CN111499735B - 一种针对hiv的双特异性抗体及其编码基因和应用 - Google Patents

Abstract

本发明公开了一种针对HIV的双特异性抗体及其编码基因和应用。本发明提供了一种IgG抗体，命名为D1‑TMLS抗体。重链可变区包括三个可变区区段，第一个可变区区段的中的CDR1、CDR2和CDR3如序列1中46‑57、75‑77、114‑121所示，第二个可变区区段的中的CDR1、CDR2和CDR3如序列1中172‑179、197‑204、243‑257所示，第三个可变区区段的中的CDR1、CDR2和CDR3如序列1中309‑306、334‑341、380‑394所示。轻链可变区中的CDR1、CDR2和CDR3如序列3中46‑51、69‑71、108‑112所示。D1‑TMLS抗体为双特异性抗体，具有强效而广谱的中和活性。D1‑TMLS抗体对于我国乃至全球艾滋疫情的防控具有重要的意义，同时对社会的稳定和谐有着深远的影响。

Description

一种针对HIV的双特异性抗体及其编码基因和应用

技术领域

本发明涉及一种针对HIV的双特异性抗体及其编码基因和应用。

背景技术

世界卫生组织(WHO)和联合国艾滋病规划署(UNAIDS)在2017年底公布，目前全球HIV-1携带者总人数约为3690万，已经死亡的艾滋病病人累计超过了4000万名。虽然有“鸡尾酒疗法”或抗病毒治疗(cART)，仅2016一年，全球仍然有100万人死于艾滋病，近180万人新近感染艾滋病病毒。我们身处的亚洲，已经成为艾滋病毒迅速传播的地区，是目前世界第二大流行区域。在我国，HIV流行趋势仍然相当严重，新感染人数逐年上升，全国宣布的HIV-1感染者总数约80余万人。当前，通过无保护的性接触传播已经成为艾滋病的主要传播途径，特别是通过男男同性恋人群，艾滋病病毒正在以惊人的速度传播。

目前，由于没有预防性疫苗，艾滋病研究领域最大的成就是高效抗逆转录病毒疗法ART的使用和推广。然而，由于HIV在感染72小时后很快建立了病毒潜伏库，ART无法彻底清除病毒库，感染者不得不终生服药。药物的毒副作用，以及长期服药的依从性难以保证，一旦停药，病人体内的病毒就迅速反弹，也导致耐药病毒的出现。

发明内容

本发明的目的是提供一种针对HIV的双特异性抗体及其编码基因和应用。

本发明提供了一种IgG抗体，命名为D1-TMLS抗体，由轻链和重链组成。

所述重链的重链可变区包括三个可变区区段，第一个可变区区段的中的CDR1、CDR2和CDR3依次如序列表的序列1中第46-57位、第75-77位、第114-121位所示，第二个可变区区段的中的CDR1、CDR2和CDR3依次如序列表的序列1中第172-179位、第197-204位、第243-257位所示，第三个可变区区段的中的CDR1、CDR2和CDR3依次如序列表的序列1中第309-306位、第334-341位、第380-394位所示。

所述轻链的轻链可变区中的CDR1、CDR2和CDR3依次如序列表的序列3中第46-51位、第69-71位、第108-112位所示。

所述重链的重链可变区中，第一个可变区区段如序列表的序列1中第20-131位所示，第二个可变区区段如序列表的序列1中第147-268位所示,第三个可变区区段如序列表的序列1中第284-405位所示。

所述重链的重链可变区如序列表的序列1中第20-405位所示。

所述轻链的轻链可变区如序列表的序列3中第20-122位所示。

所述重链的重链恒定区为人IgG1的重链恒定区。

所述轻链的轻链恒定区为人κ/λ轻链恒定区。

所述重链如序列表的序列1中第20-735位所示或者所述重链如序列表的序列1所示。

所述轻链如序列表的序列3中第20-229位所示或者所述重链如序列表的序列3所示。

编码D1-TMLS抗体的基因也属于本发明的保护范围。

编码所述重链的基因为如下(1)或(2)：

(1)序列表的序列2自5’末端第946-3093位核苷酸所示的DNA分子；

(2)序列表的序列2自5’末端第889-3096位核苷酸所示的DNA分子。

编码所述轻链的基因为如下(3)或(4)：

(3)序列表的序列4自5’末端第946-1575位核苷酸所示的DNA分子；

(4)序列表的序列4自5’末端第889-1578位核苷酸所示的DNA分子。

本发明还保护以上任一所述IgG抗体在制备药物中的应用；所述药物的功能为抑制HIV和/或中和HIV和/或预防艾滋病和/或治疗艾滋病。

本发明还保护一种药物，其活性成分为以上任一所述IgG抗体；所述药物的功能为抑制HIV和/或中和HIV和/或预防艾滋病和/或治疗艾滋病。

本发明还保护以上任一所述基因在制备药物中的应用；所述药物的功能为抑制HIV和/或中和HIV和/或预防艾滋病和/或治疗艾滋病。

以上任一所述HIV具体可为HIV-1。

D1-TMLS抗体为双特异性抗体，对HIV-1有强中和能力。中和试验的结果表明，D1-TMLS抗体具有强效而广谱的中和活性，远远优于hu5A8抗体、N6抗体以及两者的混合抗体，D1-TMLS抗体能够中和父代抗体所不能中和的HIV假病毒株，未来可以尽可能降低耐药病毒株的出现。

本发明提供的D1-TMLS抗体能够有效中和被检测的所有HIV-1假病毒，包括我国流行的三大亚型B，CRF07/08_BC,CRF01_AE及其重组、变异型，及各亚型的初始传播(T/F)病毒，其中和活性的广谱性以及强效性优于目现有的所有抗艾滋病毒单克隆抗体。D1-TMLS抗体对于我国乃至全球艾滋疫情的防控具有重要的意义，同时对社会的稳定和谐有着深远的影响。

具体实施方式

以下的实施例便于更好地理解本发明，但并不限定本发明。下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为自常规生化试剂商店购买得到的。以下实施例中的定量试验，均设置三次重复实验，结果取平均值。

293T细胞：CRL-11268。PMD18-T载体：Takara，产品目录号D101A。protein Abeads：Thermo，产品目录号10006D。质粒pNL4-3R-E-luciferase(骨架质粒)：参考文献:HeJ,Choe S,Walker R,Di Marzio P,Morgan DO,Landau NR.J Virol 69:6705–6711,1995.。Ghost细胞：美国国立卫生研究院NIH。

实施例1、抗体的描述

一、双价特异性中和抗体D1-TMLS

D1-TMLS抗体，是一种IgG抗体，由轻链和重链组成。

重链如序列表的序列1所示。序列1中，第1-19位氨基酸残基为信号肽(引导蛋白分泌到细胞外)，第20-131位氨基酸残基为hu5A8抗体的轻链可变区(CDR1、CDR2、CDR3依次如序列1的第46-57位、第75-77位、第114-121位所示)，第147-268位氨基酸残基为hu5A8抗体的重链可变区(CDR1、CDR2、CDR3依次如序列1的第172-179位、第197-204位、第243-257位所示),第284-405位氨基酸残基为N6抗体的重链可变区(CDR1、CDR2、CDR3依次如序列1的第309-306位、第334-341位、第380-394位所示)，第406-735位氨基酸残基为人IgG1的重链恒定区。

轻链如序列表的序列3所示。序列3中，第1-19位氨基酸残基为信号肽(引导蛋白分泌到细胞外)，第20-122位氨基酸残基为N6抗体的轻链可变区(CDR1、CDR2、CDR3依次如序列3的第46-51位、第69-71位、第108-112位所示)，第123-229位氨基酸残基为人κ/λ轻链恒定区。

二、N6抗体

N6抗体，是一种IgG抗体，由轻链和重链组成。

重链如序列表的序列5所示。

轻链如序列表的序列3所示。

三、Hu5A8抗体

Hu5A8抗体，是一种IgG抗体，由轻链和重链组成。

重链如序列表的序列7所示。

轻链如序列表的序列9所示。

实施例2、D1-TMLS抗体的制备

一、重组质粒的构建

将序列表的序列2所示的双链DNA分子插入PMD18-T载体，得到重链表达载体。序列2中，第1至888位核苷酸为CMV启动子，第889-3096位核苷酸编码D1-TMLS抗体的重链，第3169-3296位核苷酸为ployA终止序列。

将序列表的序列4所示的双链DNA分子插入PMD18-T载体，得到轻链表达载体。序列4中，第1至888位核苷酸为CMV启动子，第889-1578位核苷酸编码D1-TMLS抗体的轻链，第1599-1726位核苷酸为ployA终止序列。

