn Asn Glu Ser Ser Thr Thr Glu Thr
425 430 435Phe Arg Pro Gly Gly Gly Asp Met Arg Asn Asn Trp Arg Ser Glu
440 445 450Leu Tyr Lys Tyr Lys Val Val Lys Ile Glu Pro Leu Gly Val Ala
455 460 465Pro Thr Lys Ala Lys Arg Arg Val Val Gln Arg Glu Lys Arg Ala
470 475 480Val Gly Ala Leu Gly Ala Met Phe Leu Gly Phe Leu Gly Ala Xaa
485 490 495Ser Phe Xaa Thr Asp Ser Arg Gly Ser
500 504(2)SEQ ID NO:15的信息：
(ⅰ)序列特征：
(A)长度：1408个碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:15:G GTA CCT GTG TGG AAG GAA GCA ACC ACC ACT CTA TTC 37
Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu Phe
1 5 10TGT GCA TCA GAT GCT AGA GCA TAT GAC ACA GAG GTA CAT 76Cys Ala Ser Asp Ala Arg Ala Tyr Asp Thr Glu Val His
15 20 25AAT GTT TGG GCC ACA CAT GCC TGT GTA CCC ACA GAC CCT 115Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro
30 35AGT CCA CAA GAA GTA TTT TTG GGA AAT GTG ACA GAA AAT 154Ser Pro Gln Glu Val Phe Leu Gly Asn Val Thr Glu Asn
40 45 50TTT AAT ATG TGG AAA AAT AAC ATG GTA GAA CAA ATG TAT 193Phe Asn Met Trp Lys Asn Asn Met Val Glu Gln Met Tyr
55 60GAG GAT ATA ATT AGT TTA TGG GAT CAA AGC TTA AAG CCA 232Glu Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu Lys Pro65 70 75TGT GTA AAA TTA ACC CCA CTC TGT GTT ACT TTA AAT TGC 271Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Asn Cys
80 85 90AGT GAT TAT AGG AAT GCT ACT GAT TAT AAG AAT GCT ACT 310Ser Asp Tyr Arg Asn Ala Thr Asp Tyr Lys Asn Ala Thr
95 100GAT ACC ACT AGT AGT AAC GAG GGA AAG ATG GAG AGA GGA 349Asp Thr Thr Ser Ser Asn Glu Gly Lys Met Glu Arg Gly
105 110 115GAA ATA AAA AAC TGC TCT TTC AAT ATC ACC ACA AGC ATA 388Glu Ile Lys Asn Cys Ser Phe Asn Ile Thr Thr Ser Ile
120 125AAA AAT AAG ATG CAG AAA GAA TAT GCA CTT TTC TAT AAA 427Lys Asn Lys Met Gln Lys Glu Tyr Ala Leu Phe Tyr Lys130 135 140CTT AAT ATA GTA CCA ATA GAT AAT ACA AGC TAT ACA TTG 466Leu Asn Ile Val Pro Ile Asp Asn Thr Ser Tyr Thr Leu
145 150 155ATA AGT TGT AAC ACC TCA GTC ATT ACA CAG GCC TGT CCA 505Ile Ser Cys Asn Thr Ser Val Ile Thr Gln Ala Cys Pro
160 165AAG GTA TCC TTT GAA CCA ATT CCC ATA CAT TAT TGT GCT 544Lys Val Ser Phe Glu Pro Ile Pro Ile His Tyr Cys Ala
170 175 180CCG GCT GGT TTT GCG ATT CTA AAG TGT AAT GAT AAG AAG 583Pro Ala Gly Phe Ala Ile Leu Lys Cys Asn Asp Lys Lys
185 190TTC AGT GGA AAA GGA GAA TGT AAA AAT GTC AGC ACA GTA 622Phe Ser Gly Lys Gly Glu Cys Lys Asn Val Ser Thr Val195 200 205CAA TGT ACA CAT GGA ATT AGG CCA GTA GTA TCA ACT CAA 661Gln Cys Thr His Gly Ile Arg Pro Val Val Ser Thr Gln
210 215 220CTG CTG TTA AAT GGC AGT CTA GCA GAA GAA GAG GTG GTA 700Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Val Val
225 230ATT AGA TCT GAC AAT TTC ACA GAC AAT ACT AAA ACC ATA 739Ile Arg Ser Asp Asn Phe Thr Asp Asn Thr Lys Thr Ile
235 240 245ATA GTA CAG CTG AAA GAA TCT GTA GAA ATT AAT TGT ATA 778Ile Val Gln Leu Lys Glu Set Val Glu Ile Asn Cys Iie
250 255AGA CCC AAC AAT AAT ACA AGA AAA GGT ATA CAT ATA GGA 817Arg Pro Asn Asn Asn Thr Arg Lys Gly Ile His Ile Gly260 265 270CCA GGG AGA GCA TGG TAT GCA ACA GGA GAA ATA GTA GGA 856Pro Gly Arg Ala Trp Tyr Ala Thr Gly Glu Ile Val Gly
275 280 285GAT ATA AGA CAG GCA TAT TGT AAC ATT AGT AGA ACA AAA 895Asp Ile Arg Gln Ala Tyr Cys Asn Ile Ser Arg Thr Lys
290 295TGG AAT AAC ACT TTA ATA CAG ATA GCT AAC AAA TTA AAA 934Trp Asn Asn Thr Leu Ile Gln Ile Ala Asn Lys Leu Lys
300 305 310GAA AAA TAT AAT ACA ACA ATA AGC TTT AAT CGA TCC TCA 973Glu Lys Tyr Asn Thr Thr Ile Ser Phe Asn Arg Ser Ser
315 320GGA GGG GAC CCA GAA ATT GTA ACC CAT AGT TTT AAT TGT 1012Gly Gly Asp Pro Glu Ile Val Thr His Ser Phe Asn Cys325 330 335GGA GGG GAA TTT TTC TAC TGT AAT TCA ACA CAA CTG TTT 1051Gly Gly Glu Phe Phe Tyr Cys Asn Ser Thr Gln Leu Phe
340 345 350AAT AGT ACT TGG AAT TTA AAT GGT ACT TGG AAT TTT ACT 1090Asn Ser Thr Trp Asn Leu Asn Gly Thr Trp Asn Phe Thr
355 360GCA GGG TCA AAT GAA ACT GAA GGC AAT ATC ACA CTC CCA 1129Ala Gly Ser Asn Glu Thr Glu Gly Asn Ile Thr Leu Pro
365 370 375TGC AGA ATA AAA CAA ATT ATA AAC AGG TGG CAG GAA GTA 1165Cys Arg Ile Lys Gln Ile Ile Asn Arg Trp Gln Glu Val
380 385GGA AAA GCA ATG TAT GCC CCT CCC ATC AGT GGA CAA ATA 1207Gly Lys Ala Met Tyr Ala Pro Pro Ile Ser Gly Gln Ile390 395 400AGA TGC TCA TCA AAC ATT ACA GGG ATG ATA TTA ACA AGG 1246Arg Cys Ser Ser Asn Ile Thr Gly Met Ile Leu Thr Arg
405 410 415GAT GGT GGT AAC GAG AAC AAT AAT GAG AGC AGT ACT ACT 12/5Asp Gly Gly Asn Glu Asn Asn Asn Glu Ser Ser Thr Thr
420 425GAG ACC TTC AGA CCG GGA GGA GGA GAT ATG AGG AAC AAT 1324Glu Thr Phe Arg Pro Gly Gly Gly Asp Met Arg Asn Asn
430 435 440TGG AGA AGT GAA TTA TAT AAA TAT AAA GTA GTA AAA ATT 1363Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile
445 450GAG CCA TTA GGA GTA GCA CCC ACC GAC TCT AGA GGA TCC 1402Glu Pro Leu Gly Val Ala Pro Thr Asp Ser Arg Gly Ser455 460 465TCT AGA 1408Ser Arg
469(2)SEQ ID NO:16的信息：
(ⅰ)序列特征：
(A)长度：469个氨基酸
(B)类型：氨基酸
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:16:Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu Phe Cys Ala Ser1 5 10 15Asp Ala Arg Ala Tyr Asp Thr Glu Val His Asn Val Trp Ala Thr
2 25 30His Ala Cys Val Pro Thr Asp Pro Ser Pro Gln Glu Val Phe Leu
35 40 45Gly Asn Val Thr Glu Asn Phe Asn Met Trp Lys Asn Asn Met Val
50 55 60Glu Gln Met Tyr Glu Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu
65 70 75Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Asn Cys
80 85 90Ser Asp Tyr Arg Asn Ala Thr Asp Tyr Lys Asn Ala Thr Asp Thr
95 100 105Thr Ser Ser Asn Glu Gly Lys Met Glu Arg Gly Glu Ile Lys Asn
110 115 120Cys Ser Phe Asn Ile Thr Thr Ser Ile Lys Asn Lys Met Gln Lys
125 130 135Glu Tyr Ala Leu Phe Tyr Lys Leu Asn Ile Val Pro Ile Asp Asn
140 145 150Thr Ser Tyr Thr Leu Ile Ser Cys Asn Thr Ser Val Ile Thr Gln
155 160 165Ala Cys Pro Lys Val Ser Phe Glu Pro Ile Pro Ile His Tyr Cys
170 175 180Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys Asn Asp Lys Lys Phe
185 190 195Ser Gly Lys Gly Glu Cys Lys Asn Val Ser Thr Val Gln Cys Thr
200 205 210His Gly Ile Arg Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly
215 220 225Ser Leu Ala Glu Glu Glu Val Val Ile Arg Ser Asp Asn Phe Thr
230 235 240Asp Asn Thr Lys Thr Ile Ile Val Gln Leu Lys Glu Ser Val Glu
245 250 255Ile Asn Cys Ile Arg Pro Asn Asn Asn Thr Arg Lys Gly Ile His
260 265 270Ile Gly Pro Gly Arg Ala Trp Tyr Ala Thr Gly Glu Ile Val Gly
275 280 285Asp Ile Arg Gln Ala Tyr Cys Asn Ile Ser Ar9 Thr Lys Trp Asn
290 295 300Asn Thr Leu Ile Gln Ile Ala Asn Lys Leu Lys Glu Lys Tyr Asn
305 310 315Thr Thr Ile Ser Phe Asn Arg Ser ser Gly Gly Asp Pro Glu Ile
320 325 330Val Thr His Ser Phe Asn Cys Gly Gly Glu Phe Phe Tyr Cys Asn
335 340 345Ser Thr Gln Leu Phe Asn Ser Thr Trp Asn Leu Asn Gly Thr Trp
350 355 360Asn Phe Thr Ala Gly Ser Asn Glu Thr Glu Gly Asn Ile Thr Leu
365 370 375Pro Cys Ar9 Ile Lys Gln Ile Ile Asn Arg Trp Gln Glu Val Gly
380 385 390Lys Ala Met Tyr Ala Pro Pro Ile Ser Gly Gln Ile Arg Cys Ser
395 400 405Ser Asn Ile Thr Gly Met Ile Leu Thr Arg Asp Gly Gly Asn Glu
410 415 420Asn Asn Asn Glu Ser Ser Thr Thr Glu Thr Phe Arg Pro Gly Gly
425 430 435Gly Asp Met Arg Asn Asn Trp Arg Ser Glu Leu Tyr Lys Tyr Lys
440 445 450Val Val Lys Ile Glu Pro Leu Gly Val Ala Pro Thr Asp Ser Arg
455 460 465Gly ser Ser Arg
469(2)SEQ ID NO:17的信息：
(ⅰ)序列特征：
(A)长度：1499个碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:17:
GAG GTA CCT GTG TGG AAA GAA GCA ACC ACT ACT CTA 36
Glu Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu
1 5 10TTT TGT GCA TCA GAT GCT AAA GCA TAT GAC ACA GGG GTG 75Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp Thr Gly Val
15 20 25CAT AAT GTT TGG GCC ACA CAT GCC TGT GTA CCC ACA GAC 114His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp
30 35CCC AAC CCA CAA GAA ATA GAA TTG GTA AAT GTG ACA GAA 153Pro Asn Pro Gln Glu Ile Glu Leu Val Asn Val Thr Glu
40 45 50GAT TTT AAC ATG TGG AAA AAT AAA ATG GTA GAC CAG ATG 192Asp Phe Asn Met Trp Lys Asn Lya Met Val Asp Gln Met
55 60CAT GAG GAT ATA ATC AGT TTA TGG GAT GAA AGC CTA AAG 231His Glu Asp Ile Ile Ser Leu Trp Asp Glu Ser Leu Lys65 70 75CCA TGT GTA AAG TTA ACC CCA CTT TGT GTT ACT CTA AAC 270Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Asn
80 85 90TGC AGT GAT GTG AAC AAT TCC ACA AAT CCT AAT GAT ACT 309Cys Ser Asp Val Asn Asn Ser Thr Asn Pro Asn Asp Thr
95 100AAT ACT AAT TCC ACT AAT ACT ACT TCC TCT ACT CCT ACG 348Asn Thr Asn Ser Thr Asn Thr Thr Ser Ser Thr Pro Thr
105 110 115GCC ACT ACT AGT AGC GAG GAA AAG ATG GAG AAG GGA GAA 387Ala Thr Thr Ser Ser Glu Glu Lys Met Glu Lys Gly Glu
120 125ATA AAA AAC TGC TCT TTC AAT ATC ACC ACA CAC ATG AAA 426Ile Lys Asn Cys Ser Phe Asn Ile Thr Thr His Met Lys130 135 140GAT AAG GCA CAG AAA GAA TAT GCA CTT TTT TAT AAA CTT 465Asp Lys Ala Gln Lys Glu Tyr Ala Leu Phe Tyr Lys Leu
145 150 155GAT ATA GTA CCA ATA GAT GAT AAT AAT GCC AGC TAT AGG 504Asp Ile Val Pro Ile Asp Asp Asn Asn Ala Ser Tyr Arg
160 165TTG ATA AGT TGT AAT ACC TCA GAC ATT ACA CAG GCC TGT 543Leu Ile Ser Cys Asn Thr Ser Asp Ile Thr Gln Ala Cys
170 175 180CCA AAG GTG ACC TTT GAG CCA ATT CCC ATA CAT TAT TGT 582Pro Lys Val Thr Phe Glu Pro Ile Pro Ile His Tyr Cys