二、重组细胞的构建

将步骤一构建的重链表达载体和步骤一构建的轻链表达载体共转染293T细胞，得到重组细胞。

三、抗体的制备

1、取步骤二得到的重组细胞，在含2％胎牛血清的DMEM培养基培养72h，然后4℃、4000rpm离心30min，收集上清液。

2、亲和层析

亲和层析的层析柱规格：长度3cm，内径1cm；

亲和层析的柱填料：protein A beads(Thermo，产品目录号10006D)；

操作步骤：①将300mL步骤1得到的上清液上样于亲和层析柱，4℃孵育16小时；②用60ml结合缓冲液洗涤柱子；③用30mL洗脱缓冲液洗脱目的蛋白，收集过柱后溶液。

结合缓冲液：取甘氨酸112.6g、氯化钠175.2g，溶于水并用水定容至1L，用氢氧化钠调pH至8.0。

洗脱缓冲液：取甘氨酸7.5g，溶于水并用水定容至500ml，用盐酸调pH至3.0。

3、取步骤2得到的过柱后溶液，用超滤浓缩管浓缩并将体系置换为PBS缓冲液(pH7.2、10mM)，得到1ml抗体浓度为0.5mg/ml的抗体溶液，命名为D1-TMLS抗体溶液。

实施例3、对照抗体的制备

用序列表的序列6所示的DNA分子取代序列表的序列2所示的DNA分子，其他同实施例2，得到抗体溶液，命名为N6抗体溶液。

用序列表的序列8所示的DNA分子取代序列表的序列2所示的DNA分子并且用序列表的序列10所示的DNA分子取代序列表的序列4所示的DNA分子，其他同实施例2，得到抗体溶液，命名为Hu5A8抗体溶液。

实施例4、抗体的效果

一、HIV假病毒的制备

制备不同的HIV假病毒来模拟不同的HIV毒株。HIV毒株信息以及对应的膜蛋白和膜蛋白基因见表1和表2。

1、将人工合成的HIV膜蛋白基因插入质粒pcDNA3.1(+)的BamHI和NotI酶切位点之间，得到HIV膜蛋白基因重组质粒，将HIV膜蛋白基因重组质粒和质粒pNL4-3R-E-luciferase共转染293T细胞，得到重组细胞。质粒pNL4-3R-E-luciferase中含有HIV-1病毒基因组的全部基因(与野生HIV-1病毒基因组的差异仅在于envelope基因发生了移码)。HIV膜蛋白基因重组质粒和质粒pNL4-3R-E-luciferase共转染宿主细胞，可以表达HIV假病毒。HIV-1假病毒只能在被感染的细胞中复制基因组并表达荧光素酶报告基因，不能再产生有感染性的病毒颗粒。

3、取步骤2得到的重组细胞，在含10％胎牛血清的DMEM培养基培养60h。

4、完成步骤3后，取培养上清，即为HIV假病毒的病毒液(简称HIV病毒液)。

5、利用p24定量检测的ELISA试剂盒检测HIV病毒液中的病毒滴度。

二、单克隆抗体的中和活性检测

供试抗体溶液：实施例2制备的D1-TMLS抗体溶液、实施例3制备的N6抗体溶液、实施例3制备的Hu5A8抗体溶液、混合抗体溶液(即实施例3制备的N6抗体溶液和实施例3制备的Hu5A8抗体溶液混合，混合溶液中N6抗体和Hu5A8抗体质量相等)。

1、取供试抗体溶液，用PBS缓冲液(pH7.2、10mM)进行倍比稀释，得到抗体稀释液。

2、取96孔细胞培养板，每孔加入100微升抗体稀释液与50微升HIV病毒液(病毒含量为100TCID₅₀)，使得混合体系中的抗体浓度为1.8519μg/ml、0.6173μg/ml、0.2058μg/ml、0.0686μg/ml、0.0229μg/ml、0.0076μg/ml、0.0025μg/ml或0.0008μg/ml(以抗体浓度计)，37℃静置孵育1小时。用等体积PBS缓冲液(pH7.2、10mM)代替抗体稀释液，作为病毒对照。用等体积含10％胎牛血清的DMEM培养基代替HIV病毒液，作为细胞对照。

3、完成步骤2后，取所述细胞培养板，每孔接种100微升Ghost细胞悬液(用于制备细胞悬液的溶剂为含10％胎牛血清的DMEM培养基，细胞悬液中的Ghost细胞浓度为2×10⁵个细胞/ml)，37℃静置孵育64小时。

4、完成步骤3后，取所述细胞培养板，吸弃上清，每孔加入150微升裂解液(微格拉斯生物技术，货号T003，按说明书操作)，37℃静置孵育5分钟。

5、完成步骤4后，取所述细胞培养板，检测荧光素酶活性。

中和活性(％)＝(试验组的荧光强度-细胞对照的荧光强度)/(病毒对照的荧光强度-细胞对照的荧光强度)×100％。

利用Prism 5软件计算中和活性为50％时的抗体浓度，即抗体的IC₅₀值，抗体的IC₅₀值见表1和表2。

表1

表2

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ccactcccag gtccaactgc acctcggttc tatcgattga attccaccat gggatggtca 900

tgtatcatcc tttttctagt agcaactgca accggtgtac attctgacat tgtgatgact 960

cagagccccg acagcctggc cgtctcactg ggcgaaaggg tgaccatgaa ttgtaaatct 1020

tctcagagcc tgctgtacag tacaaaccag aaaaattacc tggcctggta tcagcagaaa 1080

cccggccaga gccctaagct gctgatctat tgggcaagta cccgagagtc aggagtgcca 1140

gacagattct ccgggtctgg aagtggcaca gacttcaccc tgacaattag ctccgtgcag 1200

gccgaggacg tggctgtcta ctattgccag cagtactata gctaccgaac tttcggcggg 1260

ggaaccaaac tggaaatcaa gggaggagga ggcagtggcg gaggagggtc aggaggagga 1320

ggaagccagg tgcagctgca gcagtccgga ccagaggtgg tcaaacccgg cgcaagcgtc 1380

aaaatgtcct gtaaggcatc tggctacact ttcacctctt atgtgattca ctgggtcaga 1440

cagaagcctg ggcagggact ggactggatc gggtacatta acccatataa tgatggaact 1500

gactacgatg aaaagtttaa aggcaaggcc acactgactt ccgacacctc aacaagcact 1560

gcttatatgg agctgtctag tctgaggtct gaagacacag cagtgtacta ttgcgcccgc 1620

gagaaggata actacgccac tggcgcttgg tttgcatatt ggggccaggg gaccctggtg 1680

acagtctcat ccggtggcgg tggcagcggc ggtggtggtt ccggaggcgg cggttctaga 1740

gctcatctgg tgcagagcgg cacagctatg aagaagcccg gagccagcgt gagagtgtct 1800

tgccagacca gcggctacac cttcaccgcc cacatcctgt tttggttccg gcaggctcca 1860

ggaagaggac tcgagtgggt cggttggatc aagccccagt acggagccgt gaacttcgga 1920

ggcggcttta gagacagagt gaccctgacc agggacgtgt acagggagat cgcctacatg 1980

gacatccggg gactgaagcc agacgacaca gccgtgtact attgcgccag ggacaggagc 2040

tacggcgatt cttcttgggc cctggacgct tggggacagg gaacaacagt ggtcgtgtca 2100

gctgcgtcga ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 2160

gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc tgtgacggtc 2220

tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 2280

tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacccag 2340

acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gagagttgag 2400

cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga gttcgagggg 2460

ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 2520

cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 2580

tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 2640

aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 2700

aaggagtaca agtgcaaggt ctccaacaaa gccctcccag ccagcatcga gaaaaccatc 2760

tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgcgag 2820

gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 2880

atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 2940

gtgctggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg 3000

tggcagcagg ggaacgtctt ctcatgctcc gtgctgcatg aggctctgca cagccactac 3060

acgcagaaga gcctctccct gtctccgggt aaataggtgc gacggccggc aagcccccgc 3120

tccccgggct ctcgcggtcg tacgaggaaa gcttggccgc catggcccaa cttgtttatt 3180

gcagcttata atggttacaa ataaagcaat agcatcacaa atttcacaaa taaagcattt 3240

ttttcactgc attctagttg tggtttgtcc aaactcatca atgtatctta tcatgt 3296

<210> 3

<211> 229

<212> PRT

<213> Artificial sequence

<400> 3

Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly

1 5 10 15

Val His Ser Tyr Ile His Val Thr Gln Ser Pro Ser Ser Leu Ser Val

20 25 30

Ser Ile Gly Asp Arg Val Thr Ile Asn Cys Gln Thr Ser Gln Gly Val

35 40 45

Gly Ser Asp Leu His Trp Tyr Gln His Lys Pro Gly Arg Ala Pro Lys

50 55 60

Leu Leu Ile His His Thr Ser Ser Val Glu Asp Gly Val Pro Ser Arg

65 70 75 80

Phe Ser Gly Ser Gly Phe His Thr Ser Phe Asn Leu Thr Ile Ser Asp

85 90 95

Leu Gln Ala Asp Asp Ile Ala Thr Tyr Tyr Cys Gln Val Leu Gln Phe

100 105 110

Phe Gly Arg Gly Ser Arg Leu His Ile Lys Arg Thr Val Ala Ala Pro

115 120 125

Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr

130 135 140

Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys

145 150 155 160

Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu

165 170 175

Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser

180 185 190

Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala

195 200 205

Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe

210 215 220

Asn Arg Gly Glu Cys

225

<210> 4

<211> 1726

<212> DNA

<213> Artificial sequence

<400> 4

agtaatcaat tacggggtca ttagttcata gcccatatat ggagttccgc gttacataac 60

ttacggtaaa tggcccgcct ggctgaccgc ccaacgaccc ccgcccattg acgtcaataa 120

tgacgtatgt tcccatagta acgccaatag ggactttcca ttgacgtcaa tgggtggagt 180

atttacggta aactgcccac ttggcagtac atcaagtgta tcatatgcca agtacgcccc 240

ctattgacgt caatgacggt aaatggcccg cctggcatta tgcccagtac atgaccttat 300

gggactttcc tacttggcag tacatctacg tattagtcat cgctattacc atggtgatgc 360

ggttttggca gtacatcaat gggcgtggat agcggtttga ctcacgggga tttccaagtc 420

tccaccccat tgacgtcaat gggagtttgt tttggcacca aaatcaacgg gactttccaa 480

aatgtcgtaa caactccgcc ccattgacgc aaatgggcgg taggcgtgta cggtgggagg 540

tctatataag cagagctcgt ttagtgaacc gtcagatcgc ctggagacgc catccacgct 600

gttttgacct ccatagaaga caccgggacc gatccagcct ccgcggccgg gaacggtgca 660

ttggaacgcg gattccccgt gccaagagtg acgtaagtac cgcctataga gtctataggc 720

ccaccccctt ggcttcgtta gaacgcggct acaattaata cataacctta tgtatcatac 780

acatacgatt taggtgacac tatagaataa catccacttt gcctttctct ccacaggtgt 840

ccactcccag gtccaactgc acctcggttc tatcgattga attccaccat gggatggtca 900

tgtatcatcc tttttctagt agcaactgca accggtgtac attcttacat ccacgtgacc 960

cagagcccta gcagcctgag cgtgtctatc ggcgacagag tgaccatcaa ctgccagacc 1020

agccagggag tgggaagcga cctgcattgg taccagcaca agcccggaag agcccctaag 1080

ctgctgatcc accacacatc tagcgtggag gacggagtgc ctagcagatt cagcggaagc 1140

ggcttccaca ccagcttcaa cctgaccatc agcgacctgc aggcagacga catcgccacc 1200

tactactgcc aggtgctgca gttcttcggc aggggaagca gactgcacat caagcgtacg 1260

gtggctgcac catctgtctt catcttcccg ccatctgatg agcagttgaa atctggaact 1320

gcctctgttg tgtgcctgct gaataacttc tatcccagag aggccaaagt acagtggaag 1380

gtggataacg ccctccaatc gggtaactcc caggagagtg tcacagagca ggacagcaag 1440

gacagcacct acagcctcag cagcaccctg acgctgagca aagcagacta cgagaaacac 1500

aaagtctacg cctgcgaagt cacccatcag ggcctgagct cgcccgtcac aaagagcttc 1560

aacaggggag agtgttagaa gcttggccgc catggcccaa cttgtttatt gcagcttata 1620

atggttacaa ataaagcaat agcatcacaa atttcacaaa taaagcattt ttttcactgc 1680

attctagttg tggtttgtcc aaactcatca atgtatctta tcatgt 1726

<210> 5

<211> 471

<212> PRT

<213> Artificial sequence

<400> 5

Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly

1 5 10 15

Val His Ser Arg Ala His Leu Val Gln Ser Gly Thr Ala Met Lys Lys

20 25 30

Pro Gly Ala Ser Val Arg Val Ser Cys Gln Thr Ser Gly Tyr Thr Phe

35 40 45

Thr Ala His Ile Leu Phe Trp Phe Arg Gln Ala Pro Gly Arg Gly Leu

50 55 60

Glu Trp Val Gly Trp Ile Lys Pro Gln Tyr Gly Ala Val Asn Phe Gly

65 70 75 80

Gly Gly Phe Arg Asp Arg Val Thr Leu Thr Arg Asp Val Tyr Arg Glu

85 90 95

Ile Ala Tyr Met Asp Ile Arg Gly Leu Lys Pro Asp Asp Thr Ala Val

100 105 110

Tyr Tyr Cys Ala Arg Asp Arg Ser Tyr Gly Asp Ser Ser Trp Ala Leu

115 120 125

Asp Ala Trp Gly Gln Gly Thr Thr Val Val Val Ser Ala Ala Ser Thr

130 135 140

Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser

145 150 155 160

Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu

165 170 175

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His

180 185 190

Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser

195 200 205

Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys

210 215 220

Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu

225 230 235 240

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

245 250 255

Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

260 265 270

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

275 280 285

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

290 295 300

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

305 310 315 320

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

325 330 335

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

340 345 350

Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

355 360 365

Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys

370 375 380

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

385 390 395 400

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

405 410 415

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

420 425 430

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

435 440 445

Cys Ser Val Leu His Glu Ala Leu His Ser His Tyr Thr Gln Lys Ser

450 455 460

Leu Ser Leu Ser Pro Gly Lys

465 470

<210> 6

<211> 2504

<212> DNA

<213> Artificial sequence

<400> 6

agtaatcaat tacggggtca ttagttcata gcccatatat ggagttccgc gttacataac 60

ttacggtaaa tggcccgcct ggctgaccgc ccaacgaccc ccgcccattg acgtcaataa 120

tgacgtatgt tcccatagta acgccaatag ggactttcca ttgacgtcaa tgggtggagt 180

atttacggta aactgcccac ttggcagtac atcaagtgta tcatatgcca agtacgcccc 240

ctattgacgt caatgacggt aaatggcccg cctggcatta tgcccagtac atgaccttat 300

gggactttcc tacttggcag tacatctacg tattagtcat cgctattacc atggtgatgc 360

ggttttggca gtacatcaat gggcgtggat agcggtttga ctcacgggga tttccaagtc 420

tccaccccat tgacgtcaat gggagtttgt tttggcacca aaatcaacgg gactttccaa 480

aatgtcgtaa caactccgcc ccattgacgc aaatgggcgg taggcgtgta cggtgggagg 540

tctatataag cagagctcgt ttagtgaacc gtcagatcgc ctggagacgc catccacgct 600

gttttgacct ccatagaaga caccgggacc gatccagcct ccgcggccgg gaacggtgca 660

ttggaacgcg gattccccgt gccaagagtg acgtaagtac cgcctataga gtctataggc 720

ccaccccctt ggcttcgtta gaacgcggct acaattaata cataacctta tgtatcatac 780

acatacgatt taggtgacac tatagaataa catccacttt gcctttctct ccacaggtgt 840

ccactcccag gtccaactgc acctcggttc tatcgattga attccaccat gggatggtca 900

tgtatcatcc tttttctagt agcaactgca accggtgtac attctagagc tcatctggtg 960

cagagcggca cagctatgaa gaagcccgga gccagcgtga gagtgtcttg ccagaccagc 1020

ggctacacct tcaccgccca catcctgttt tggttccggc aggctccagg aagaggactc 1080

gagtgggtcg gttggatcaa gccccagtac ggagccgtga acttcggagg cggctttaga 1140

gacagagtga ccctgaccag ggacgtgtac agggagatcg cctacatgga catccgggga 1200

ctgaagccag acgacacagc cgtgtactat tgcgccaggg acaggagcta cggcgattct 1260

tcttgggccc tggacgcttg gggacaggga acaacagtgg tcgtgtcagc tgcgtcgacc 1320

aagggcccat cggtcttccc cctggcaccc tcctccaaga gcacctctgg gggcacagcg 1380

gccctgggct gcctggtcaa ggactacttc cccgaacctg tgacggtctc gtggaactca 1440

ggcgccctga ccagcggcgt gcacaccttc ccggctgtcc tacagtcctc aggactctac 1500

tccctcagca gcgtggtgac cgtgccctcc agcagcttgg gcacccagac ctacatctgc 1560

aacgtgaatc acaagcccag caacaccaag gtggacaaga gagttgagcc caaatcttgt 1620

gacaaaactc acacatgccc accgtgccca gcacctgagt tcgagggggg accgtcagtc 1680

ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 1740

tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 1800

ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 1860

cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 1920

tgcaaggtct ccaacaaagc cctcccagcc agcatcgaga aaaccatctc caaagccaaa 1980

gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgcgagga gatgaccaag 2040

aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 2100

tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 2160

gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 2220

aacgtcttct catgctccgt gctgcatgag gctctgcaca gccactacac gcagaagagc 2280

ctctccctgt ctccgggtaa ataggtgcga cggccggcaa gcccccgctc cccgggctct 2340

cgcggtcgta cgaggaaagc ttggccgcca tggcccaact tgtttattgc agcttataat 2400

ggttacaaat aaagcaatag catcacaaat ttcacaaata aagcattttt ttcactgcat 2460

tctagttgtg gtttgtccaa actcatcaat gtatcttatc atgt 2504

<210> 7

<211> 471

<212> PRT

<213> Artificial sequence

<400> 7

Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly

1 5 10 15

Val His Ser Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Val Val Lys

20 25 30

Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe

35 40 45

Thr Ser Tyr Val Ile His Trp Val Arg Gln Lys Pro Gly Gln Gly Leu

50 55 60

Asp Trp Ile Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Asp Tyr Asp

65 70 75 80

Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ser Asp Thr Ser Thr Ser

85 90 95

Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val

100 105 110

Tyr Tyr Cys Ala Arg Glu Lys Asp Asn Tyr Ala Thr Gly Ala Trp Phe

115 120 125

Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr

130 135 140

Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser

145 150 155 160

Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu

165 170 175

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His

180 185 190

Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser

195 200 205

Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys

210 215 220

Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu

225 230 235 240

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

245 250 255

Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

260 265 270

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

275 280 285

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

290 295 300

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

305 310 315 320

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

325 330 335

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

340 345 350

Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

355 360 365

Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys

370 375 380

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

385 390 395 400

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

405 410 415

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

420 425 430

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

435 440 445

Cys Ser Val Leu His Glu Ala Leu His Ser His Tyr Thr Gln Lys Ser

450 455 460

Leu Ser Leu Ser Pro Gly Lys

465 470

<210> 8

<211> 2504

<212> DNA

<213> Artificial sequence

<400> 8

agtaatcaat tacggggtca ttagttcata gcccatatat ggagttccgc gttacataac 60

ttacggtaaa tggcccgcct ggctgaccgc ccaacgaccc ccgcccattg acgtcaataa 120

tgacgtatgt tcccatagta acgccaatag ggactttcca ttgacgtcaa tgggtggagt 180

atttacggta aactgcccac ttggcagtac atcaagtgta tcatatgcca agtacgcccc 240

ctattgacgt caatgacggt aaatggcccg cctggcatta tgcccagtac atgaccttat 300

gggactttcc tacttggcag tacatctacg tattagtcat cgctattacc atggtgatgc 360

ggttttggca gtacatcaat gggcgtggat agcggtttga ctcacgggga tttccaagtc 420

tccaccccat tgacgtcaat gggagtttgt tttggcacca aaatcaacgg gactttccaa 480