185 190GCC CCG GCT GGT TTT GCG ATT CTA AAG TGT AAA GAT AAG 621Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys Lys Asp Lys195 200 205AAG TTC AAT GGA ACA GGA CCA TGT TCA AAG GTC AGC ACA 660Lys Phe Asn Gly Thr Gly Pro Cys Ser Lys Val Ser Thr
210 215 220GTA CAA TGT ACA CAT GGA ATT AGG CCA GTA GTA TCA ACT 699Val Gln Cys Thr His Gly Ile Arg Pro Val Val Ser Thr
225 230CAA CTG TTG TTA AAT GGC AGT CTT GCA GAA GAA GAA GTA 738Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Val
235 240 245GTA ATT AGA TCT GTC AAT TTC ACA GAC AAT GCT AAA ATC 777Val Ile Arg Ser Val Asn Phe Thr Asp Asn Ala Lys Ile
250 255ATA ATA GTA CAG CTG AAA GAA CCT GTA GCA ATT AAT TGT 816Ile Ile Val Gln Leu Lys Glu Pro Val Ala Ile Asn Cys260 265 270ACA AGA CCC AAC AAC AAT ACA AGA AAA GGT ATA CAT CTA 855Thr Arg Pro Asn Asn Asn Thr Arg Lys Gly Ile His Leu
275 280 285GGA CCA GGG AgC ACA TTT TAT ACA ACA GGA GAA ATA ATA 894Gly Pro Gly Ser Thr Phe Tyr Thr Thr Gly Glu Ile Ile
290 295GGA GAC ATA AGA AAA GCA TAT TGC AAG ATT AGT AAA GAA 933Gly Asp Ile Arg Lys Ala Tyr Cys Lys Ile Ser Lys Glu
300 305 310AAA TGG AAT AAC ACT TTA AGA CAG GTA GTT AAA AAA TTA 972Lys Trp Asn Asn Thr Leu Arg Gln Val Val Lys Lys Leu
315 320AGA GAA CAA TTT GGG AAT AAA ACA ATA ATT TTT AAT CGA 1011Arg Glu Gln Phe Gly Asn Lys Thr Ile Ile Phe Asn Arg325 330 335TCC TCA GGA GGG GAC CCA GAA ATT GTA ATG CAC AGT TTT 1050Ser Ser Gly Gly Asp Pro Glu Ile Val Met His Ser Phe
340 345 350AAC TGT GGA GGG GAG TTT TTC TAC TGT AAT ACA ACA CAA 1089Asn Cys Gly Gly Glu Phe Phe Tyr Cys Asn Thr Thr Gln
355 360CTG TTT AAT AGT ACT TGG AAT AAT ACT GAA GGG ACA AAT 1128Leu Phe Asn Ser Thr Trp Asn Asn Thr Glu Gly Thr Asn
365 370 375AGC ACT GAA GGA AAT AGC ACA ATC ACA CTC CCA TGC AGA 1167Ser Thr Glu Gly Asn Ser Thr Ile Thr Leu Pro Cys Arg
380 385ATA AAA CAA ATT ATA AAT ATG TGG CAG GAA GTA GGA AAA 1206Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Lys390 395 400GCA ACG TAT GCC CCT CCC ATC AGA GGA CGA ATT AGA TGC 1245Ala Thr Tyr Ala Pro Pro Ile Arg Gly Arg Ile Arg Cys
405 410 415ATA TCA AAT ATT ACA GGA CTG CTA TTA ACA AGA GAT GGT 1284Ile Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly
420 425GGT AGG AAT GTC ACA AAC AAT ACCGAA ACC TTC AGA CCT 1323Gly Arg Asn Val Thr Asn Asn Thr Glu Thr Phe Arg Pro
430 435 440GGA GGA GGA GAC ATG AGG GAC AAT TGG AGA AGT GAA TTA 1362Gly Gly Gly Asp Met Arg Asp Asn Trp Arg Ser Glu Leu
445 450TAT AAA TAT AAA GTA GTA AAA GTT GAA CCA TTA GGA ATA 1401Tyr Lys Tyr Lys Val Val Lys Val Glu Pro Leu Gly Ile455 460 465GCA CCC ACC AAG GCA AAG AGA AGA GTG GTG CAC AGA GAC 1440Ala Pro Thr Lys Ala Lys Arg Arg Val Val His Arg Asp
470 475 480AAA AGA GCA GCA CTA GGA GCC TTG TTC CTT GGG TTC TTA 1479Lys Arg Ala Ala Leu Gly Ala Leu Phe Leu Gly Phe Leu
485 490GGA GCA TAA AAG CTT CTA GA 1499Gly Ala Xaa Lys Leu Leu
495 499(2)SEQ ID NO:18的信息：
(ⅰ)序列特征：
(A)长度：499个氨基酸
(B)类型：氨基酸
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:18:Glu Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu Phe Cys Ala1 5 10 15Ser Asp Ala Lys Ala Tyr Asp Thr Gly Val His Asn Val Trp Ala
20 25 30Thr His Ala Cys Val Pro Thr Asp Pro Asn Pro Gln Glu Ile Glu
35 40 45Leu Val Asn Val Thr Glu Asp Phe Asn Met Trp Lys Asn Lys Met
50 55 60Val Asp Gln Met His Glu Asp Ile Ile Ser Leu Trp Asp Glu Ser
65 70 75Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Asn
80 85 90Cys Ser Asp Val Asn Asn Ser Thr Asn Pro Asn Asp Thr Asn Thr
95 100 105Asn Ser Thr Asn Thr Thr Ser Ser Thr Pro Thr Ala Thr Thr Ser
110 115 120Ser Glu Glu Lys Met Glu Lys Gly Glu Ile Lys Asn Cys Ser Phe
125 130 135Asn Ile Thr Thr His Met Lys Asp Lys Ala Gln Lys Glu Tyr AIa
140 145 150Leu Phe Tyr Lys Leu Asp Ile Val Pro Ile Asp Asp Asn Asn Ala
155 160 165Ser Tyr Arg Leu Ile Ser Cys Asn Thr Ser Asp Ile Thr Gln Ala
170 175 180Cys Pro Lys Val Thr Phe Glu Pro Ile Pro Ile His Tyr Cys Ala
185 190 195Pro Ala Gly Phe Ale Ile Leu Lys Cys Lys Asp Lys Lys Phe Asn
200 205 210Gly Thr Gly Pro Cys Ser Lys Val Ser Thr Val Gln Cys Thr His
215 220 225Gly Ile Arg Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser
230 235 240Leu Ala Glu Glu Glu Val Val Ile Arg Ser Val Asn Phe Thr Asp
245 250 255Asn Ala Lys Ile Ile Ile Val Gln Leu Lys Glu Pro Val Ala I1e
260 265 270Asn Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys Gly Ile His Leu
275 280 285Gly Pro Gly Ser Thr Phe Tyr Thr Thr Gly Glu Ile Ile Gly Asp
290 295 300Ile Arg Lys Ala Tyr Cys Lys Ile Ser Lys Glu Lys Trp Asn Asn
305 310 315Thr Leu Arg Gln Val Val Lys Lys Leu Arg Glu Gln Phe Gly Asn
320 325 330Lys Thr Ile Ile Phe Asn Arg Ser Ser Gly Gly Asp Pro Glu Ile
335 340 345Val Met His Ser Phe Asn Cys Gly Gly Glu Phe Phe Tyr Cys Asn
350 355 360Thr Thr Gln Leu Phe Asn Ser Thr Trp Asn Asn Thr Glu Gly Thr
365 370 375Asn Ser Thr Glu GIy Asn Ser Thr Ile Thr Leu Pro Cys Arg Ile
380 385 390Lys Gln Ile Ile Asn Mer Trp Gln Glu Val Gly Lys Ala Thr Tyr
395 400 405Ala Pro Pro Ile Arg Gly Arg Ile Arg Cys Ile Ser Asn Ile Thr
410 415 420Gly Leu Leu Leu Thr Arg Asp Gly Gly Arg Asn Val Thr Asn Asn
425 430 435Thr Glu Thr Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp
440 445 450Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys Val Glu Pro Leu
455 460 465Gly Ile Ala Pro Thr Lys Ala Lys Arg Arg Val Val His Arg Asp
470 475 480Lys Arg Ala Ala Leu Gly Ala Leu Phe Leu Gly Phe Leu Gly Ala
485 490 495Xaa Lys Leu Leu
499(2)SEQ ID NO:19的信息：
(ⅰ)序列特征：
(A)长度：1499个碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:19:
GAG GTA CCT GTA TGG AAA GAA GCA ACC ACT ACT CTA 36
Glu Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu
1 5 10TTT TGT GCA TCA GAT GCT AAA GCA TAT GAC ACA GAG GTG 75Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp Thr Glu Val
15 20 25CAT AAT GTT TGG GCC ACA CAT GCC TGT GTA CCC ACA GAC 114His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp
30 35CCC AAC CCA CAA GAA ATA GAA TTG GTA AAT GTG ACA GAA 153Pro Asn Pro Gln Glu Ile Glu Leu Val Asn Val Thr Glu
40 45 50GAT TTT AAC ATG TGG AAA AAT AAA ATG GTA GAC CAG ATG 192Asp Phe Asn Met Trp Lys Asn Lys Met Val Asp Gln Met
55 60CAT GAG GAT ATA ATC AGT TTA TGG GAT GAA AGC CTA AAG 231His Glu Asp Ile Ile Ser Leu Trp Asp Glu Ser Leu Lys65 70 75CCA TGT GTA AAG TTA ACC CCA CTT TGT GTT ACT CTA AAC 270Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Asn
80 85 90TGC AGT GAT GTG AAC AAT TCC ACA AAT CCT AAT GAT ACT 309Cys Ser Asp Val Asn Asn Ser Thr Asn Pro Asn Asp Thr
95 100AAT ACT AAT TCC ACT AAT ACT ACT TCC TCT ACT CCT ACG 348Asn Thr Asn Ser Thr Asn Thr Thr Ser Ser Thr Pro Thr
105 110 115GCC ACT ACT AGT AGC GAG GAA AAG ATG GAG AAG GGA GAA 387Ala Thr Thr Ser Ser Glu Glu Lys Met Glu Lys Gly Glu
120 125ATA AAA AAC TGC TCT TTC AAT ATC ACC ACA CAC ATG AAA 426Ile Lys Asn Cys Ser Phe Asn Ile Thr Thr His Met Lys130 135 140GAT AAG GTA CAG AAA GAA TAT GCA CTT TTT TAT AAA CTT 465Asp Lys Val Gln Lys Glu Tyr Ala Leu Phe Tyr Lys Leu
145 150 155GAT ATA GTA CCA ATA GAT GAT AAT AAT ACC AGC TAT AGG 504Asp Ile Val Pro Ile Asp Asp Asn Asn Thr Ser Tyr Arg
160 165TTG ATA AGT TGT AAT ACC TCA GTC ATT ACA CAG GCC TGT 543Leu Ile Ser Cys Asn Thr Ser Val Ile Thr Gln Ala Cys
170 175 180CCA ATG GTG ACC TTT GAG CCA ATT CCC ATA CAT TAT TGT 582Pro Met Val Thr Phe Glu Pro Ile Pro Ile His Tyr Cys
185 190GCC CCG GCT GGT TTT GCG ATT CTA AAG TGT AAA GAT AAG 621Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys Lys Asp Lys195 200 205AAG TTC AAT GGA ACA GGA CCA TGT TCA AAG GTC AGC ACA 660Lys Phe Asn Gly Thr Gly Pro Cys Ser Lys Val Ser Thr
210 215 220GTA CAA TGT ACA CAT GGA ATT AGG CCA GTA GTA TCA ACT 699Val Gln Cys Thr His Gly Ile Arg Pro Val Val Ser Thr
225 230CAA CTG TTG TTA AAT GGC AGT CTT GCA GAA GAA GAA GTA 738Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Val
235 240 245GTA ATT AGA TCT GTC AAT TTC ACA GAC AAT GCT AAA ATC 777Val Ile Arg Ser Val Asn Phe Thr Asp Asn Ala Lys Ile
250 255ATA ATA GTA CAG CTG AAA GAA CCT GTA GCA ATT AAT TGT 816Ile Ile Val Gln Leu Lys Glu Pro Val Ala Ile Asn Cys260 265 270ACA AGA CCC AAC AAC AAT ACA AGA AAA GGT ATA CAT CTA 855Thr Ar9 Pro Asn Asn Asn Thr Arg Lys Gly Ile His Leu
275 280 285GGA CCA GGG AGC ACA TTT TAT ACA ACA GGA GAA ATA ATA 894Gly Pro Gly Ser Thr Phe Tyr Thr Thr Gly Glu Ile Ile
290 295GGA GAC ATA AGA AAA GCA TAT TGC AAG ATT AGT AAA GAA 933Gly Asp Ile Arg Lys Ala Tyr Cys Lys Ile Ser Lys Glu
300 305 310AAA TGG AAT AAC ACT TTA AGA CAG GTA GTT AAA AAA TTA 972Lys Trp Asn Asn Thr Leu Arg Gln Val Val Lys Lys Leu
315 320AGA GAA CAA TTT GGG AAT AAA ACA ATA ATT TTT AAT CGA 1011Arg Glu Gln Phe Gly Asn Lys Thr Ile Ile Phe Asn Arg325 330 335TCC TCA GGA GGG GAC CCA GAA ATT GTA ATG CAC AGT TTT 1050Ser Ser Gly Gly Asp Pro Glu Ile Val Met His Ser Phe
340 345 350AAC TGT GGA GGG GAG TTT TTC TAC TGT AAT ACA ACA CAA 1089Asn Cys Gly Gly Glu Phe Phe Tyr Cys Asn Thr Thr Gln
355 360CTG TTT AAT AGT ACT TGG AAT AAT ACT GAA GGG ACA AAT 1128Leu Phe Asn Ser Thr Trp Asn Asn Thr Glu Gly Thr Asn
365 370 375AGC ACT GAA GGA AAT AGC ACA ATC ACA CTC CCA TGC AGA 1167Ser Thr Glu Gly Asn Ser Thr Ile Thr Leu Pro Cys Arg
380 385ATA AAA CAA ATT ATA AAT ATG TGG CAG GAA GTA GGA AAA 1206Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Lys390 395 400GCA ACG TAT GCC CCT CCC ATC AGA GGA CGA ATT AGA TGC 1245Ala Thr Tyr Ala Pro Pro Ile Arg Gly Arg Ile Arg Cys