aatgtcgtaa caactccgcc ccattgacgc aaatgggcgg taggcgtgta cggtgggagg 540

tctatataag cagagctcgt ttagtgaacc gtcagatcgc ctggagacgc catccacgct 600

gttttgacct ccatagaaga caccgggacc gatccagcct ccgcggccgg gaacggtgca 660

ttggaacgcg gattccccgt gccaagagtg acgtaagtac cgcctataga gtctataggc 720

ccaccccctt ggcttcgtta gaacgcggct acaattaata cataacctta tgtatcatac 780

acatacgatt taggtgacac tatagaataa catccacttt gcctttctct ccacaggtgt 840

ccactcccag gtccaactgc acctcggttc tatcgattga attccaccat gggatggtca 900

tgtatcatcc tttttctagt agcaactgca accggtgtac attctcaggt gcagctgcag 960

cagtccggac cagaggtggt caaacccggc gcaagcgtca aaatgtcctg taaggcatct 1020

ggctacactt tcacctctta tgtgattcac tgggtcagac agaagcctgg gcagggactg 1080

gactggatcg ggtacattaa cccatataat gatggaactg actacgatga aaagtttaaa 1140

ggcaaggcca cactgacttc cgacacctca acaagcactg cttatatgga gctgtctagt 1200

ctgaggtctg aagacacagc agtgtactat tgcgcccgcg agaaggataa ctacgccact 1260

ggcgcttggt ttgcatattg gggccagggg accctggtga cagtctcatc cgcgtcgacc 1320

aagggcccat cggtcttccc cctggcaccc tcctccaaga gcacctctgg gggcacagcg 1380

gccctgggct gcctggtcaa ggactacttc cccgaacctg tgacggtctc gtggaactca 1440

ggcgccctga ccagcggcgt gcacaccttc ccggctgtcc tacagtcctc aggactctac 1500

tccctcagca gcgtggtgac cgtgccctcc agcagcttgg gcacccagac ctacatctgc 1560

aacgtgaatc acaagcccag caacaccaag gtggacaaga gagttgagcc caaatcttgt 1620

gacaaaactc acacatgccc accgtgccca gcacctgagt tcgagggggg accgtcagtc 1680

ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 1740

tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 1800

ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 1860

cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 1920

tgcaaggtct ccaacaaagc cctcccagcc agcatcgaga aaaccatctc caaagccaaa 1980

gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgcgagga gatgaccaag 2040

aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 2100

tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 2160

gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 2220

aacgtcttct catgctccgt gctgcatgag gctctgcaca gccactacac gcagaagagc 2280

ctctccctgt ctccgggtaa ataggtgcga cggccggcaa gcccccgctc cccgggctct 2340

cgcggtcgta cgaggaaagc ttggccgcca tggcccaact tgtttattgc agcttataat 2400

ggttacaaat aaagcaatag catcacaaat ttcacaaata aagcattttt ttcactgcat 2460

tctagttgtg gtttgtccaa actcatcaat gtatcttatc atgt 2504

<210> 9

<211> 238

<212> PRT

<213> Artificial sequence

<400> 9

Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly

1 5 10 15

Val His Ser Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val

20 25 30

Ser Leu Gly Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gln Ser Leu

35 40 45

Leu Tyr Ser Thr Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys

50 55 60

Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu

65 70 75 80

Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

85 90 95

Thr Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Val Ala Val Tyr Tyr

100 105 110

Cys Gln Gln Tyr Tyr Ser Tyr Arg Thr Phe Gly Gly Gly Thr Lys Leu

115 120 125

Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro

130 135 140

Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu

145 150 155 160

Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn

165 170 175

Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser

180 185 190

Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala

195 200 205

Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly

210 215 220

Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

225 230 235

<210> 10

<211> 1753

<212> DNA

<213> Artificial sequence

<400> 10

agtaatcaat tacggggtca ttagttcata gcccatatat ggagttccgc gttacataac 60

ttacggtaaa tggcccgcct ggctgaccgc ccaacgaccc ccgcccattg acgtcaataa 120

tgacgtatgt tcccatagta acgccaatag ggactttcca ttgacgtcaa tgggtggagt 180

atttacggta aactgcccac ttggcagtac atcaagtgta tcatatgcca agtacgcccc 240

ctattgacgt caatgacggt aaatggcccg cctggcatta tgcccagtac atgaccttat 300

gggactttcc tacttggcag tacatctacg tattagtcat cgctattacc atggtgatgc 360

ggttttggca gtacatcaat gggcgtggat agcggtttga ctcacgggga tttccaagtc 420

tccaccccat tgacgtcaat gggagtttgt tttggcacca aaatcaacgg gactttccaa 480

aatgtcgtaa caactccgcc ccattgacgc aaatgggcgg taggcgtgta cggtgggagg 540

tctatataag cagagctcgt ttagtgaacc gtcagatcgc ctggagacgc catccacgct 600

gttttgacct ccatagaaga caccgggacc gatccagcct ccgcggccgg gaacggtgca 660

ttggaacgcg gattccccgt gccaagagtg acgtaagtac cgcctataga gtctataggc 720

ccaccccctt ggcttcgtta gaacgcggct acaattaata cataacctta tgtatcatac 780

acatacgatt taggtgacac tatagaataa catccacttt gcctttctct ccacaggtgt 840

ccactcccag gtccaactgc acctcggttc tatcgattga attccaccat gggatggtca 900

tgtatcatcc tttttctagt agcaactgca accggtgtac attctgacat tgtgatgact 960

cagagccccg acagcctggc cgtctcactg ggcgaaaggg tgaccatgaa ttgtaaatct 1020

tctcagagcc tgctgtacag tacaaaccag aaaaattacc tggcctggta tcagcagaaa 1080

cccggccaga gccctaagct gctgatctat tgggcaagta cccgagagtc aggagtgcca 1140

gacagattct ccgggtctgg aagtggcaca gacttcaccc tgacaattag ctccgtgcag 1200

gccgaggacg tggctgtcta ctattgccag cagtactata gctaccgaac tttcggcggg 1260

ggaaccaaac tggaaatcaa gcgtacggtg gctgcaccat ctgtcttcat cttcccgcca 1320

tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 1380

cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 1440

gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 1500

ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 1560

ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttagaagct tggccgccat 1620

ggcccaactt gtttattgca gcttataatg gttacaaata aagcaatagc atcacaaatt 1680

tcacaaataa agcatttttt tcactgcatt ctagttgtgg tttgtccaaa ctcatcaatg 1740

tatcttatca tgt 1753

<210> 11

<211> 846

<212> PRT

<213> Human Immunodeficiency Virus

<400> 11

Met Arg Val Lys Gly Ile Arg Lys Asn Tyr Gln His Leu Trp Arg Trp

1 5 10 15

Gly Thr Met Leu Leu Gly Met Leu Met Ile Cys Ser Ala Ala Glu Asn

20 25 30

Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys Glu Ala Thr

35 40 45

Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp Thr Glu Val

50 55 60

His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro Asn Pro

65 70 75 80

Gln Glu Val Val Leu Gly Asn Val Thr Glu Asp Phe Asn Met Trp Glu

85 90 95

Asn Asn Met Val Asp Gln Met His Glu Asp Ile Ile Ser Leu Trp Asp

100 105 110

Gln Ser Leu Lys Pro Cys Val Arg Leu Thr Pro Leu Cys Val Thr Leu

115 120 125

Asn Cys Thr Asn Trp Asn Ala Thr Asn Leu Gly Asn Asp Thr Asn Thr

130 135 140

Ile Ser Met Ile Lys Glu Gly Glu Ile Lys Asn Cys Ser Phe Asn Ile

145 150 155 160

Thr Thr Asn Ile Arg Thr Lys Val Arg Asp Tyr Ala Leu Phe Tyr Ala

165 170 175

Leu Asp Val Val Pro Ile Asp Asn Ala Ser Trp Arg Leu Thr Ser Cys

180 185 190

Asn Thr Ser Val Ile Thr Gln Ala Cys Pro Lys Val Ser Phe Glu Pro

195 200 205

Ile Pro Ile His Tyr Cys Thr Pro Ala Gly Phe Ala Ile Leu Lys Cys

210 215 220

Asn Asp Lys Lys Phe Asn Gly Thr Gly Pro Cys Thr Asn Val Ser Thr

225 230 235 240

Val Gln Cys Thr His Gly Ile Arg Pro Val Val Ser Thr Gln Leu Leu

245 250 255

Leu Asn Gly Ser Leu Ala Glu Glu Glu Ile Val Ile Arg Ser Ser Asn