405 410 415ATA TCA AAT ATT ACA GGA CTG CTA TTA ACA AGA GAT GGT 1284Ile Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly
420 425GGT AGG AAT GTC ACA AAC AAT ACC GAN NCC TTC AGA CCT 1323Gly Arg Asn Val Thr Asn Asn Thr Xaa Xaa Phe Arg Pro
430 435 440GGA GGA GGA GAC ATG AGG GAC AAT TGG AGA AGT GAA TTA 1362Gly Gly Gly Asp Met Arg Asp Asn Trp Arg Ser Glu Leu
445 450TAT AAA TAT AAA GTA GTA AAA GTT GAA CCA TTA GGA ATA 1401Tyr Lys Tyr Lys Val Val Lys Val Glu Pro Leu Gly Ile455 460 465GCA CCC ACC AAG GCA AAG AGA AGA GTG GTG CAC AGA GAC 1440Ala Pro Thr Lys Ala Lys Arg Arg Val Val His Arg Asp
470 475 480AAA AGA GCA GCA CTA GGA GCT TTG TTC CTT GGG TTC TTA 1479Lys Arg Ala Ala Leu Gly Ala Leu Phe Leu Gly Phe Leu
485 490GGA GCA TAA AAG CTT CTA GA 1499Gly Ala Xaa Lys Leu Leu
495 499(2)SEQ ID NO:20的信息：
(ⅰ)序列特征：
(A)长度：499个氨基酸
(B)类型：氨基酸
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:20:Glu Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu Phe Cys Ala1 5 10 15Ser Asp Ala Lys Ala Tyr Asp Thr Glu Val His Asn Val Trp Ala
20 25 30Thr His Ala Cys Val Pro Thr Asp Pro Asn Pro Gln Glu Ile Glu
35 40 45Leu Val Asn Val Thr Glu Asp Phe Asn Met Trp Lys Asn Lys Met
50 55 60Val Asp Gln Met His Glu Asp Ile Ile Ser Leu Trp Asp Glu Ser
65 70 75Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Asn
80 85 90Cys Ser Asp Val Asn Asn Ser Thr Asn Pro Asn Asp Thr Asn Thr
95 100 105Asn Ser Thr Asn Thr Thr Ser Ser Thr Pro Thr Ala Thr Thr Ser
110 115 120Ser Glu Glu Lys Met Glu Lys Gly Glu Ile Lys Asn Cys Ser Phe
125 130 135Asn Ile Thr Thr His Met Lys Asp Lys Val Gln Lys Glu Tyr Ala
140 145 150Leu Phe Tyr Lys Leu Asp Ile Val Pro Ile Asp Asp Asn Asn Thr
155 160 165Ser Tyr Arg Leu Ile Ser Cys Asn Thr Ser Val Ile Thr Gln Ala
170 175 180Cys Pro Met Val Thr Phe Glu Pro Ile Pro Ile His Tyr Cys Ala
185 190 195Pro Ala Gly Phe Ala Ile Leu Lys Cys Lys Asp Lys Lys Phe Asn
200 205 210Gly Thr Gly Pro Cys Ser Lys Val Ser Thr Val Gln Cys Thr His
215 220 225Gly Ile Arg Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser
230 235 240Leu Ala Glu Glu Glu Val Val Ile Arg Ser Val Asn Phe Thr Asp
245 250 255Asn Ala Lys Ile Ile Ile Val Gln Leu Lys Glu pro Val Ala Ile
260 265 270Asn Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys Gly Ile His Leu
275 280 285Gly Pro Gly Ser Thr Phe Tyr Thr Thr Gly Glu Ile Ile Gly Asp
290 295 300Ile Arg Lys Ala Tyr Cys Lys Ile Ser Lys Glu Lys Trp Asn Asn
305 310 315Thr Leu Arg Gln Val Val Lys Lys Leu Arg Glu Gln Phe Gly Asn
320 325 330Lys Thr Ile Ile Phe Asn Arg Ser Ser Gly Gly Asp Pro Glu Ile
335 340 345Val Met His Ser Phe Asn Cys Gly Gly Glu Phe Phe Tyr Cys Asn
350 355 360Thr Thr Gln Leu Phe Asn Ser Thr Trp Asn Asn Thr Glu Gly Thr
365 370 375Asn Ser Thr GLu Gly Asn Ser Thr Ile Thr Leu Pro Cys Arg Ile
380 385 390Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Lys Ala Thr Tyr
395 400 405Ala Pro Pro Ile Arg Gly Arg Ile Arg Cys Ile Ser Asn Ile Thr
410 415 420Gly Leu Leu Leu Thr Arg Asp Gly Gly Arg Asn Val Thr Asn Asn
425 430 435Thr Xaa Xaa Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp
440 445 450Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys Val Glu Pro Leu
455 460 465Gly Ile Ala Pro Thr Lys Ala Lys Arg Arg Val Val His Arg Asp
470 475 480Lys Arg Ala Ala Leu Gly Ala Leu Phe Leu Gly Phe Leu Gly Ala
485 490 495Xaa Lys Leu Leu
499(2)SEQ ID NO:21的信息：
(ⅰ)序列特征：
(A)长度：1475个碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:21:
GTA CCT GTG TGG AAA GAA GCA AAC ACA ACT CTA TTT 37
Val Pro Val Trp Lys Glu Ala Asn Thr Thr Leu Phe
1 5 10TGT GCA TCA GAT GCT AAA GCA TAT GAT AGA GAA GTA CAT 76Cys Ala Ser Asp Ala Lys Ala Tyr Asp Arg Glu Val His
15 20 25AAT GTT TGG GCA ACA CAT GCC TGT GTA CCC ACA GAC CCC 115Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro
30 35AAC CCA CAA GAA ATA GTA TTG GGA AAT GTG ACA GAA AAT 154Asn Pro Gln Glu Ile Val Leu Gly Asn Val Thr Glu Asn
40 45 50TTT AAC ATG TGG AAA AAT AAC ATG GTA GAA CAA ATG CAT 193Phe Asn Met Trp Lys Asn Asn Met Val Glu Gln Met His
55 60GAG GAT ATA ATC AAT TTA TGG GAT CAA AGC TTA AAG CCA 232Glu Asp Ile Ile Asn Leu Trp Asp Gln Ser Leu Lys Pro65 70 75TGT GTA AAG TTA ACT CCA CTC TGT GTT ACT TTA AAG TGC 271Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Lys Cys
80 85 90AAG GAT CTG GAG AGG AAT ACT ACC TAT AAT AGC ACT ATT 310Lys Asp Leu Glu Arg Asn Thr Thr Tyr Asn Ser Thr Ile
95 100ACC AAT AAT AGT AGT TTG GAG GGA CTA AGA GAA CAA ATG 349Thr Asn Asn Ser Ser Leu Glu Gly Leu Arg Glu Gln Met
105 110 115ACA AAC TGC TCT TTC AAC ATC ACC ACA AGT ATA AGA GAT 388Thr Asn Cys Ser Phe Asn Ile Thr Thr Ser Ile Arg Asp
120 125AAG GTG CAG AAA GAA TAT GCA CTT TTG TAT AAA CTT GAT 427Lys Val Gln Lys Glu Tyr Ala Leu Leu Tyr Lys Leu Asp130 135 140GTA GTA CCA ATA GAA GAA GAT GAC AAT ACT AGC TAT AGA 466Val Val Pro Ile Glu Glu Asp Asp Asn Thr Ser Tyr Arg
145 150 155TTG ATA AGT TGT AAC ACC TCA GTC ATT ACA CAG GCT TGT 505Leu Ile Ser Cys Asn Thr Ser Val Ile Thr Gln Ala Cys
160 165CCA AAG ACA TCC TTT GAG CCA ATT CCC ATA CAT TAT TGT 544Pro Lys Thr Ser Phe Glu Pro Ile Pro Ile His Tyr Cys
170 175 180GCC CCG GCT GGT TTT GCG ATT CTA AAG TGT AAT GAT AAG 583Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys Asn Asp Lys
185 190AAG TTC AAT GGA ACA GGA CCA TGT AAA AAT GTC AGC ACA 622Lys Phe Asn Gly Thr Gly Pro Cys Lys Asn Val Ser Thr195 200 205GTA CAA TGT ACA CAT GGA ATT AGG CCA GTA GTA TCA ACT 661Val Gln Cys Thr His Gly Ile Arg Pro Val Val Ser Thr
210 215 220CAA CTG TTG TTA AAT GGC AGT CTA GCA GAA GAA GAG GTA 700Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Val
225 230GTA ATC AGA TCT GCC AAT TTC ACA GAC AAT GCT AAA ACC 739Val Ile Arg Ser Ala Asn Phe Thr Asp Asn Ala Lys Thr
235 240 245ATA ATA GTA CAT CTA AAT GAA ACT GTA AAA ATT AAT TGT 778Ile Ile Val His Leu Asn Glu Thr Val Lys Ile Asn Cys
250 255ACA AGA CTT GGC AAC AAT ACA AGA AAA AGT ATA AAT ATA 817Thr Arg Leu Gly Asn Asn Thr Arg Lys Ser Ile Asn Ile260 265 270GGA CCA GGG AGA GTA CTC TAT GCA ACA GGA GAA ATA ATA 856Gly Pro Gly Arg Val Leu Tyr Ala Thr Gly Glu Ile Ile
275 280 285GGA GAC ATA AGA CAA GCA CAT TGT AAC ATT AGT AGA GCA 895Gly Asp Ile Arg Gln Ala His Cys Asn Ile Ser Arg Ala
290 295CAA TGG AAT AAG ACT TTA GAA AAG GTA GTT GAC AAA TTA 934Gln Trp Asn Lys Thr Leu Glu Lys Val Val Asp Lys Leu
300 305 310AGA AAA CAA TTT GGG GAT AAT ACA ACA ATA GCT TTT AAT 973Arg Lys Gln Phe Gly Asp Asn Thr Thr Ile Ala Phe Asn
315 320CGA TCC TCA GGA GGG GAC CCA GAA ATT GTA ATG CAC ACT 1012Arg Ser Ser Gly Gly Asp Pro Glu Ile Val Met His Thr325 330 335TTT AAT TGT GGA GGG GAA TTT TTC TAC TGT AAT ACA ACA 1051Phe Asn Cys Gly Gly Glu Phe Phe Tyr Cys Asn Thr Thr
340 345 350CAA CTG TTT AAT AGT ACT TGG AAT AAT ACT TGG AAG GAT 1090Gln Leu Phe Asn Ser Thr Trp Asn Asn Thr Trp Lys Asp
355 360CCT AAC AGG AGT GAC AAT ATC ACA CTC CCA TGC AGA ATA 1129Pro Asn Arg Ser Asp Asn Ile Thr Leu Pro Cys Arg Ile
365 370 375AAA CAA ATT ATA AAC ATG TGG CAG GAA GTA GGA AAA GCA 1168Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Lys Ala
380 385ATG TAC GCC CCT CCC ATC AGA GGG GAA ATT AGA TGT TCA 1207Met Tyr Ala Pro Pro Ile Arg Gly Glu Ile Arg Cys Ser390 395 400TCA AAT ATC ACA GGG CTG CTA CTA ACA AGA GAT GGT GGT 1246Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly
405 410 415AAT GAC GAT GGT AAT GAC ACG ACC ACA AAC AGG ACC GAG 1285Asn Asp Asp Gly Asn Asp Thr Thr Thr Asn Arg Thr Glu
420 425ATC TTC AGA CCT GGA GGA GGA GAT ATG AGG GAC AAT TGG 1324Ile Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp
430 435 440AGA AGT GAA TTA TAT AGA TAT AAA GTA GTA AAA ATT GAA 1363Arg Ser Glu Leu Tyr Arg Tyr Lys Val Val Lys Ile Glu
445 450CCA TTA GGA ATA GCA CCC ACC AGG GCA AAG AGA AGA GTG 1402Pro Leu Gly Ile Ala Pro Thr Arg Ala Lys Arg Arg Val455 460 465GTG CAG AGA GAA AAA AGA GCA GTA GGA CTA GGA GCT TTG 1441Val Gln Arg Glu Lys Arg Ala Val Gly Leu Gly Ala Leu
47 475 480TTC CTT GGG T TCTTAGGAG CATAAAGCTT CTAGA 1475Phe Leu Gly
483(2)SEQ ID NO:22的信息：
(ⅰ)序列特征：
(A)长度：491个氨基酸
(B)类型：氨基酸
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:22:Val Pro Val Trp Lys Glu Ala Asn Thr Thr Leu Phe Cys Ala Ser1 5 10 15Asp Ala Lys Ala Tyr Asp Arg Glu Val His Asn Val Trp Ala Thr
20 25 30His Ala Cys Val Pro Thr Asp Pro Asn Pro Gln Glu Ile Val Leu
35 40 45Gly Asn Val Thr Glu Asn Phe Asn Met Trp Lys Asn Asn Met Val
50 55 60Glu Gln Met His Glu Asp Ile Ile Asn Leu Trp Asp Gln Ser Leu
65 70 75Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Lys Cys
80 85 90Lys Asp Leu Glu Arg Asn Thr Thr Tyr Asn Ser Thr Ile Thr Asn
95 100 105Asn Ser Ser Leu Glu Gly Leu Arg Glu Gln Met Thr Asn Cys Ser
110 115 120Phe Asn Ile Thr Thr Ser Ile Arg Asp Lys Val Gln Lys Glu Tyr
125 130 135Ala Leu Leu Tyr Lys Leu Asp Val Val Pro Ile Glu Glu Asp Asp
140 145 150Asn Thr Ser Tyr Arg Leu Ile Ser Cys Asn Thr Ser Val Ile Thr
155 160 165Gln Ala Cys Pro Lys Thr Ser Phe Glu Pro Ile Pro Ile His Tyr
170 175 180Cys Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys Asn Asp Lys Lys
185 190 195Phe Asn Gly Thr Gly Pro Cys Lys Asn Val Ser Thr Val Gln Cys
200 205 210Thr His Gly Ile Arg Pro Val Val Ser Thr Gln Leu Leu Leu Asn
215 220 225Gly Ser Leu Ala Glu Glu Glu Val Val Ile Arg Ser Ala Asn Phe
230 235 240Thr Asp Asn Ala Lys Thr Ile Ile Val His Leu Asn Glu Thr Val
245 250 255Lys Ile Asn Cys Thr Arg Leu Gly Asn Asn Thr Arg Lys Ser Ile
260 265 270Asn Ile Gly Pro Gly Arg Val Leu Tyr Ala Thr Gly Glu Ile Ile
275 280 285Gly Asp Ile Arg Gln Ala His Cys Asn Ile Ser Arg Ala Gln Trp
290 295 300Asn Lys Thr Leu Glu Lys Val Val Asp Lys Leu Arg Lys Gln Phe
305 310 315Gly Asp Asn Thr Thr Ile Ala Phe Asn Arg Ser Ser Gly Gly Asp
320 325 330Pro Glu Ile Val Met His Thr Phe Asn Cys Gly Gly Glu Phe Phe
335 340 345Tyr Cys Asn Thr Thr Gln Leu Phe Asn Ser Thr Trp Asn Asn Thr
350 355 360Trp Lys Asp Pro Asn Arg Ser Asp Asn Ile Thr Leu Pro Cys Arg
365 370 375Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Lys Ala Met
380 385 390Tyr Ala Pro Pro Ile Arg Gly Glu Ile Arg Cys Ser Ser Asn Ile
395 400 405Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly Asn Asp Asp Gly Asn
410 415 420Asp Thr Thr Thr Asn Arg Thr Glu Ile Phe Arg Pro Gly Gly Gly
425 430 435Asp Met Arg Asp Asn Trp Arg Ser Glu Leu Tyr Arg Tyr Lys Val
440 445 450Val Lys Ile Glu Pro Leu Gly Ile Ala Pro Thr Arg Ala Lys Arg
455 460 465Arg Val Val Gln Arg Glu Lys Arg Ala Val Gly Leu Gly Ala Leu
470 475 480Phe Leu Gly Phe Leu Gly Ala Leu Phe Leu Gly
485 490 491(2)SEQ ID NO:23的信息：
(ⅰ)序列特征：
(A)长度：1475个碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:23:G GTA CCT GTG TGG AAA GAA GCA AAC ACA ACT CTA TTT 37
Val Pro Val Trp Lys Glu Ala Asn Thr Thr Leu Phe
1 5 10TGT GCA TCA GAT GCT AAA GCA TAT GAT AGA GAA GTA CAT 76Cys Ala Ser Asp Ala Lys Ala Tyr Asp Arg Glu Val His
15 20 25AAT GTT TGG GCA ACA CAT GCC TGT GTA CCC ACA GAC CCC 115Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro
30 35AAC CCA CAA GAA ATA GTA TTG GGA AAT GTG ACA GAA AAT 154Asn Pro Gln Glu Ile Val Leu Gly Asn Val Thr Glu Asn
40 45 50TTT AAC ATG TGG AAA AAT AAC ATG GTA GAA CAA ATG CAT 193Phe Asn Met Trp Lys Asn Asn Met Val Glu Gln Met His
55 60GAG GAT ATA ATC AAT TTA TGG GAT CAA AGC TTA AAG CCA 232Glu Asp Ile Ile Asn Leu Trp Asp Gln Ser Leu Lys Pro65 70 75TGT GTA AAG TTA ACT CCA CTC TGT GTT ACT TTA AAG TGC 271Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Lys Cys
80 85 90AAG GAT CTG GAG AGG AAT ACT ACC TAT AAT AGC ACT ATT 310Lys Asp Leu Glu Arg Asn Thr Thr Tyr Asn Ser Thr Ile
95 100ACC AAT AAT AGT AGT TTG GAG GGA CTA AGA GAA CAA ATG 349Thr Asn Asn Ser Ser Leu Glu Gly Leu Arg Glu Gln Met
105 110 115ACA AAC TGC TCT TTC AAC ATC ACC ACA AGT ATA AGA GAT 388Thr Asn Cys Ser Phe Asn Ile Thr Thr Ser Ile Arg Asp
120 125AAG GTG CAG AAA GAA TAT GCA CTT TTG TAT AAA CTT GAT 427Lys Val Gln Lys Glu Tyr Ala Leu Leu Tyr Lys Leu Asp130 135 140GTA GTA CCA ATA GAA GAA GAT GAC AAT ACT AGC TAT AGA 466Val Val Pro Ile Glu Glu Asp Asp Asn Thr Ser Tyr Arg
145 150 155TTG ATA AGT TGT AAC ACC TCA GTC ATT ACA CAG GCT TGT 505Leu Ile Ser Cys Asn Thr Ser Val Ile Thr Gln Ala Cys
160 165CCA AAG ACA TCC TTT GAG CCA ATT CCC ATA CAT TAT TGT 544Pro Lys Thr Ser Phe Glu Pro Ile Pro Ile His Tyr Cys
170 175 180GCC CCG GCT GGT TTT GCG ATT CTA AAG TGT AAT GAT AAG 583Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys Asn Asp Lys
185 190AAG TTC AAT GGA ACA GGA CCA TGT AAA AAT GTC AGC ACA 622Lys Phe Asn Gly Thr Gly Pro Cys Lys Asn Val Ser Thr195 200 205GTA CAA TGT ACA CAT GGA ATT AGG CCA GTA GTA TCA ACT 661Val Gln Cys Thr His Gly Ile Arg Pro Val Val Ser Thr
210 215 220CAA CTG TTG TTA AAT GGC AGT CTA GCA GAA GAA GAG GTA 700Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Glu Val
225 230GTA ATC AGA TCT GCC AAT TTC ACA GAC AAT GCT AAA ACC 739Val Ile Arg Ser Ala Asn Phe Thr Asp Asn Ala Lys Thr
235 240 245ATA ATA GTA CAT CTA AAT GAA ACT GTA AAA ATT AAT TGT 778Ile Ile Val His Leu Asn Glu Thr Val Lys Ile Asn Cys
250 255ACA AGA CTT GGC AAC AAT ACA AGA AAA AGT ATA AAT ATA 817Thr Arg Leu Gly Asn Asn Thr Arg Lys Ser Ile Asn Ile260 265 270GGA CCA GGG AGA GTA CTC TAT GCA ACA GGA GAA ATA ATA 856Gly Pro Gly Arg Val Leu Tyr Ala Thr Gly Glu Ile Ile
275 280 285GGA GAC ATA AGA CAA GCA CAT TGT AAC ATT AGT AGA GCA 895Gly Asp Ile Arg Gln Ala His Cys Asn Ile Ser Arg Ala
290 295CAA TGG AAT AAG ACT TTA GAA AAG GTA GTT GAC AAG TTA 934Gln Trp Asn Lys Thr Leu Glu Lys Val Val Asp Lys Leu
300 305 310AGA AAA CAA TTT GGG GAT AAT ACA ACA ATA GCT TTT AAT 973Arg Lys Gln Phe Gly Asp Asn Thr Thr Ile Ala Phe Asn
315 320CGA TCC TCA GGA GGG GAC CCA GAA ATT GTA ATG CAC ACT 1012Arg Ser Ser Gly Gly Asp Pro Glu Ile Val Met His Thr325 330 335TTT AAT TGT GGA GGG GAA TTT TTC TAC TGT AAT ACA ACA 1051Phe Asn Cys Gly Gly Glu Phe Phe Tyr Cys Asn Thr Thr
340 345 350CAA CTG TTT AAT AGT ACT TGG AAT AAT ACT TGG AAG GAT 1090Gln Leu Phe Asn Ser Thr Trp Asn Asn Thr Trp Lys Asp
355 360CCT AAC AGG AGT GAC AAT ATC ACA CTC CCA TGC AGA ATA 1129Pro Asn Arg Ser Asp Asn Ile Thr Leu Pro Cys Arg Ile
365 370 375AAA CAA ATT ATA AAC ATG TGG CAG GAA GTA GGA AAA GCA 1168Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Lys Ala
380 385ATG TAC GCC CCT CCC ATC AGA GGG GAA ATT AGA TGT TCA 1207Met Tyr Ala Pro Pro Ile Arg Gly Glu Ile Arg Cys Ser390 395 400TCA AAT ATC ACA GGG CTG CTA CTA ACA AGA GAT GGT GGT 1246Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly
405 410 415AAT GAC GAT GGT AAT GAC ACG ACC ACA AAC AGG ACC GAG 1285Asn Asp Asp Gly Asn Asp Thr Thr Thr Asn Arg Thr Glu
420 425ATC TTC AGA CCT GGA GGA GGA GAT ATG AGG GAC AAT TGG 1324Ile Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp
430 435 440AGA AGT GAA TTA TAT AGA TAT AAA GTA GTA AAA ATT GAA 1363Arg Ser Glu Leu Tyr Arg Tyr Lys Val Val Lys Ile Glu
445 450CCA TTA GGA ATA GCA CCC ACC AGG GCA AAG AGA AGA GTG 1402Pro Leu Gly Ile Ala Pro Thr Arg Ala Lys Arg Arg Val455 460 465GTG CAG AGA GAA AAA AGA GCA GTA GGA CTA GGA GCT TTG 1441Val Gln Arg Glu Lys Arg Ala Val Gly Leu Gly Ala Leu
470 475 480TTC CTT GGG TTC TTG GGA GCA TAA AGC TTC TAG A 1475Phe Leu Gly Phe Leu Gly Ala Xaa Ser Phe Xaa
485 490 491(2)SEQ ID NO:24的信息：
(ⅰ)序列特征：
(A)长度：491个氨基酸
(B)类型：氨基酸
(D)拓扑结构：线型
(ⅹi)序列描述：SEQ ID NO:24:Val Pro Val Trp Lys Glu Ala Asn Thr Thr Leu Phe Cys Ala Ser1 5 10 15Asp Ala Lys Ala Tyr Asp Arg Glu Val His Asn Val Trp Ala Thr
20 25 30His Ala Cys Val Pro Thr Asp Pro Asn Pro Gln Glu Ile Val Leu
35 40 45Gly Asn Val Thr Glu Asn Phe Asn Met Trp Lys Asn Asn Met Val
50 55 60Glu Gln Met His Glu Asp Ile Ile Asn Leu Trp Asp Gln Ser Leu
65 70 75Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Lys Cys
80 85 90Lys Asp Leu Glu Arg Asn Thr Thr Tyr Asn Ser Thr Ile Thr Asn
95 100 105Asn Ser Ser Leu Glu Gly Leu Arg Glu Gln Met Thr Asn Cys Ser
110 115 120Phe Asn Ile Thr Thr Ser Ile Arg Asp Lys Val Gln Lys Glu Tyr
125 130 135Ala Leu Leu Tyr Lys Leu Asp Val Val Pro Ile Glu Glu Asp Asp
140 145 150Asn Thr Ser Tyr Arg Leu Ile Ser Cys Asn Thr Ser Val Ile Thr
155 160 165Gln Ala Cys Pro Lys Thr Ser Phe Glu Pro Ile Pro Ile His Tyr
170 175 180Cys Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys Asn Asp Lys Lys
185 190 195Phe Asn Gly Thr Gly Pro Cys Lys Asn Val Ser Thr Val Gln Cys
200 205 210Thr His Gly Ile Arg Pro Val Val Ser Thr Gln Leu Leu Leu Asn
215 220 225Gly Ser Leu Ala Glu Glu Glu Val Val Ile Arg Ser Ala Asn Phe
230 235 240Thr Asp Asn Ala Lys Thr Ile Ile Val His Leu Asn Glu Thr Val
245 250 255Lys Ile Asn Cys Thr Arg Leu Gly Asn Asn Thr Arg Lys Ser Ile
260 265 270Asn Ile Gly Pro Gly Arg Val Leu Tyr Ala Thr Gly Glu Ile Ile
275 280 285Gly Asp Ile Arg Gln Ala His Cys Asn Ile Ser Arg Ala Gln Trp
290 295 300Asn Lys Thr Leu Glu Lys Val Val Asp Lys Leu Arg Lys Gln Phe
305 310 315Gly Asp Asn Thr Thr Ile Ala Phe Asn Arg Ser Ser Gly Gly Asp
320 325 330Pro Glu Ile Val Met His Thr Phe Asn Cys Gly Gly Glu Phe Phs
335 340 345Tyr Cys Asn Thr Thr Gln Leu Phe Asn Ser Thr Trp Asn Asn Thr
350 355 360Trp Lys Asp Pro Asn Arg Ser Asp Asn Ile Thr Leu Pro Cys Arg
365 370 375Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Lys Ala Met
380 385 390Tyr Ala Pro Pro Ile Arg Gly Glu Ile Arg Cys Ser Ser Asn Ile
395 400 405Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly Asn Asp Asp Gly Asn
410 415 420Asp Thr Thr Thr Asn Arg Thr Glu Ile Phe Arg Pro Gly Gly Gly
425 430 435Asp Met Arg Asp Asn Trp Arg Ser Glu Leu Tyr Arg Tyr Lys Val
440 445 450Val Lys Ile Glu Pro Leu Gly Ile Ala Pro Thr Arg Ala Lys Arg
455 460 465Arg Val Val Gln Arg Glu Lys Arg Ala Val Gly Leu Gly Ala Leu
470 475 480Phe Leu Gly Phe Leu Gly ALa Xaa Ser Phe Xaa
485 490 491(2)SEQ ID NO:25的信息：
(ⅰ)序列特征：
(A)长度：1435个碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:25:
CTC GAG GTA CCT GTG TGG AAA GAA GCA ACC ACC ACT 36
Leu Glu Val Pro Val Trp Lys Glu Ala Thr Thr Thr
1 5 10CTA TTT TGT GCA TCA GAT GCT AAA GCA TAT GAT TCA GAG 75Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp Ser Glu
15 20 25GCA CAT AAT GTT TGG GCC ACA CAT GCC TGT GTA CCC ACA 114Ala His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr
30 35GAC CCC AAC CCA CAA GAA GTA GAA TTG GAA AAT GTG ACA 153Asp Pro Asn Pro Gln Glu Val Glu Leu Glu Asn Val Thr
40 45 50GAA AAT TTT AAC ATG TGG AAA AAT AAC ATG GTA GAA CAG 192Glu Asn Phe Asn Met Trp Lys Asn Asn Met Val Glu Gln
55 60ATG CAT GGG GAT ATA ATT AGT TTA TGG GAT CAA AGC CTA 231Met His Gly Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu65 70 75AAG CCA TGT GTA AAA TTA ACC CCA CTC TGT GTT ACG TTA 270Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