260 265 270

Leu Ser Ile Asn His Lys Asn Ile Ile Val Gln Leu Asn Lys Ser Val

275 280 285

Glu Ile Asn Cys Thr Arg Pro Asn Asn Asn Thr Leu Lys Ser Ile Gln

290 295 300

Leu Gly Leu Gly Arg Ala Trp His Ala Thr Gly Gln Ile Ile Gly Asp

305 310 315 320

Ile Arg Gln Ala His Cys Asn Leu Ser Gly Thr Asp Trp Asn Asn Thr

325 330 335

Leu Asn Leu Ile Thr Glu Lys Leu Arg Glu Gln Phe Gly Ser Lys Thr

340 345 350

Ile Val Phe Lys Pro His Val Gly Gly Asp Pro Glu Val Val Met His

355 360 365

Asn Phe Asn Cys Gly Gly Glu Phe Phe Tyr Cys Asn Thr Ser Gln Leu

370 375 380

Phe Asn Ser Thr Trp His Val Asn Gly Thr Trp Asn Gly Thr Thr Glu

385 390 395 400

Asn Gly Thr Ile Thr Leu Pro Cys Arg Ile Lys Gln Ile Val Asn Met

405 410 415

Trp Gln Glu Val Gly Lys Ala Met Tyr Ala Pro Pro Ile Ser Gly Lys

420 425 430

Ile Arg Cys Ser Ser Lys Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly

435 440 445

Gly Ala Ala Glu Ser Asp Leu Ile Phe Arg Pro Thr Gly Gly Asp Met

450 455 460

Arg Asp Asn Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile

465 470 475 480

Glu Pro Leu Gly Ile Ala Pro Thr Lys Ala Lys Arg Arg Val Val Gln

485 490 495

Arg Glu Lys Arg Ala Val Gly Thr Ile Gly Ala Met Phe Leu Gly Phe

500 505 510

Leu Gly Ala Ala Gly Ser Thr Met Gly Ala Ala Ser Val Thr Leu Thr

515 520 525

Val Gln Ala Arg Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Arg Asn

530 535 540

Leu Leu Met Ala Ile Glu Ala Gln Gln His Leu Leu Gln Leu Thr Val

545 550 555 560

Trp Gly Ile Lys Gln Leu Gln Ala Arg Val Leu Ala Ile Glu Arg Tyr

565 570 575

Leu Lys Asp Gln Gln Leu Leu Gly Ile Trp Gly Cys Ser Gly Lys Leu

580 585 590

Ile Cys Thr Thr Ala Val Pro Trp Asn Thr Ser Trp Ser Asp Lys Ser

595 600 605

Leu Glu Glu Ile Trp Asp Asn Met Thr Trp Met Gln Trp Glu Lys Glu

610 615 620

Ile Asn Asn Tyr Thr Lys Glu Ile Tyr Thr Leu Ile Glu Gln Ser Gln

625 630 635 640

Asn Gln Gln Glu Lys Asn Glu Leu Glu Leu Leu Glu Leu Asp Lys Trp

645 650 655

Ala Ser Leu Trp Asn Trp Phe Asp Ile Thr Asn Trp Leu Trp Tyr Ile

660 665 670

Lys Ile Phe Ile Met Ile Val Gly Gly Leu Val Gly Leu Arg Ile Val

675 680 685

Phe Ala Ile Leu Ser Ile Val Asn Arg Val Arg Gln Gly Tyr Ser Pro

690 695 700

Leu Ser Leu Gln Thr Arg Phe Pro Ala Gln Arg Gly Pro Gly Arg Pro

705 710 715 720

Glu Gly Ile Glu Glu Glu Gly Gly Glu Arg Asp Lys Asp Arg Ser Glu

725 730 735

Arg Leu Val Asn Gly Phe Leu Thr Leu Ile Trp Glu Asp Leu Arg Ser

740 745 750

Leu Cys Leu Phe Ser Tyr His Arg Leu Arg Asp Leu Leu Leu Ile Val

755 760 765

Thr Arg Ile Val Glu Leu Leu Gly Arg Arg Gly Trp Glu Ala Leu Arg

770 775 780

Tyr Trp Trp Asn Leu Leu Gln Tyr Trp Ser Gln Glu Leu Lys Asn Ser

785 790 795 800

Ala Val Ser Leu Leu Asn Ala Thr Ala Ile Ala Val Ala Glu Gly Thr

805 810 815

Asp Arg Ile Ile Glu Val Ile Gln Arg Ala Tyr Arg Ala Ile Leu His

820 825 830

Ile Pro Arg Arg Ile Arg Gln Gly Leu Glu Arg Ser Leu Leu

835 840 845

<210> 12

<211> 2538

<212> DNA

<213> Human Immunodeficiency Virus

<400> 12

atgagagtga aggggatcag gaagaattat cagcacttat ggagatgggg cacgatgctc 60

cttgggatgt tgatgatctg tagtgctgca gaaaatttgt gggtcacagt ctattatggg 120

gtacctgtat ggaaagaagc aaccaccact ctattttgtg catcagatgc taaagcatat 180

gatacagagg tgcataatgt ctgggccaca catgcctgtg tacccacaga ccccaaccca 240

caagaagtag tcttgggtaa tgtgacagaa gattttaaca tgtgggaaaa taacatggta 300

gaccagatgc atgaagatat aattagtttg tgggatcaaa gcctaaagcc atgtgtaaga 360

ttaaccccac tctgtgttac tttaaattgc actaattgga atgctactaa tttgggaaat 420

gatactaata ccattagtat gataaaggaa ggagaaataa aaaactgctc tttcaatatc 480

acaacaaaca taagaactaa ggtgagagat tatgcacttt tttatgcact tgatgtagta 540

ccaatagata atgctagctg gaggttgaca agttgtaaca cctcagtcat tacacaagct 600

tgtccaaagg tatcctttga gccaattccc atacattatt gtaccccagc tggttttgcg 660

attctaaagt gtaatgataa aaagttcaat ggaacaggac catgtacaaa tgttagtaca 720

gtacaatgta cacatggaat taggccagta gtatcaactc aactgctgtt aaatggcagt 780

ttagcagaag aagagatagt aattagatca agcaacctct cgataaatca taaaaacata 840

atagtgcagc tgaataaatc tgtagaaatt aattgtacaa gacccaacaa caatacatta 900

aaaagtatac agctaggact agggcgagca tggcatgcaa caggacagat aataggagat 960

ataaggcaag cacattgtaa ccttagtggc acagattgga ataacacttt aaacctgata 1020

actgaaaaat taagagaaca atttgggagc aaaacaatag tctttaagcc acacgtagga 1080

ggggacccag aggttgtgat gcacaatttt aattgtggag gggaattttt ctactgtaat 1140

acatcacaac tatttaatag tacttggcat gttaatggta cttggaatgg tactacagaa 1200

aatggcacta tcacgctccc ttgcagaata aaacaaattg taaacatgtg gcaggaagta 1260

ggaaaagcaa tgtatgcccc ccccattagc gggaaaatca gatgttcatc aaaaattaca 1320

gggttgctat taacaagaga tggtggtgct gctgaaagcg acctcatctt cagacctaca 1380

ggaggagata tgagggacaa ttggagaagt gaattatata aatataaagt agtaaaaatt 1440

gaaccattag gaatagcacc caccaaggca aagagaagag tggtgcagag agaaaaaaga 1500

gcagtgggaa caataggagc tatgttcctt gggttcttgg gagcagcagg aagcactatg 1560

ggcgcagcgt cggtaacgct gacggtacag gccagacaat tgttgtctgg tatagtgcaa 1620

cagcagagaa atctgctgat ggctattgag gcgcaacagc atttgttgca actcaccgtc 1680

tggggcatca agcagctcca ggcaagagtc ctggctatag aaagatacct aaaggatcaa 1740

cagctcctag ggatttgggg ttgctctgga aaactcattt gtaccactgc tgtgccttgg 1800

aatactagtt ggagtgataa atctttggag gagatttggg ataacatgac ttggatgcag 1860

tgggaaaaag aaattaataa ttacacaaaa gaaatataca ccctaattga acaatcgcag 1920

aaccaacaag aaaagaatga actagaatta ttggaattgg ataagtgggc aagcttgtgg 1980

aattggtttg acataacaaa ctggctgtgg tatataaaaa tattcataat gatagtagga 2040

ggcttagtag gtttaagaat agtttttgct atactttcta tagtaaatag agttaggcag 2100

ggttactcac cattgtcatt gcagacccgc ttcccagccc agaggggacc cggcaggccc 2160

gaaggaatcg aagaagaagg tggagagcga gacaaagaca gatccgagag attagtgaac 2220

ggattcttga cacttatctg ggaggatcta aggagcctgt gcctcttcag ctaccaccgc 2280

ttgagagact tactcttgat tgtgacaagg attgtggaac ttctgggacg cagggggtgg 2340

gaagccctca gatattggtg gaatcttcta cagtattgga gtcaggaact aaagaatagt 2400

gctgttagct tgctcaatgc tacagctata gcagtagctg aggggacaga taggattata 2460

gaagtaatac aaagagctta tagagctatt ctccacatac ctagaagaat aagacagggc 2520

ctcgaaagga gtttgcta 2538

<210> 13

<211> 863

<212> PRT

<213> Human Immunodeficiency Virus

<400> 13

Met Arg Val Lys Glu Lys Tyr Gln His Leu Trp Arg Trp Gly Trp Arg

1 5 10 15

Trp Gly Thr Met Leu Leu Gly Met Leu Met Ile Cys Ser Ala Thr Glu

20 25 30

Lys Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys Glu Ala

35 40 45

Thr Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp Lys Glu

50 55 60

Lys His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asn Pro Asn

65 70 75 80

Pro Gln Glu Ile Asp Leu Ile Asn Val Thr Glu Glu Phe Asn Ala Trp

85 90 95

Glu Asn Asn Met Val Glu Gln Met His Glu Asp Ile Ile Ser Leu Trp

100 105 110

Asp Gln Ser Leu Lys Pro Cys Val Glu Leu Thr Pro Leu Cys Val Thr

115 120 125

Leu Asn Cys Thr Asp Gln Arg Lys Asn Thr Ser Pro Leu Gly Glu Ala

130 135 140

Glu Lys Met Glu Lys Gly Glu Met Lys Asn Cys Ser Phe Lys Val Thr

145 150 155 160

Thr Arg Leu Arg Asn Lys Val Gln Lys Glu Tyr Ala Leu Phe Asn Lys

165 170 175

Leu Asp Val Val Pro Ile Asp Asn Asp Asn Lys Thr Asn Thr Asn Tyr

180 185 190