80 85 90AAT TGC ACT GAC CCA AAT GTT ACT AAT AGC GAG AGA ACG 309Asn Cys Thr Asp Pro Asn Val Thr Asn Ser Glu Arg Thr
95 100ATA GAG GGG GGA GAA ATA AAA AAT TGC TCT TTC AAT ATC 348Ile Glu Gly Gly Glu Ile Lys Asn Cys Ser Phe Asn Ile
105 110 115ACC ACA AAC ATA AGA GAT AGG TTT CAG AAA GAA TAT GCA 387Thr Thr Asn Ile Arg Asp Arg Phe Gln Lys Glu Tyr Ala
120 125CTT TTT TAT AAA CTT GAT GTA ATA CCA TTA GGT AAT GAT 426Leu Phe Tyr Lys Leu Asp Val Ile Pro Leu Gly Asn Asp130 135 140AAT ACT AGC TAT AGG TTG ATA AGT TGT AAC ACC TCA GTC 465Asn Thr Ser Tyr Arg Leu Ile Ser Cys Asn Thr Ser Val
145 150 155ATT ACA CAG GCC TGT CCA AAG GTA TCC TTT GAG CCA ATT 504Ile Thr Gln Ala Cys Pro Lys Val Ser Phe Glu Pro Ile
160 165CCC ATA CAT TAT TGT GCC CCG GCT GGT TTT GCG ATT CTA 543Pro Ile His Tyr Cys Ala Pro Ala Gly Phe Ala Ile Leu
170 175 180AAG TGT AAA GAT AAG AAG TTC AAT GGA ACA GGA CCA TGT 582Lys Cys Lys Asp Lys Lys Phe Asn Gly Thr Gly Pro Cys
185 190ACA AAT GTC AGC ACA GTA CAA TGT ACA CAT GGA ATT AAG 621Thr Asn Val Ser Thr Val Gln Cys Thr His Gly Ile Lys195 200 205CCA GTA GTA TCA ACT CAA CTG TTG TTA AAT GGC AGT CTA 660Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu
210 215 220GCA GAA GAA GAC ATA GTA ATT AGA TCC GCC AAT CTC ACA 699Ala Glu Glu Asp Ile Val Ile Arg Ser Ala Asn Leu Thr
225 230GAC AAT GCT AAA AAC ATA ATA GTA CAG CTG AAT GAA TCT 738Asp Asn Ala Lys Asn Ile Ile Val Gln Leu Asn Glu Ser
235 240 245GTA ACA ATG AAT TGT ACA AGA CCC AAC AAC AAT ACA ATG 777Val Thr Met Asn Cys Thr Arg Pro Asn Asn Asn Thr Met
250 255AAA AGT ATA CAT ATA GGA CCA GGC ACA GCA TTT TAT GCA 816Lys Ser Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Ala260 265 270ACA GGA AAC ATA ATA GGA GAT ATA AGA CAA GCA CAT TGT 855Thr Gly Asn Ile Ile Gly Asp Ile Arg Gln Ala His Cys
275 280 285AAC ATT AGT GGA ACA AAA TGG AAT GAC ACT TTG AAA AAG 894Asn Ile Ser Gly Thr Lys Trp Asn Asp Thr Leu Lys Lys
290 295ATA GCT ATA AAA TTA AGA GAA CAA TTT AAT AAG ACA ATA 933Ile Ala Ile Lys Leu Arg Glu Gln Phe Asn Lys Thr Ile
300 305 310GTC TTT AAT CAA TCC TCA GGA GGG GAC CCA GAA ATT GCA 972Val Phe Asn Gln Ser Ser Gly Gly Asp Pro Glu Ile Ala
315 320ACG CTC AGT TTT AAT TGT GGA GGG GAA TTT TTC TAC TGT 1011Thr Leu Ser Phe Asn Cys Gly Gly Glu Phe Phe Tyr Cys325 330 335AAT TCA ACA CAA CTG TTT AAT AGT ACT TGG AAT AGT ACT 1050Asn Ser Thr Gln Leu Phe Asn Ser Thr Trp Asn Ser Thr
340 345 350GGG TCA AAT AAC ACT AAA GGA AAT GAC ACA ATC ACA CTC 1089Gly Ser Asn Asn Thr Lys Gly Asn Asp Thr Ile Thr Leu
355 360CCA TGC AGA ATA AGA CAA ATT ATA AAC ATG TGG CAG AAA 1128Pro Cys Arg Ile Arg Gln Ile Ile Asn Met Trp Gln Lys
365 370 375ATA GGA AAA GCA ATG TAT GCC CCT CCC ATC AAA GGG CAA 1167Ile Gly Lys Ala Met Tyr Ala Pro Pro Ile Lys Gly Gln
380 385ATT AGA TGT TCA TCA AAT ATT ACA GGG CTA ATA TTA ACA 1206Ile Arg Cys Ser Ser Asn Ile Thr Gly Leu Ile Leu Thr390 395 400AGA GAT GGT GGT AAC AAC AAC ATG AGC AAG ACC ACC GAG 1245Arg Asp Gly Gly Asn Asn Asn Met Ser Lys Thr Thr Glu
405 410 415ACC TTC AGA CCT GGA GGA GGA GAT ATG AGG GAC AAT TGG 1284Thr Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp
420 425AGA AGT GAA TTA TAT AAA TAT AAA GTA GTA AAA ATT GAA 1323Arg Ser Glu Leu Tyr Lys Tyr Lys val Val Lys Ile Glu
430 435 440CCA TTA GGA GTA GCA CCC ACC AGG GCA AAG AGA AGA GTG 1362Pro Leu Gly Val Ala Pro Thr Arg Ala Lys Arg Arg Val
445 450GTG CAG AGA GAA AAA AGA GCA GTG GGA ATA GGA GCT GTG 1401Val Gln Arg Glu Lys Arg Ala Val Gly Ile Gly Ala Val455 460 465TTC CTT GGG TTC TTG GGA GCA TAA AGC TTC TAG A 1435Phe Leu Gly Phe Leu Gly Ala Xaa Ser Phe Xaa
470 475 478(2)SEQ ID NO:26的信息：
(ⅰ)序列特征：
(A)长度：478个氨基酸
(B)类型：氨基酸
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:26:Leu Glu Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu Phe Cys1 5 10 15Ala Ser Asp Ala Lys Ala Tyr Asp Ser Glu Ala His Asn Val Trp
20 25 30Ala Thr His Ala Cys Val Pro Thr Asp Pro Asn Pro Gln Glu Val
35 40 45Glu Leu Glu Asn Val Thr Glu Asn Phe Asn Met Trp Lys Asn Asn
50 55 60Met Val Glu Gln Met His Gly Asp lle lle Ser Leu Trp Asp Gln
65 70 75Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
80 85 90Asn Cys Thr Asp Pro Asn Val Thr Asn Ser Glu Arg Thr Ile Glu
95 100 105Gly Gly Glu Ile Lys Asn Cys Ser Phe Asn Ile Thr Thr Asn Ile
110 115 120Arg Asp Arg Phe Gln Lys Glu Tyr Ala Leu Phe Tyr Lys Leu Asp
125 130 135Val Ile Pro Leu Gly Asn Asp Asn Thr Ser Tyr Arg Leu Ile Ser
140 145 150Cys ASn Thr Ser Val Ile Thr Gln Ala Cys Pro Lys Val Ser Phe
155 160 165Glu Pro Ile Pro Ile His Tyr Cys Ala Pro Ala Gly Phe Ala Ile
170 175 180Leu Lys Cys Lys Asp Lys Lys Phe Asn Gly Thr Gly Pro Cys Thr
185 190 195Asn Val Ser Thr Val Gln Cys Thr His Gly Ile Lys Pro Val Val
200 205 210Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Asp Ile
215 220 225Val Ile Arg Ser Ala Asn Leu Thr Asp Asn Ala Lys Asn Ile Ile
230 235 240Val Gln Leu Asn Glu Ser Val Thr Met Asn Cys Thr Arg Pro Asn
245 250 255Asn Asn Thr Met Lys Ser Ile His Ile Gly Pro Gly Arg Ala Phe
260 265 270Tyr Ala Thr Gly Asn Ile Ile Gly Asp Ile Arg Gln Ala His Cys
275 280 285Asn Ile Ser Gly Thr Lys Trp Asn Asp Thr Leu Lys Lys Ile Ala
290 295 300Ile Lys Leu Arg Glu Gln Phe Asn Lys Thr Ile Val Phe Asn Gln
305 310 315Ser Ser Gly Gly Asp Pro Glu Ile Ala Thr Leu Ser Phe Asn Cys
320 325 330Gly Gly Glu Phe Phe Tyr Cys Asn Ser Thr Gln Leu Phe Asn Ser
335 340 345Thr Trp Asn Ser Thr Gly Ser Asn Asn Thr Lys Gly Asn Asp Thr
350 355 360Ile Thr Leu Pro Cys Arg Ile Arg Gln Ile Ile Asn Met Trp Gln
365 370 375Lys Ile Gly Lys Ala Met Tyr Ala Pro Pro Ile Lys Gly Gln Ile
380 385 390Arg Cys Ser Ser Asn Ile Thr Gly Leu Ile Leu Thr Arg Asp Gly
395 400 405Gly Asn Asn Asn Met Ser Lys Thr Thr Glu Thr Phe Arg Pro Gly
410 415 420Gly Gly Asp Met Arg Asp Asn Trp Arg Ser Glu Leu Tyr Lys Tyr
425 430 435Lys Val Val Lys Ile Glu Pro Leu Gly Val Ala Pro Thr Arg Ala
440 445 450Lys Arg Ar9 Val Val Gln Arg Glu Lys Arg Ala Val Gly Ile Gly
455 460 465Ala VaI Phe Leu Gly Phe Leu Gly Ala Xaa Ser Phe Xaa
470 475 478(2)SEQ ID NO:27的信息：
(ⅰ)序列特征：
(A)长度：1435个碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:27:
CTC GAG GTA CCT GTG TGG AAA GAA GCA ACC ACC ACT 36
Leu Glu Val Pro Val Trp Lys Glu Ala Thr Thr Thr
1 5 10CTA TTT TGT GCA TCA GAT GCT AAA GCA TAT GAT TCA GAG 75Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp Ser Glu
15 20 25GCA CAT AAT GTT TGG GCC ACA CAT GCC TGT GTA CCC ACA 114Ala His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr
30 35GAC CCC AAC CCA CAA GAA GTA GAA TTG GAA AAT GTG ACA 153Asp Pro Asn Pro Gln Glu Val Glu Leu Glu Asn Val Thr
40 45 50GAA AAT TTT AAC ATG TGG AAA AAT AAC ATG GTA GAA CAG 192Glu Asn Phe Asn Met Trp Lys Asn Asn Met Val Glu Gln
55 50ATG CAT GGG GAT ATA ATT AGT TTA TGG GAT CAA AGC CTA 231Met His Gly Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu65 70 75AAG CCA TGT GTA AAA TTA ACC CCA CTC TGT GTT ACG TTA 270Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
80 85 90AAT TGC ACT GAC CCA AAT GTT ACT AAT AGC GAG AGA ACG 309Asn Cys Thr Asp Pro Asn Val Thr Asn Ser Glu Arg Thr
95 100ATA GAG GGG GGA GAA ATA AAA AAT TGC TCT TTC AAT ATC 348Ile Glu Gly Gly Glu Ile Lys Asn Cys Ser Phe Asn Ile
105 110 115ACC ACA AAC ATA AGA GAT AGG TTT CAG AAA GAA TAT GCA 387Thr Thr Asn Ile Arg Asp Arg Phe Gln Lys Glu Tyr Ala
120 125CTT TTT TAT AAA CTT GAT GTA ATA CCA TTA GGT AAT GAT 426Leu Phe Tyr Lys Leu Asp Val Ile Pro Leu Gly Asn Asp130 135 140AAT ACT AGC TAT AGG TTG ATA AGT TGT AAC ACC TCA GTC 465Asn Thr Ser Tyr Arg Leu Ile Ser Cys Asn Thr Ser Val
145 150 155ATT ACA CAG GCC TGT CCA AAG GTA TCC TTT GAG CCA ATT 504Ile Thr Gln Ala Cys Pro Lys Val Ser Phe Glu Pro Ile
160 165CCC ATA CAT TAT TGT GCC CCG GCT GGT TTT GCG ATT CTA 543Pro Ile His Tyr Cys Ala Pro Ala Gly Phe Ala Ile Leu
170 175 180AAG TGT AAA GAT AAG AAG TTC AAT GGA ACA GGA CCA TGT 582Lys Cys Lys Asp Lys Lys Phe Asn Gly Thr Gly Pro Cys
185 190ACA AAT GTC AGC ACA GTA CAA TGT ACA CAT GGA ATT AAG 621Thr Asn Val Ser Thr Val Gln Cys Thr His Gly Ile Lys195 200 205CCA GTA GTA TCA ACT CAA CTG TTG TTA AAT GGC AGT CTA 660Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu
210 215 220GCA GAA GAA GAC ATA GTA ATT AGA TCC GCC AAT CTC ACA 699Ala Glu Glu Asp Ile Val Ile Arg Ser Ala Asn Leu Thr
225 230GAC AAT GCT AAA AAC ATA ATA GTA CAG CTG AAT GAA TCT 738Asp Asn Ala Lys Asn Ile Ile Val Gln Leu Asn Glu Ser
235 240 245GTA ACA ATG AAT TGT ACA AGA CCC AAC AAC AAT ACA ATG 777Val Thr Met Asn Cys Thr Arg Pro Asn Asn Asn Thr Met
250 255AAA AGT ATA CAT ATA GGA CCA GGC AGA GCA TTT TAT GCA 816Lys Ser Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Ala260 265 270ACA GGA AAC ATA ATA GGA GAT ATA AGA CAA GCA CAT TGT 855Thr Gly Asn Ile Ile Gly Asp Ile Arg Gln Ala His Cys
275 280 285AAC ATT AGT GGA ACA AAA TGG AAT GAC ACT TTG AAA AAG 894Asn Ile Ser Gly Thr Lys Trp Asn Asp Thr Leu Lys Lys
290 295ATA GCT ATA AAA TTA AGA GAA CAA TTT AAT AAG ACA ATA 933Ile Ala Ile Lys Leu Arg Glu Gln PheAsn Lys Thr Ile
300 305 310GTC TTT AAT CAA TCC TCA GGA GGG GAC CCA GAA ATT GCA 972Val Phe Asn Gln Ser Ser Gly Gly Asp Pro Glu Ile Ala