Ser Ser Tyr Lys Leu Ile Ser Cys Asn Thr Ser Val Val Thr Gln Ala

195 200 205

Cys Pro Lys Val Ser Phe Glu Pro Ile Pro Ile His Tyr Cys Ala Pro

210 215 220

Ala Gly Phe Ala Ile Leu Lys Cys Lys Asp Lys Lys Phe Asn Gly Thr

225 230 235 240

Gly Arg Cys Glu Asn Val Ser Thr Val Gln Cys Thr His Gly Ile Arg

245 250 255

Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu

260 265 270

Glu Val Val Leu Arg Ser Lys Asn Phe Thr Gln Asn Ala Glu Thr Ile

275 280 285

Ile Val Gln Leu Asn Glu Ser Val Val Ile Asn Cys Thr Arg Pro Asn

290 295 300

Asn Asn Thr Lys Arg Ser Ile Thr Arg Gly Pro Gly Arg Val Tyr Tyr

305 310 315 320

Thr Thr Gly Asp Ile Val Gly Asp Ile Arg Gln Ala His Cys Asn Leu

325 330 335

Ser Arg Ala His Trp Asn Thr Thr Leu Gly His Ile Ala Arg Lys Leu

340 345 350

Arg Glu Lys Tyr Gly Glu Asn Lys Thr Ile Ile Phe Asn Pro Pro Ile

355 360 365

Arg Gly Gly Asp Pro Glu Ile Val Met His Asn Phe Asn Cys Gly Gly

370 375 380

Glu Phe Phe Tyr Cys Asn Ser Thr Gln Leu Phe Asn Ser Thr Trp Asn

385 390 395 400

Asp Asn Ser Asp Trp Thr Trp Asn Tyr Thr Arg Gly Thr Tyr Asn Pro

405 410 415

Asn Asp Thr Ile Thr Leu Pro Cys Arg Ile Lys Gln Ile Ile Asn Leu

420 425 430

Trp Gln Lys Val Gly Lys Ala Met Tyr Ala Pro Pro Ile Arg Gly Gln

435 440 445

Ile Arg Cys Leu Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly

450 455 460

Gly Lys Asn Gly Thr Glu Gly Thr Glu Ile Phe Arg Pro Ile Gly Gly

465 470 475 480

Asn Met Arg Asp Asn Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val

485 490 495

Lys Ile Glu Pro Leu Gly Val Ala Pro Thr Lys Ala Lys Arg Arg Val

500 505 510

Val Arg Arg Glu Lys Arg Ala Val Gly Ile Gly Ala Val Phe Leu Gly

515 520 525

Phe Leu Gly Ala Ala Gly Ser Thr Met Gly Ala Ala Ala Val Thr Leu

530 535 540

Thr Val Gln Ala Arg Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Asn

545 550 555 560

Asn Leu Leu Arg Ala Ile Glu Ala Gln Gln His Met Leu Arg Leu Thr

565 570 575

Val Trp Gly Ile Lys Gln Leu Gln Ala Arg Val Leu Ala Val Glu Arg

580 585 590

Tyr Leu Lys Asp Gln Gln Leu Leu Gly Ile Trp Gly Cys Ser Gly Lys

595 600 605

Leu Ile Cys Thr Thr Ala Val Pro Trp Asn Ala Ser Trp Ser Asn Lys

610 615 620

Ser Leu Asp Asp Ile Trp Asn Asn Met Thr Trp Met Gln Trp Glu Lys

625 630 635 640

Glu Ile Asp Asn Tyr Thr Ser Leu Ile Tyr Thr Leu Ile Glu Glu Ser

645 650 655

Gln Asn Gln Gln Asp Lys Asn Glu Lys Glu Leu Leu Glu Leu Asp Lys

660 665 670

Trp Ala Ser Leu Trp Asn Trp Phe Asp Ile Thr Gln Trp Leu Trp Tyr

675 680 685

Ile Arg Ile Phe Ile Met Ile Val Gly Gly Leu Ile Gly Leu Arg Ile

690 695 700

Val Phe Ala Val Leu Ser Ile Val Lys Arg Val Arg Gln Gly Tyr Ser

705 710 715 720

Pro Leu Ser Phe Gln Thr His Pro Pro Ala Pro Arg Gly Pro Asp Arg

725 730 735

Pro Glu Gly Ile Glu Glu Gly Gly Gly Glu Arg Asp Arg Asp Ile Tyr

740 745 750

Asp Arg Leu Val Asn Gly Ser Leu Ala Leu Ile Trp Asp Asp Leu Arg

755 760 765

Ser Leu Cys Leu Phe Ser Tyr His Arg Leu Arg Asp Leu Leu Leu Ile

770 775 780

Val Thr Arg Ile Val Glu Leu Leu Gly Arg Arg Gly Trp Glu Ala Leu

785 790 795 800

Lys Tyr Trp Trp Asn Leu Leu Gln Tyr Trp Ser Gln Glu Leu Lys Asn

805 810 815

Ser Ala Val Ser Leu Leu Asn Ala Thr Ala Ile Ala Val Ala Glu Gly

820 825 830

Thr Asp Arg Val Ile Glu Val Val Gln Gly Ala Cys Arg Ala Ile Arg

835 840 845

His Ile Pro Arg Arg Ile Arg Gln Gly Leu Glu Arg Ile Leu Leu

850 855 860

<210> 14

<211> 2592

<212> DNA

<213> Human Immunodeficiency Virus

<400> 14

atgagagtga aggagaaata tcagcacttg tggagatggg ggtggagatg gggcaccatg 60

ctccttggga tgttgatgat ctgtagtgct acagaaaaat tgtgggtcac agtctattat 120

ggggtacctg tgtggaaaga agcaaccacc actctatttt gtgcatcaga tgctaaagca 180

tatgataaag agaagcataa tgtttgggcc acacatgcct gtgtacccac aaaccccaac 240

ccacaagaaa tagacttgat taatgtgaca gaagagttta atgcgtggga aaataacatg 300

gtagaacaga tgcatgagga tataattagt ttatgggatc aaagcctaaa gccatgtgta 360

gaattaaccc cactctgtgt tactttgaat tgcactgatc agaggaaaaa taccagtccc 420

ttaggtgaag cagaaaagat ggagaaagga gaaatgaaaa actgctcttt caaggtcacc 480

acaagattaa gaaataaggt gcaaaaagag tatgcacttt ttaataaact tgatgtagtg 540

ccaatagata atgataataa gactaatacc aactatagca gctataagtt gataagttgt 600

aacacctcag tcgttacaca ggcctgtcca aaggtatcct ttgagccaat tcccatacat 660

tattgtgccc cggctggttt tgcgattcta aagtgtaaag acaagaaatt caatggaaca 720

ggacgatgtg aaaatgtcag cacagtacaa tgtacacatg gaattaggcc agtagtatca 780

actcaattgc tgttaaatgg cagtctagca gaagaagagg tagtacttag atctaaaaat 840

ttcacacaaa atgctgaaac cataatagta cagctgaacg aatcagtagt aattaattgt 900

acaagaccca acaacaatac aaaaaggagt ataactaggg gaccagggag agtatattat 960

acaacaggag acatagtagg agatataaga caagcacatt gtaaccttag tagagcacat 1020

tggaatacca ccttaggaca tatagcaaga aaattaagag aaaaatatgg ggaaaataaa 1080

acaataatct ttaatcctcc catcagagga ggggacccag aaattgtaat gcacaatttt 1140

aattgtggag gggaattttt ctactgtaat tcaacacaac tgtttaatag tacttggaat 1200

gataatagtg attggacttg gaattatact agagggacat ataaccctaa tgacactatc 1260

acactcccat gcagaataaa acaaattata aacttgtggc agaaagtagg aaaagcaatg 1320

tatgcccctc ccatcagggg acaaattaga tgtttatcaa atattacagg gctgctatta 1380

acaagagatg gtggtaagaa tgggaccgag gggaccgaga ttttcagacc tataggagga 1440

aatatgaggg acaattggag aagtgaatta tataaatata aagtagtaaa aattgaacca 1500

ttaggagtag cacccaccaa ggcaaagaga agagtggtgc ggagagaaaa aagagcagtg 1560

ggaataggag ctgtgttcct tgggttcttg ggagcagcag gaagcactat gggcgcagcg 1620

gcagtgacgc tgacggtaca ggccagacaa ttattgtctg gtatagtgca acagcagaac 1680

aatttgctga gggctattga ggcgcaacag catatgctgc gactcacagt ctggggcatc 1740

aagcagctcc aggcaagagt cctggctgtg gaaagatacc taaaggatca acagctcctg 1800

gggatttggg gttgctctgg aaaactcatt tgcaccactg ctgtgccttg gaatgctagt 1860

tggagtaata aatctctgga tgatatttgg aataacatga cctggatgca gtgggaaaaa 1920

gaaattgata attacacaag cttaatatac accttaattg aagaatcgca gaaccaacaa 1980

gacaagaatg aaaaagaatt attggaatta gataaatggg caagtttgtg gaattggttt 2040

gacataacac aatggctgtg gtatataaga atattcataa tgatagtagg aggcttgata 2100

ggtttaagaa tagtttttgc tgtactttct atagtgaaaa gagttaggca gggatactca 2160

ccattatcgt ttcagaccca ccccccagca ccgaggggac ccgacaggcc cgaaggaatc 2220

gaagaaggag gtggagagag agacagagac atatacgatc gattagtgaa cggatccttg 2280

gcacttatct gggacgatct gcggagcctg tgcctcttca gctaccaccg cttgagagac 2340

ttactcttga ttgtaacgag gattgtggaa cttctgggac gcagggggtg ggaagccctc 2400

aaatattggt ggaatctcct acagtattgg agtcaggaac taaagaatag tgctgttagc 2460

ttgctcaatg ccacagccat agcagtagct gaggggacag atagggttat agaagtagta 2520

caaggagctt gtagagctat tcgccacata cctagaagaa taagacaggg cttggaaagg 2580

attttgctat aa 2592

<210> 15

<211> 863

<212> PRT

<213> Human Immunodeficiency Virus

<400> 15

Met Arg Val Lys Glu Lys Tyr Gln His Leu Trp Arg Trp Gly Trp Arg

1 5 10 15

Trp Gly Thr Met Leu Leu Gly Met Leu Met Ile Cys Ser Ala Thr Glu

20 25 30

Lys Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys Glu Ala

35 40 45

Thr Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Asp Lys Glu

50 55 60

Lys His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asn Pro Asn

65 70 75 80

Pro Gln Glu Ile Asp Leu Ile Asn Val Thr Glu Glu Phe Asn Ala Trp