315 320ACG CTC AGT TTT AAT TGT GGA GGG GAA TTT TTC TAC TGT 1011Thr Leu Ser Phe Asn Cys Gly Gly Glu Phe Phe Tyr Cys325 330 335AAT TCA ACA CAA CTG TTT AAT AGT ACT TGG AAT AGT ACT 1050Asn Ser Thr Gln Leu Phe Asn Ser Thr Trp Asn Ser Thr
340 345 350GGG TCA AAT AAC ACT AAA GGA AAT GAC ACA ATC ACA CTC 1089Gly Ser Asn Asn Thr Lys Gly Asn Asp Thr Ile Thr Leu
355 360CCA TGC AGA ATA AGA CAA ATT ATA AAC ATG TGG CAG AAA 1128Pro Cys Arg Ile Arg Gln Ile Ile Asn Met Trp Gln Lys
365 370 375ATA GGA AAA GCA ATG TAT GCC CCT CCC ATC AAA GGG CAA 1167Ile Gly Lys Ala Met Tyr Ala Pro Pro Ile Lys Gly Gln
380 385ATT AGA TGT TCA TCA AAT ATT ACA GGG CTA ATA TTA ACA 1206Ile Arg Cys Ser Ser Asn Ile Thr Gly Leu Ile Leu Thr390 395 400AGA GAT GGT GGT AAC AAC AAC ATG AGC AAG ACC ACC GAG 1245Arg Asp Gly Gly Asn Asn Asn Met Ser Lys Thr Thr Glu
405 410 415ACC TTC AGA CCT GGA GGA GGA GAT ATG AGG GAC AAT TGG 1284Thr Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Asn Trp
420 425AGA AGT GAA TTA TAT AAA TAT AAA GTA GTA AAA ATT GAA 1323Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile Glu
430 435 440CCA TTA GGA GTA GCA CCC ACC AGG GCA AAG AGA AGA GTG 1362Pro Leu Gly Val Ala Pro Thr Arg Ala Lys Arg Arg Val
445 450GTG CAG AGA GAA AAA AGA GCA GTG GGA ATA GGA GCT GTG 1401Val Gln Arg Glu Lys Arg Ala Val Gly Ile Gly Ala Val455 460 465TTC CTT GGG TTC TTG GGA GCA TAA AGC TTC TAG A 1435Phe Leu Gly Phe Leu Gly Ala Xaa Ser Phe Xaa
470 475 478(2)SEQ ID NO:28的信息：
(ⅰ)序列特征：
(A)长度：478个氨基酸
(B)类型：氨基酸
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:28:Leu Glu Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu Phe Cys1 5 10 15Ala Ser Asp Ala Lys Ala Tyr Asp Ser Glu Ala His Asn Val Trp
20 25 30Ala Thr His Ala Cys Val Pro Thr Asp Pro Asn Pro Gln Glu Val
35 40 45Glu Leu Glu Asn Val Thr Glu Asn Phe Asn Met Trp Lys Asn Asn
50 55 60Met Val Glu Gln Met His Gly Asp Ile Ile Ser Leu Trp Asp Gln
65 70 75Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
80 85 90Asn Cys Thr Asp Pro Asn Val Thr Asn Ser Glu Arg Thr Ile Glu
95 100 105Gly Gly Glu Ile Lys Asn Cys Ser Phe Asn Ile Thr Thr Asn Ile
110 115 120Arg Asp Arg Phe Gln Lys Glu Tyr Ala Leu Phe Tyr Lys Leu Asp
125 130 135Val Ile Pro Leu Gly Asn Asp Asn Thr Ser Tyr Arg Leu Ile Ser
140 145 150Cys Asn Thr Ser Val Ile Thr Gln Ala Cys Pro Lys Val Ser Phe
155 160 165Glu Pro Ile Pro Ile His Tyr Cys Ala Pro Ala Gly Phe Ala Ile
170 175 180Leu Lys Cys Lys Asp Lys Lys Phe Asn Gly Thr Gly Pro Cys Thr
185 190 195Asn Val Ser Thr Val Gln Cys Thr His Gly Ile Lys Pro Val Val
200 205 210Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu Asp Ile
215 220 225Val Ile Arg Ser Ala Asn Leu Thr Asp Asn Ala Lys Asn Ile Ile
230 235 240Val Gln Leu Asn Glu Ser Val Thr Met Asn Cys Thr Arg Pro Asn
245 250 255Asn Asn Thr Met Lys Ser Ile His Ile Gly Pro Gly Arg Ala Phe
260 265 270Tyr Ala Thr Gly Asn Ile Ile Gly Asp Ile Arg Gln Ala His Cys
275 280 285Asn Ile Ser Gly Thr Lys Trp Asn Asp Thr Leu Lys Lys Ile Ala
290 295 300Ile Lys Leu Arg Glu Gln Phe Asn Lys Thr Ile Val Phe Asn Gln
305 310 315Ser Ser Gly Gly Asp Pro Glu Ile Ala Thr Leu Ser Phe Asn Cys
320 325 330Gly Gly Glu Phe Phe Tyr Cys Asn Ser Thr Gln Leu Phe Asn Ser
335 340 345Thr Trp Asn Ser Thr Gly Ser Asn Asn Thr Lys Gly Asn Asp Thr
350 355 360Ile Thr Leu Pro Cys Arg Ile Arg Gln Ile Ile Asn Met Trp Gln
365 370 375Lys Ile Gly Lys Ala Met Tyr Ala Pro Pro Ile Lys Gly Gln Ile
380 385 390Arg Cys Ser Ser Asn Ile Thr Gly Leu Ile Leu Thr Arg Asp Gly
395 400 405Gly Asn Asn Asn Met Ser Lys Thr Thr Glu Thr Phe Arg Pro Gly
410 415 420Gly Gly Asp Met Arg Asp Asn Trp Arg Ser Glu Leu Tyr Lys Tyr
425 430 435Lys Val Val Lys Ile Glu Pro Leu Gly Val Ala Pro Thr Arg Ala
440 445 450Lys Arg Arg Val Val Gln Arg Glu Lys Arg Ala Val Gly Ile Gly
455 460 465Ala Val Phe Leu Gly Phe Leu Gly Ala Xaa Ser Phe Xaa
470 475 478(2)SEQ ID NO:29的信息：
(ⅰ)序列特征：
(A)长度：511个氨基酸
(B)类型：氨基酸
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:29:Met Arg Val Lys Gly Ile Arg Arg Asn Tyr Gln His Trp Trp Gly Arg1 5 10 15Gly Thr Met Leu Leu Gly Leu Leu Met Ile Cys Ser Ala Thr Glu Lys
20 25 30Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys Glu Ala Thr
35 40 45Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp Thr Glu Ala
50 55 60His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro Asn Pro65 70 75 80Gln Glu Val Glu Leu Val Asn Val Thr Glu Asn Phe Asn Met Trp Lys
85 90 95Asn Asn Met Val Glu Gln Met His Glu Asp Ile Ile Ser Leu Trp Asn
100 105 110Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
115 120 125Asn Cys Thr Asp Leu Arg Asn Thr Thr Asn Thr Asn Asn Ser Thr Asp
130 135 140Asn Asn Asn Ser Lys Ser Glu Gly Thr Ile Lys Gly Gly Glu Met Lys145 150 155 160Asn Cys ser Phe Asn Ile Thr Thr Ser Ile Gly Asp Lys Met Gln Lys
165 170 175Glu Tyr Ala Leu Leu Tyr Lys Leu Asp Ile Glu Pro Ile Asp Asn Asp
180 185 190Ser Thr Ser Tyr Arg Leu Ile Ser Cys Asn Thr Ser Val Ile Thr Gln
195 200 205Ala Cys Pro Lys Ile Ser Phe Glu Pro Ile Pro Ile His Tyr Cys Ala
210 215 220Pro Ala Gly Phe Ala Ile Leu Lys Cys Asn Asp Lys Lys Phe Ser Gly225 230 235 240Lys Gly Ser Cys Lys Asn Val Ser Thr Val Gln Cys Thr His Gly Ile
245 250 255Arg Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu
260 265 270Glu Glu Val Val Ile Arg Ser Glu Asp Phe Thr Asp Asn Ala Lys Thr
275 280 285Ile Ile Val His Leu Lys Glu Ser Val Gln Ile Asn Cys Thr Arg Pro
290 295 300Asn Tyr Asn Lys Arg Lys Arg Ile His Ile Gly Pro Gly Arg Ala Phe305 310 315 320Tyr Thr Thr Lys Asn Ile Lys Gly Thr Ile Arg Gln Ala His Cys Ile
325 330 335Ile Ser Arg Ala Lys Trp Asn Asp Thr Leu Arg Gln Ile Val Ser Lys
340 345 350Leu Lys Glu Gln Phe Lys Asn Lys Thr Ile Val Phe Asn Pro Ser Ser
355 360 365Gly Gly Asp Pro Glu Ile Val Met His Ser Phe Asn Cys Gly Gly Glu
370 375 380Phe Phe Tyr Cys Asn Thr Ser Pro Leu Phe Asn Ser Ile Trp Asn Gly385 390 395 400Asn Asn Thr Trp Asn Asn Thr Thr Gly Ser Asn Asn Asn Ile Thr Leu
405 410 415Gln Cys Lys Ile Lys Gln Ile Ile Asn Met Trp Gln Lys Val Gly Lys
420 425 430Ala Met Tyr Ala Pro Pro Ile Glu Gly Gln Ile Arg Cys Ser Ser Asn
435 440 445Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly Glu Asp Thr Asp Thr
450 455 460Asn Asp Thr Glu Ile Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Asn465 470 475 480Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Thr Ile Glu Pro Leu
485 490 495Gly Val Ala Pro Thr Lys Ala Lys Arg Arg Val Val Gln Arg Glu
500 505 510(2)SEQ ID NO:30的信息：
(ⅰ)序列特征：
(A)长度：2800个碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:30:TTCGAGCTCG CCCGACATTG ATTATTGACT AGAGTCGATC GACAGCTGTG 50GAATGTGTGT CAGTTAGGGT GTGGAAAGTC CCCAGGCTCC CCAGCAGGCA 100GAAGTATGCA AAGCATGCAT CTCAATTAGT CAGCAACCAG GTGTGGAAAG 150TCCCCAGGCT CCCCAGCAGG CAGAAGTATG CAAAGCATGC ATCTCAATTA 200GTCAGCAACC ATAGTCCCGC CCCTAACTCC GCCCATCCCG CCCCTAACTC 250CGCCCAGTTC CGCCCATTCT CCGCCCCATG GCTGACTAAT TTTTTTTATT 300TATGCAGAGG CCGAGGCCGC CTCGGCCTCT GAGCTATTCC AGAAGTAGTG 350AGGAGGCTTT TTTGGAGGCC TAGGCTTTTG CAAAAAGCTA GCTTATCCGG 400CCGGGAACGG TGCATTGGAA CGCGGATTCC CCGTGCCAAG AGTCAGGTAA 450GTACCGCCTA TAGAGTCTAT AGGCCCACCC CCTTGGCTTC GTTAGAACGC 500GGCTACAATT AATACATAAC CTTTTGGATC GATCCTACTG ACACTGACAT 550CCACTTTTTC TTTTTCTCCA CAGGTGTCCA CTCCCAGGTC CAACTGCACC 600TCGGTTCGCG AAGCTAGCTT GGGCTGCATC GATTGAATTC CACTGCCTTC 650CACCAAGCTC TGCAGGATCC CAGAGTCAGG GG TCT GTA TCT TCC TGC 697
Ser Val Ser Ser Cys
1 5TGG TGG CTC CAG TTC AGG AAC AGT AAA CCC TGC TCC GAA TAT 739Trp Trp Leu Gln Phe Arg Asn Ser Lys Pro Cys Ser Glu Tyr
10 15TGC CTC TCA CAT CTC GTC AAT CTC CGC GAG GAC TGG GGA CCC 781Cys Leu Ser His Leu Val Asn Leu Arg Glu Asp Trp Gly Pro20 25 30TCT GAC AAG CTT CAG CGC GAA CGA CCA ACT ACC CCG ATC ATC 823Cys Asp Lys Leu Gln Arg Glu Arg Pro Thr Thr Pro Ile Ile
35 40 45AGT TAT CCT TAA GGT CTC TTT TGT GTG GTG CGT TCC GGT ATG 865Ser Tyr Pro ＊ Gly Leu Phe Cys Val Val Arg Ser Gly Met
50 55 60GGG GGG ACT GCC GCC AGG TTG GGG GCC GTG ATT TTG TTT GTC 907Gly Gly Thr Ala Ala Arg Leu Gly Ala Val Ile Leu Phe Val62 65 70 75GTC ATA GTG GGC CTC CAT GGG GTC CGC GGC AAA TAT GCC TTG 949Val Ile Val Gly Leu His Gly Val Arg Gly Lys Tyr Ala Leu
80 85GCG GAT GCC TCT CTC AAG ATG GCC GAC CCC AAT CGA TTT CGC 991Ala Asp Ala Ser Leu Lys Met Ala Asp Pro Asn Arg Phe Arg90 95 100GGC AAA GAC CTT CCG GTC CTG GAC CAG CTG CTC GAG GTA CCT 1033Gly Lys Asp Leu Pro Val Leu Asp Gln Leu Leu Glu Val Pro
105 110 115GTG TGG AAA GAA GCA AAC ACC ACT CTA TTT TGT GCA TCA GAT 1075Val Trp Lys Glu Ala Asn Thr Thr Leu Phe Cys Ala Ser Asp
120 125 130GCT AAA GCA TAT AAG ACA GAG GCA CAT AAT GTT TGG GCC ACA 1117Ala Lys Ala Tyr Lys Thr Glu Ala His Asn Val Trp Ala Thr
135 140 145CAT GCC TGT GTA CCC ACA GAC CCC AAA CCA CAA GAA ATA AAA 1159His Ala Cys Val Pro Thr Asp Pro Lys Pro Gln Glu Ile Lys
150 155TTG GAA AAT GTG ACA GAA AAT TTT AAC ATG TGG AAA AAT AAC 1201Leu Glu Asn Val Thr Glu Asn Phe Asn Met Trp Lys Asn Asn160 165 170ATG GTA GAA CAG ATG CAT GAG GAT ATA ATC AGT TTA TGG GAT 1243Met Val Glu Gln Met His Glu Asp Ile Ile Ser Leu Trp Asp
175 180 185CAA AGC CTA AAG CCA TGT GTA AAA TTA ACC CCA CTC TGT GTT 1285Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val
190 195 200ACT TTA AAT TGC ACT GAT TTG AGG AAT AAT ACT AAT ACC AAT 1327Thr Leu Asn Cys Thr Asp Leu Arg Asn Asn Thr Asn Thr Asn
205 210 215AGT ACC TAC GGA AAA ATA ATG GAG GGA GGA GAG ATA AAA AAC 1369Ser Thr Tyr Gly Lys Ile Met Glu Gly Gly Glu Ile Lys Asn
220 225TGC TCT TTC AAT ATC ACC ACA AGC ATA AAA GAT AAG CTG AAA 1411Cys Ser Phe Asn Ile Thr Thr Ser Ile Lys Asp Lys Leu Lys230 235 240GAT ATG TCA CTT TTT TAT AAA CTT GAT GTA GTA CCA ATA GGT 1453Asp Met Ser Leu Phe Tyr Lys Leu Asp Val Val Pro Ile Gly
245 250 255AAT AAT AGT AAT ACT ACT AGT TAT AGG TTG ATA AGT TGT AAC 1495Asn Asn Ser Asn Thr Thr Ser Tyr Arg Leu Ile Ser Cys Asn
260 265 270ACC TCA GTC ATT ACA CAA GCC TGT CCA AAG ACA TCC TTT GAG 1537Thr Ser Val Ile Thr Gln Ala Cys Pro Lys Thr Ser Phe Glu
275 280 285CCA ATT CCC ATA CAT TAT TGT GCC CCG GCT GGT TTT GCG ATT 1579Pro Ile Pro Ile His Tyr Cys Ala Pro Ala Gly Phe Ala Ile
290 295CTC AAG TGT AAT GAT AAT AAG TTC AAT GGA ACA GGA CCA TGT 1621Leu Lys Cys Asn Asp Asn Lys Phe Asn Gly Thr Gly Pro Cys300 305 310CCA AAT GTC AGC ACA GTA CAA TGT ACA CAT GGA ATT AGG CCA 1663Pro Asn Val Ser Thr Val Gln Cys Thr His Gly Ile Arg Pro
315 320 325GTA GTA TCA ACT CAA CTG CTG TTA AAT GGC AGT CTA GCA GAA 1705Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu
330 335 340AAA GAG GTA GTC CTT AGA TCT GAA AAT TTC ACG GAC AAT GCT 1747Lys Glu Val Val Leu Arg Ser Glu Asn Phe Thr Asp Asn Ala
345 350 355AAA ACC ATA ATA GTA CAG CTG AAC GAA TCT GTA ATA ATT GAT 1789Lys Thr Ile Ile Val Gln Leu Asn Glu Ser Val Ile Ile Asp
360 365TGT ATG AGA CCC AAC AAC AAT ACA AGA ACA AGT ATA CCT ATG 1831Cys Met Arg Pro Asn Asn Asn Thr Arg Thr Ser Ile Pro Met370 375 380GGA CCA GGG AAA GCA TTT TAT GCA ACA GGA GAT GTA ATA GGA 1873Gly Pro Gly Lys Ala Phe Tyr Ala Thr Gly Asp Val Ile Gly
385 390 395GAT ATA AGA CGA GCA CAT TGT AAC ATT AGT AGA GCA GGA TGG 1915Asp Ile Arg Arg Ala His Cys Asn Ile Ser Arg Ala Gly Trp
400 405 410AAT ACC ACT TTA CAA CAG ATA GCT AAA AAA TTA AGA GAA AAA 1957Asn Thr Thr Leu Gln Gln Ile Ala Lys Lys Leu Arg Glu Lys
415 420 425TTT GAG AAC AAA ACA ATA GTT TTT AAT CAC TCC TCA GGA GGG 1999Phe Glu Asn Lys Thr Ile Val Phe Asn His Ser Ser Gly Gly
430 435GAC CCA GAA ATT GTA ATG CAC ACT TTT AAT TGT GGA GGG GAA 2041Asp Pro Glu Ile Val Met His Thr Phe Asn Cys Gly Gly Glu440 445 450TTT TTC TGC TGT AAT TCA ACA CCA CTG TTT AAT AGT ACT TGG 2083Phe Phe Cys Cys Asn Ser Thr Pro Leu Phe Asn Ser Thr Trp
455 460 465AAT GAT GCA CAA CTG TTT AAT AGT ACT TGG GAT GAT ACT AAA 2125Asn Asp Ala Gln Leu Phe Asn Ser Thr Trp Asp Asp Thr Lys
470 475 480TGG TCA AAA GGC ACT AAC GAA AAT GAC ACA ATC ACC CTC CAT 2167Trp Ser Lys Gly Thr Asn Glu Asn Asp Thr Ile Thr Leu His
485 490 495TGC AGA ATA AAA CAA ATT ATA AAT ATG TGG CAG GAA GTA GGA 2209Cys Arg Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly
500 505AAA GCA ATG TAT GCC CCT CCC ATC AAA GGA CAA ATT AGA TGT 2251Lys Ala Met Tyr Ala Pro Pro Ile Lys Gly Gln Ile Arg Cys510 515 520GAA TCA AAT ATT ACA GGG CTG CTA TTA ACA AGA GAT GGT GGT 2293Glu Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly
525 530 535AAC GAC ACG AGC AAG AAT AAC ACT GAG ATT TTC AGA CCT GGA 2335Asn Asp Thr Ser Lys Asn Asn Thr Glu Ile Phe Arg Pro Gly
540 545 550GGA GGA AAT ATG AAG GAC AAT TGG AGA AGT GAA TTA TAT AAA 2377Gly Gly Asn Met Lys Asp Asn Trp Arg Ser Glu Leu Tyr Lys
555 560 565TAT AAA GTA ATA AAA ATT GAA CCA TTA GGA GTA GCA CCC ATC 2419Tyr Lys Val Ile Lys Ile Glu Pro Leu Gly Val Ala Pro Ile
570 575 579TAGGCAAAGA GAAGAGTGGT GCAGAGAGAA AAAAGAGCAG TGACACTAGG 2469AGCTATGTTC CTTGGGTTCT TGGGAGCAGC AGGAAGCACT ATGGGCGATA 2519AGCTTTAATG CGGTAGTTTA TCACAGTTAA ATTCGTAACG CAGTCAGGCA 2569CCGTGTATGA AATCTAACAA TGCGACCTGC AGAAGCTTAG AACCGAGGAA 2619CTTGTTTATT GCAGCTTATA ATGGTTACAA ATAAAGCAAT AGCATCACAA 2669ATTTCACAAA TAAAGCATTT TTTTCACTGC ATTCTAGTTG TGGTTTGTCC 2719AAACTCATCA ATGTATCTTA TCATGTCTGG ATCGGGAATT AATTCGGCGC 2769AGCACCATGG CCTGAAATAA CCTCTGAAAG A 2800(2)SEQ ID NO:31的信息：
(ⅰ)序列特征：
(A)长度：579个氨基酸
(B)类型：氨基酸
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:31:Ser Val Ser Ser Cys Trp Trp Leu Gln Phe Arg Asn Ser Lys Pro Cys1 5 10 15Ser Glu Tyr Cys Leu Ser His Leu Val Asn Leu Arg Glu Asp Trp Gly
20 25 30Pro Cys Asp Lys Leu Gln Arg Glu Arg Pro Thr Thr Pro Ile Ile Ser
35 40 45Tyr Pro ＊ Gly Leu Phe Cys Val Val Arg Ser Gly Met Gly Gly Thr
50 55 60Ala Ala Arg Leu Gly Ala Val Ile Leu Phe Val Val Ile Val Gly Leu65 70 75 80His Gly Val Arg Gly Lys Tyr Ala Leu Ala Asp Ala Ser Leu Lys Met
85 90 95Ala Asp Pro Asn Arg Phe Arg Gly Lys Asp Leu Pro Val Leu Asp Gln
100 105 110Leu Leu Glu Val Pro Val Trp Lys Glu Ala Asn Thr Thr Leu Phe Cys
115 120 125Ala Ser Asp Ala Lys Ala Tyr Lys Thr Glu Ala His Asn Val Trp Ala
130 135 140Thr His Ala Cys Val Pro Thr Asp Pro Lys Pro Gln Glu Ile Lys Leu145 150 155 160Glu Asn Val Thr Glu Asn Phe Asn Met Trp Lys Asn Asn Met Val Glu
165 170 175Gln Met His Glu Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu Lys Pro
180 185 190Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu Asn Cys Thr Asp Leu
195 200 205Arg Asn Asn Thr Asn Thr Asn Ser Thr Tyr Gly Lys Ile Met Glu Gly
210 215 220Gly Glu Ile Lys Asn Cys Ser Phe Asn Ile Thr Thr Ser Ile Lys Asp225 230 235 240Lys Leu Lys Asp Met Ser Leu Phe Tyr Lys Leu Asp Val Val Pro Ile
245 250 255Gly Asn Asn Ser Asn Thr Thr Ser Tyr Arg Leu Ile Ser Cys Asn Thr
260 265 270Ser Val Ile Thr Gln Ala Cys Pro Lys Thr Ser Phe Glu Pro Ile Pro
275 280 285Ile His Tyr Cys Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys Asn Asp
290 295 300Asn Lys Phe Asn Gly Thr Gly Pro Cys Pro Asn Val Ser Thr Val Gln305 310 315 320Cys Thr His Gly Ile Arg Pro Val Val Ser Thr Gln Leu Leu Leu Asn
325 330 335Gly Ser Leu Ala Glu Lys Glu Val Val Leu Arg Ser Glu Asn Phe Thr
340 345 350Asp Asn Ala Lys Thr Ile Ile Val Gln Leu Asn Glu Ser Val Ile Ile
355 360 365Asp Cys Met Arg Pro Asn Asn Asn Thr Arg Thr Ser Ile Pro Met Gly
370 375 380Pro Gly Lys Ala Phe Tyr Ala Thr Gly Asp Val Ile Gly Asp Ile Arg385 390 395 400Arg Ala His Cys Asn Ile Ser Arg Ala Gly Trp Asn Thr Thr Leu Gln
405 410 415Gln Ile Ala Lys Lys Leu Arg Glu Lys Phe Glu Asn Lys Thr Ile Val
420 425 430Phe Asn His Ser Ser Gly Gly Asp Pro Glu Ile Val Met His Thr Phe
435 440 445Asn Cys Gly Gly Glu Phe Phe Cys Cys Asn Ser Thr Pro Leu Phe Asn
450 455 460Ser Thr Trp Asn Asp Ala Gln Leu Phe Asn Ser Thr Trp Asp Asp Thr465 470 475 480Lys Trp Ser Lys Gly Thr Asn Glu Asn Asp Thr Ile Thr Leu His Cys
485 490 495Arg Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Lys Ala Met
500 505 510Tyr Ala Pro Pro Ile Lys Gly Gln Ile Arg Cys Glu Set Asn Ile Thr
515 520 525Gly Leu Leu Leu Thr Arg Asp Gly Gly Asn Asp Thr Ser Lys Asn Asn
530 535 540Thr Glu Ile Phe Arg Pro Gly Gly Gly Asn Met Lys Asp Asn Trp Arg545 550 555 560Ser Glu Leu Tyr Lys Tyr Lys Val Ile Lys Ile Glu Pro Leu Gly Val
565 570 575Ala Pro Ile(2)SEQ ID NO:32的信息：
(ⅰ)序列特征：
(A)长度：1533个碱基对
(B)类型：核酸
(C)链型：单链
D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:32:ATGGGGGGGA CTGCCGCCAG GTTGGGGGCC GTGATTTTGT TTGTCGTCAT 50AGTGGGCCTC CATGGGGTCC GCGGCAAATA TGCCTTGGCG GATGCCTCTC 100TCAAGATGGC CGACCCCAAT CGATTTCGCG GCAAAGACCT TCCGGTCCTG 150GACCAGCTGC TCGAG GTA CCT GTG TGG AAA GAA GCA ACC ACC 192
Val Pro Val Trp Lys Glu Ala Thr Thr
1 5ACT CTA TTT TGT GCA TCA GAT GCT AAA GCA TAT GAT ACA GAG 234Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp Thr Glu10 15 20GTA CAT AAT GTT TGG GCC ACA CAT GCC TGT GTA CCC ACA GAC 276Val His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp
25 30 35CCC AAC CCA CAA GAA ATA GGA TTG GAA AAT GTA ACA GAA AAT 318Pro Asn Pro Gln Glu Ile Gly Leu Glu Asn Val Thr Glu Asn
40 45 50TTT AAC ATG TGG AAA AAT AAC ATG GTA GAA CAG ATG CAT GAG 360Phe Asn Met Trp Lys Asn Asn Met Val Glu Gln Met His Glu
55 60 65GAT ATA ATC AGT TTA TGG GAT CAA AGC TTA AAG CCA TGT GTA 402Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu Lys Pro Cys Val
70 75AAA TTA ACC CCA CTA TGT GTT ACT TTA AAT TGC ACT GAT TTG 444Lys Leu Thr Pro Leu Cys Val Thr Leu Asn Cys Thr Asp Leu80 85 90AAA AAT GCT ACT AAT ACC ACT AGT AGC AGC TGG GGA AAG ATG 486Lys Asn Ala Thr Asn Thr Thr Ser Ser Ser Trp Gly Lys Met
95 100 105GAG AGA GGA GAA ATA AAA AAC TGC TCT TTC AAT GTC ACC ACA 528Glu Arg Gly Glu Ile Lys Asn Cys Ser Phe Asn Val Thr Thr
110 115 120AGT ATA AGA GAT AAG ATG AAG AAT GAA TAT GCA CTT TTT TAT 570Ser Ile Arg Asp Lys Met Lys Asn Glu Tyr Ala Leu Phe Tyr
125 130 135AAA CTT GAT GTA GTA CCA ATA GAT AAT GAT AAT ACT AGC TAT 612Lys Leu Asp Val Val Pro Ile Asp Asn Asp Asn Thr Ser Tyr
140 145AGG TTG ATA AGT TGT AAC ACC TCA GTC ATT ACA CAG GCC TGT 654Arg Leu Ile Ser Cys Asn Thr Ser Val Ile Thr Gln Ala Cys150 155 160CCA AAG GTG TCC TTT GAG CCA ATT CCC ATA CAT TAT TGT GCC 696Pro Lys Val Ser Phe Glu Pro Ile Pro Ile His Tyr Cys Ala
165 170 175CCG GCT GGT TTT GCG ATT CTA AAG TGT AGA GAT AAA AAG TTC 738Pro Ala Gly Phe Ala Ile Leu Lys Cys Arg Asp Lys Lys Phe
180 185 190AAC GGA ACA GGA CCA TGT ACA AAT GTC AGC ACA GTA CAA TGT 780Asn Gly Thr Gly Pro Cys Thr Asn Val Ser Thr Val Gln Cys
195 200 205ACA CAT GGA ATT AGG CCA GTA GTA TCA ACT CAA CTG CTG TTA 822Thr His Gly Ile Arg Pro Val Val Ser Thr Gln Leu Leu Leu
210 215AAT GGC AGT TTA GCA GAA GAA GAA GTA GTA ATT AGA TCT GCC 864Asn Gly Ser Leu Ala Glu Glu Glu Val Val Ile Arg Ser Ala220 225 230AAT TTC TCG GAC AAT GCT AAA ACC ATA ATA GTA CAG CTG AAC 906Asn Phe Ser Asp Asn Ala Lys Thr Ile Ile Val Gln Leu Asn
235 240 245GAA TCT GTA GAA ATT AAT TGT ACA AGA CCC AAC AAC AAT ACA 948Glu Ser Val Glu Ile Asn Cys Thr Arg Pro Asn Asn Asn Thr
250 255 260AGA AGA AGT ATA CAT ATA GGA CCA GGG AGA GCA TTT TAT GCA 990Arg Ar9 Ser Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Ala
265 270 275ACA GGA GAA ATA ATA GGA GAC ATA AGA CAA GCA CAT TGT AAC 1032Thr Gly Glu Ile Ile Gly Asp Ile Arg Gln Ala His Cys Asn
280 285CTT AGT AGC ACA AAA TGG AAT AAT ACT TTA AAA CAG ATA GTT 1074Leu Ser Ser Thr Lys Trp Asn Asn Thr Leu Lys Gln Ile Val290 295 300ACA AAA TTA AGA GAA CAT TTT AAT AAA ACA ATA GTC TTT AAT 1116Thr Lys Leu Arg Glu His Phe Asn Lys Thr Ile Val Phe Asn
305 310 315CAC TCC TCA GGA GGG GAC CCA GAA ATT GTA ATG CAC AGT TTT 1158His Ser Ser Gly Gly Asp Pro Glu Ile Val Met His Ser Phe
320 325 330AAT TGT GGA GGG GAA TTT TTC TAC TGT AAT ACA ACA CCA CTG 1200Asn Cys Gly Gly Glu Phe Phe Tyr Cys Asn Thr Thr Pro Leu
335 340 345TTT AAT AGT ACT TGG AAT TAT ACT TAT ACT TGG AAT AAT ACT 1242Phe Asn Ser Thr Trp Asn Tyr Thr Tyr Thr Trp Asn Asn Thr
350 355GAA GGG TCA AAT GAC ACT GGA AGA AAT ATC ACA CTC CAA TGC 1284Glu Gly Ser Asn Asp Thr Gly Arg Asn Ile Thr Leu Gln Cys360 365 370AGA ATA AAA CAA ATT ATA AAC ATG TGG CAG GAA GTA GGA AAA 1326Arg Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Lys
375 380 385GCA ATG TAT GCC CCT CCC ATA AGA GGA CAA ATT AGA TGC TCA 1368Ala Met Tyr Ala Pro Pro Ile Arg Gly Gln Ile Arg Cys Ser
390 395 400TCA AAT ATT ACA GGG CTG CTA TTA ACA AGA GAT GGT GGT AAT 1410Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly Asn
405 410 415AAC AGC GAA ACC GAG ATC TTC AGA CCT GGA GGA GGA GAT ATG 1452Asn Ser Glu Thr Glu Ile Phe Arg Pro Gly Gly Gly Asp Met
420 425AGG GAC AAT TGG AGA AGT GAA TTA TAT AAA TAT AAA GTA GTA 1494Arg Asp Asn Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val430 435 440AAA ATT GAA CCA TTA GGA GTA GCA CCC ACC AAG GCA TAA 1533Lys Ile Glu Pro Leu Gly Val Ala Pro Thr Lys Ala ＊
445 450 455(2)SEQ ID NO:33的信息：
(ⅰ)序列特征：
(A)长度：456个氨基酸
(B)类型：氨基酸
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:33:Val Pro Val Trp Lys Glu Ala Thr Thr Thr Leu Phe Cys Ala Ser Asp1 5 10 15Ala Lys Ala Tyr Asp Thr Glu Val His Asn Val Trp Ala Thr His Ala
20 25 30Cys Val Pro Thr Asp Pro Asn Pro Gln Glu Ile Gly Leu Glu Asn Val
35 40 45Thr Glu Asn Phe Asn Met Trp Lys Asn Asn Met Val Glu Gln Met His
50 55 60Glu Asp Ile Ile Ser Leu Trp Asp Gln Ser Leu Lys Pro Cys Val Lys65 70 75 80Leu Thr Pro Leu Cys Val Thr Leu Asn Cys Thr Asp Leu Lys Asn Ala
85 90 95Thr Asn Thr Thr Ser Ser Ser Trp Gly Lys Met Glu Arg Gly Glu Ile
100 105 110Lys Asn Cys Ser Phe Asn Val Thr Thr Ser Ile Arg Asp Lys Met Lys
115 120 125Asn Glu Tyr Ala Leu Phe Tyr Lys Leu Asp Val Val Pro Ile Asp Asn
130 135 140Asp Asn Thr Ser Tyr Arg Leu Ile Ser Cys Asn Thr Ser Val Ile Thr145 150 155 160Gln Ala Cys Pro Lys Val Ser Phe Glu Pro Ile Pro Ile His Tyr Cys
165 170 175Ala Pro Ala Gly Phe Ala Ile Leu Lys Cys Arg Asp Lys Lys Phe Asn
180 185 190Gly Thr Gly Pro Cys Thr Asn Val Ser Thr Val Gln Cys Thr His Gly
195 200 205Ile Arg Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala
210 215 220Glu Glu Glu Val Val Ile Arg Ser Ala Asn Phe Ser Asp Asn Ala Lys225 230 235 240Thr Ile Ile Val Gln Leu Asn Glu Ser Val Glu Ile Asn Cys Thr Arg
245 250 255Pro Asn Asn Asn Thr Arg Arg Ser Ile His Ile Gly Pro Gly Arg Ala
260 265 270Phe Tyr Ala Thr Gly Glu Ile Ile G1y Asp Ile Arg Gln Ala His Cys
275 280 285Asn Leu Ser Ser Thr Lys Trp Asn Asn Thr Leu Lys Gln Ile Val Thr
290 295 300Lys Leu Arg Glu His Phe Asn Lys Thr Ile Val Phe Asn His Ser Ser305 310 315 320Gly Gly Asp Pro Glu Ile Val Met His Ser Phe Asn Cys Gly Gly Glu
325 330 335Phe Phe Tyr Cys Asn Thr Thr Pro Leu Phe Asn Ser Thr Trp Asn Tyr
340 345 350Thr Tyr Thr Trp Asn Asn Thr Glu Gly Ser Asn Asp Thr Gly Arg Asn
355 360 365Ile Thr Leu Gln Cys Arg Ile Lys Gln Ile Ile Asn Met Trp Gln Glu
370 375 380Val Gly Lys Ala Met Tyr Ala Pro Pro Ile Arg Gly Gln Ile Arg Cys385 390 395 400Ser Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly Asn Asn
405 410 415Ser Glu Thr Glu Ile Phe Arg Pro Gly Gly Gly Asp Met Arg Asp Asn
420 425 430Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile Glu Pro Leu
435 440 445Gly Val Ala Pro Thr Lys Ala ＊
450 455(2)SEQ ID NO:34的信息：
(ⅰ)序列特征：
(A)长度：37个碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:34:
GGGAATTCGG ATCCAGAGCA GAAGACAGTG GCAATGA 37(2)SEQ IDNO:35的信息：
(ⅰ)序列特征：
(A)长度：33个碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ IDNO:35:
CTCGAGCTCC TGAACACAGT CAGACTCATC AAG 33(2)SEQ ID NO:36的信息：
(ⅰ)序列特征：
(A)长度：39个碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:36:
GGTCTAGAAG CTTTAGCCCA TAGTGCTTCC TGCTGCTCC 39(2)SEQ ID NO:37的信息：
(ⅰ)序列特征：
(A)长度：36个碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:37:
GGGCGGATCC TCGAGGTACC TGTRTGGAAA GAAGCA 36(2)SEQ ID NO:38的信息：
(ⅰ)序列特征：
(A)长度：38个碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQID NO:38:
GGTCTAGAAG CTTTATGCTC CYAAGAACCC AAGGAACA 38(2)SEQ ID NO:39的信息：
(ⅰ)序列特征：
(A)长度：7个氨基酸
(B)类型：氨基酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:39:
Ile GlyPro GlyArgAlaPhe
l 5(2)SEQID NO:40的信息：
(ⅰ)序列特征：
(A)长度：7个氨基酸
(B)类型：氨基酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:40:
Ile Gly Pro Gly Arg Ala Trp
1 5(2)SEQ IDNO：41的信息：
(ⅰ)序列特征：
(A)长度：7个氨基酸
(B)类型：氨基酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:41:
Leu Gly Pro Gly Ser Thr Phe
l 5(2)SEQIDNO:42的信息：
(ⅰ)序列特征：
(A)长度：7个氨基酸
(B)类型：氨基酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:42:
Ile Gly Pro Gly Arg Val Leu
l 5(2)SEQ ID NO:43的信息：
(ⅰ)序列特征：
(A)长度：7个氨基酸
(B)类型：氨基酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:43:
Ile Gly Pro Gly Ser Ala Phe
1 5(2)SEQ ID NO:44的信息：
(ⅰ)序列特征：
(A)长度：5个氨基酸
(B)类型：氨基酸
(C)链型：单链
(D)拓扑结构：线型
(ⅹⅰ)序列描述：SEQ ID NO:44:
Ile Gly Pro Gly Arg
1 5
Claims (25)
1．一种分离的多肽，该多肽包含HIV gp120的氨基酸序列，所说的氨基酸序列选自由SEQ IDNo.2,4,6,8,10,12,14,16,18,20,22,24,26和28，以及它们的片段组成的组。
2．权利要求1的多肽，其中所说的多肽还包含标记表位序列。
3．权利要求2的多肽，其中所说的标记表位序列是HSV gD-1标记表位序列。
4．权利要求2的多肽，其中所说的标记表位序列是融合到HIVgp120氨基酸序列中的。
5．一种不超过五千碱基的寡核苷酸序列，其编码HIV gp120多肽序列，该多肽序列包含选自由SEQ ID No.2,4,6,8,10,12,14,16,18,20,22,24,26和28，以及它们的片段组成的组的氨基酸序列。
6．权利要求5的寡核苷酸，其中所说的寡核苷酸包含选自由SEQ ID No.1,3,5,7,9,11,13,15,17,19,21,23,25和27，以及它们的片段组成的组的核苷酸序列。
7．权利要求5的寡核苷酸，其中由该寡核苷酸编码的氨基酸序列还包含一个标记表位。
8．权利要求5的寡核苷酸，其中所说的标记表位是HSV gD-1标记表位。
9．权利要求7的寡核苷酸，其中所说的标记表位是融合到HIVgp120氨基酸序列中的。
10．一种疫苗，该疫苗包含在合适载体中的gp120 MN和HIVgp120多肽序列，所说的多肽序列选自由SEQ ID No.2,4,6,8,10,12,14,16,18,20,22,24,26和28，以及它们的片段组成的组。
11．一种疫苗，该疫苗包含：
a．第一gp120多肽序列或其片段；和
b．一种逃逸分离物HIV gp120多肽序列或其片段，其来自用所
说的第一HIV gp120多肽序列接种的被接种者；
其中所说的HIV gp120多肽序列在合适的载体中。
12．权利要求11的疫苗，其中所说的第一HIV gp120多肽序列包括gp120MN,gp120 A244,gp120MN-GNE6(SEQ ID No.31)，或gp120MN-GNE8(SEQ ID No.33)。
13．权利要求12的疫苗，其中所说的疫苗还包含第二gp120多肽序列或其片段，所说的第二gp120多肽序列包括gp120MN,gp120A244,gp120MN-GNE6(SEQ ID No.31)，或gp120MN-GNE8(SEQ IDNo.33)，其中所说的第二HIV gp120多肽序列不同于第一HIV gp120多肽序列。
14．权利要求13的疫苗，其中所说的第一gp120多肽序列包括gp120MN，并且所说的第二gp120多肽序列包括gp120.A244。
15．权利要求14的疫苗，其中所说的逃逸分离物包含在合适载体中的HIV gp120多肽序列，该序列选自由SEQID No.2,4,6,8,10,12,14,16,18,20,22,24,26和28，以及它们的片段组成的组。
16．权利要求13的疫苗，其中所说的第一gp120多肽序列包括gp120MN，并且所说的第二gp120多肽序列包括gp120 MN-GNE8(SEQ ID No.33)。
17．权利要求16的疫苗，其中所说的逃逸分离物HIV gp120多肽序列是在合适载体中的HIV gp120多肽序列，该序列选自由SEQ IDNo.2,4,6,8,10,12,14,16,18,20,22,24,26和28，以及它们的片段组成的组。
18．权利要求13的疫苗，其中所说的逃逸分离物HIV gp120多肽来自用所说的第一和第二HIV gp120多肽序列接种的被接种者。
19．一种制备HIV疫苗的方法，该方法包括将来自被接种者的逃逸分离物HIV gp120多肽序列或其片段添加至用于接种到被接种者的疫苗中。
20．权利要求11的疫苗，其中所说的第一gp120多肽序列来自亲巨噬细胞的HIV-1菌株。
21．权利要求11的疫苗，其中所说的第一gp120多肽序列来自亲T-细胞的HIV-1菌株。
22．权利要求21的疫苗，其中所说的疫苗还包含来自亲巨噬细胞的HIV-1菌株的第二gp120多肽序列或其片段。
23．权利要求22的疫苗，其中所说的第一和第二gp120多肽序列结合在不同的趋化因子受体上。
24．权利要求23的疫苗，其中所说的第一gp120多肽序列结合在CC-CKR-5上，而所说的第二gp120多肽序列结合在CXC-CKR-4上。
25．权利要求11的疫苗，其中所说的疫苗还包含人工改造的用于诱导细胞毒性T-细胞反应的病毒。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 97196244 CN1225132A (zh) | 1996-07-08 | 1997-07-03 | Hiv包膜多肽和疫苗 |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/676,737 | 1996-07-08 | ||
| CN 97196244 CN1225132A (zh) | 1996-07-08 | 1997-07-03 | Hiv包膜多肽和疫苗 |
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| Publication Number | Publication Date |
|---|---|
| CN1225132A true CN1225132A (zh) | 1999-08-04 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 97196244 Pending CN1225132A (zh) | 1996-07-08 | 1997-07-03 | Hiv包膜多肽和疫苗 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1225132A (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104955847A (zh) * | 2012-12-04 | 2015-09-30 | 马里兰州大学(巴尔的摩) | HIV-1 Env结合抗体、融合蛋白及其使用方法 |
| CN106800603A (zh) * | 2017-01-24 | 2017-06-06 | 中国食品药品检定研究院 | 检测抗hiv抗体的adcc活性的方法 |
-
1997
- 1997-07-03 CN CN 97196244 patent/CN1225132A/zh active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104955847A (zh) * | 2012-12-04 | 2015-09-30 | 马里兰州大学(巴尔的摩) | HIV-1 Env结合抗体、融合蛋白及其使用方法 |
| CN106800603A (zh) * | 2017-01-24 | 2017-06-06 | 中国食品药品检定研究院 | 检测抗hiv抗体的adcc活性的方法 |
| CN106800603B (zh) * | 2017-01-24 | 2020-07-28 | 中国食品药品检定研究院 | 检测抗hiv抗体的adcc活性的方法 |
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