85 90 95

Glu Asn Asn Met Val Glu Gln Met His Glu Asp Ile Ile Ser Leu Trp

100 105 110

Asp Gln Ser Leu Lys Pro Cys Val Glu Leu Thr Pro Leu Cys Val Thr

115 120 125

Leu Asn Cys Thr Asp Gln Arg Lys Asn Thr Ser Pro Leu Gly Glu Ala

130 135 140

Glu Lys Met Glu Lys Gly Glu Met Lys Asn Cys Ser Phe Lys Val Thr

145 150 155 160

Thr Arg Leu Arg Asn Lys Val Gln Lys Glu Tyr Ala Leu Phe Asn Lys

165 170 175

Leu Asp Val Val Pro Ile Asp Asn Asp Asn Lys Thr Asn Thr Asn Tyr

180 185 190

Ser Ser Tyr Lys Leu Ile Ser Cys Asn Thr Ser Val Val Thr Gln Ala

195 200 205

Cys Pro Lys Val Ser Phe Glu Pro Ile Pro Ile His Tyr Cys Ala Pro

210 215 220

Ala Gly Phe Ala Ile Leu Lys Cys Lys Asp Lys Lys Phe Asn Gly Thr

225 230 235 240

Gly Arg Cys Glu Asn Val Ser Thr Val Gln Cys Thr His Gly Ile Arg

245 250 255

Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu Glu

260 265 270

Glu Val Val Leu Arg Ser Lys Asn Phe Thr Gln Asn Ala Glu Thr Ile

275 280 285

Ile Val Gln Leu Asn Glu Ser Val Val Ile Asn Cys Thr Arg Pro Asn

290 295 300

Asn Asn Thr Lys Arg Ser Ile Thr Arg Gly Pro Gly Arg Val Tyr Tyr

305 310 315 320

Thr Thr Gly Asp Ile Val Gly Asp Ile Arg Gln Ala His Cys Asn Leu

325 330 335

Ser Arg Ala His Trp Asn Thr Thr Leu Gly His Ile Ala Arg Lys Leu

340 345 350

Arg Glu Lys Tyr Gly Glu Asn Lys Thr Ile Ile Phe Asn Pro Pro Ile

355 360 365

Arg Gly Gly Asp Pro Glu Ile Val Met His Asn Phe Asn Cys Gly Gly

370 375 380

Glu Phe Phe Tyr Cys Asn Ser Thr Gln Leu Phe Asn Ser Thr Trp Asn

385 390 395 400

Asp Asn Ser Asp Trp Thr Trp Asn Tyr Thr Arg Gly Thr Tyr Asn Pro

405 410 415

Asn Asp Thr Ile Thr Leu Pro Cys Arg Ile Lys Gln Ile Ile Asn Leu

420 425 430

Trp Gln Lys Val Gly Lys Ala Met Tyr Ala Pro Pro Ile Arg Gly Gln

435 440 445

Ile Arg Cys Leu Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly

450 455 460

Gly Lys Ala Gly Thr Glu Gly Thr Glu Ile Phe Arg Pro Ile Gly Gly

465 470 475 480

Asn Met Arg Asp Asn Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val

485 490 495

Lys Ile Glu Pro Leu Gly Val Ala Pro Thr Lys Ala Lys Arg Arg Val

500 505 510

Val Arg Arg Glu Lys Arg Ala Val Gly Ile Gly Ala Val Phe Leu Gly

515 520 525

Phe Leu Gly Ala Ala Gly Ser Thr Met Gly Ala Ala Ala Val Thr Leu

530 535 540

Thr Val Gln Ala Arg Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Asn

545 550 555 560

Asn Leu Leu Arg Ala Ile Glu Ala Gln Gln His Met Leu Arg Leu Thr

565 570 575

Val Trp Gly Ile Lys Gln Leu Gln Ala Arg Val Leu Ala Val Glu Arg

580 585 590

Tyr Leu Lys Asp Gln Gln Leu Leu Gly Ile Trp Gly Cys Ser Gly Lys

595 600 605

Leu Ile Cys Thr Thr Ala Val Pro Trp Asn Ala Ser Trp Ser Asn Lys

610 615 620

Ser Leu Asp Asp Ile Trp Asn Asn Met Thr Trp Met Gln Trp Glu Lys

625 630 635 640

Glu Ile Asp Asn Tyr Thr Ser Leu Ile Tyr Thr Leu Ile Glu Glu Ser

645 650 655

Gln Asn Gln Gln Asp Lys Asn Glu Lys Glu Leu Leu Glu Leu Asp Lys

660 665 670

Trp Ala Ser Leu Trp Asn Trp Phe Asp Ile Thr Gln Trp Leu Trp Tyr

675 680 685

Ile Arg Ile Phe Ile Met Ile Val Gly Gly Leu Ile Gly Leu Arg Ile

690 695 700

Val Phe Ala Val Leu Ser Ile Val Lys Arg Val Arg Gln Gly Tyr Ser

705 710 715 720

Pro Leu Ser Phe Gln Thr His Pro Pro Ala Pro Arg Gly Pro Asp Arg

725 730 735

Pro Glu Gly Ile Glu Glu Gly Gly Gly Glu Arg Asp Arg Asp Ile Tyr

740 745 750

Asp Arg Leu Val Asn Gly Ser Leu Ala Leu Ile Trp Asp Asp Leu Arg

755 760 765

Ser Leu Cys Leu Phe Ser Tyr His Arg Leu Arg Asp Leu Leu Leu Ile

770 775 780

Val Thr Arg Ile Val Glu Leu Leu Gly Arg Arg Gly Trp Glu Ala Leu

785 790 795 800

Lys Tyr Trp Trp Asn Leu Leu Gln Tyr Trp Ser Gln Glu Leu Lys Asn

805 810 815

Ser Ala Val Ser Leu Leu Asn Ala Thr Ala Ile Ala Val Ala Glu Gly

820 825 830

Thr Asp Arg Val Ile Glu Val Val Gln Gly Ala Cys Arg Ala Ile Arg

835 840 845

His Ile Pro Arg Arg Ile Arg Gln Gly Leu Glu Arg Ile Leu Leu

850 855 860

<210> 16

<211> 2592

<212> DNA

<213> Human Immunodeficiency Virus

<400> 16

atgagagtga aggagaaata tcagcacttg tggagatggg ggtggagatg gggcaccatg 60

ctccttggga tgttgatgat ctgtagtgct acagaaaaat tgtgggtcac agtctattat 120

ggggtacctg tgtggaaaga agcaaccacc actctatttt gtgcatcaga tgctaaagca 180

tatgataaag agaagcataa tgtttgggcc acacatgcct gtgtacccac aaaccccaac 240

ccacaagaaa tagacttgat taatgtgaca gaagagttta atgcgtggga aaataacatg 300

gtagaacaga tgcatgagga tataattagt ttatgggatc aaagcctaaa gccatgtgta 360

gaattaaccc cactctgtgt tactttgaat tgcactgatc agaggaaaaa taccagtccc 420

ttaggtgaag cagaaaagat ggagaaagga gaaatgaaaa actgctcttt caaggtcacc 480

acaagattaa gaaataaggt gcaaaaagag tatgcacttt ttaataaact tgatgtagtg 540

ccaatagata atgataataa gactaatacc aactatagca gctataagtt gataagttgt 600

aacacctcag tcgttacaca ggcctgtcca aaggtatcct ttgagccaat tcccatacat 660

tattgtgccc cggctggttt tgcgattcta aagtgtaaag acaagaaatt caatggaaca 720

ggacgatgtg aaaatgtcag cacagtacaa tgtacacatg gaattaggcc agtagtatca 780

actcaattgc tgttaaatgg cagtctagca gaagaagagg tagtacttag atctaaaaat 840

ttcacacaaa atgctgaaac cataatagta cagctgaacg aatcagtagt aattaattgt 900

acaagaccca acaacaatac aaaaaggagt ataactaggg gaccagggag agtatattat 960

acaacaggag acatagtagg agatataaga caagcacatt gtaaccttag tagagcacat 1020

tggaatacca ccttaggaca tatagcaaga aaattaagag aaaaatatgg ggaaaataaa 1080

acaataatct ttaatcctcc catcagagga ggggacccag aaattgtaat gcacaatttt 1140

aattgtggag gggaattttt ctactgtaat tcaacacaac tgtttaatag tacttggaat 1200

gataatagtg attggacttg gaattatact agagggacat ataaccctaa tgacactatc 1260

acactcccat gcagaataaa acaaattata aacttgtggc agaaagtagg aaaagcaatg 1320

tatgcccctc ccatcagggg acaaattaga tgtttatcaa atattacagg gctgctatta 1380

acaagagatg gtggtaaggc tgggaccgag gggaccgaga ttttcagacc tataggagga 1440

aatatgaggg acaattggag aagtgaatta tataaatata aagtagtaaa aattgaacca 1500

ttaggagtag cacccaccaa ggcaaagaga agagtggtgc ggagagaaaa aagagcagtg 1560

ggaataggag ctgtgttcct tgggttcttg ggagcagcag gaagcactat gggcgcagcg 1620

gcagtgacgc tgacggtaca ggccagacaa ttattgtctg gtatagtgca acagcagaac 1680

aatttgctga gggctattga ggcgcaacag catatgctgc gactcacagt ctggggcatc 1740

aagcagctcc aggcaagagt cctggctgtg gaaagatacc taaaggatca acagctcctg 1800

gggatttggg gttgctctgg aaaactcatt tgcaccactg ctgtgccttg gaatgctagt 1860

tggagtaata aatctctgga tgatatttgg aataacatga cctggatgca gtgggaaaaa 1920

gaaattgata attacacaag cttaatatac accttaattg aagaatcgca gaaccaacaa 1980

gacaagaatg aaaaagaatt attggaatta gataaatggg caagtttgtg gaattggttt 2040

gacataacac aatggctgtg gtatataaga atattcataa tgatagtagg aggcttgata 2100

ggtttaagaa tagtttttgc tgtactttct atagtgaaaa gagttaggca gggatactca 2160

ccattatcgt ttcagaccca ccccccagca ccgaggggac ccgacaggcc cgaaggaatc 2220

gaagaaggag gtggagagag agacagagac atatacgatc gattagtgaa cggatccttg 2280

gcacttatct gggacgatct gcggagcctg tgcctcttca gctaccaccg cttgagagac 2340

ttactcttga ttgtaacgag gattgtggaa cttctgggac gcagggggtg ggaagccctc 2400

aaatattggt ggaatctcct acagtattgg agtcaggaac taaagaatag tgctgttagc 2460

ttgctcaatg ccacagccat agcagtagct gaggggacag atagggttat agaagtagta 2520

caaggagctt gtagagctat tcgccacata cctagaagaa taagacaggg cttggaaagg 2580

attttgctat aa 2592

<210> 17

<211> 846

<212> PRT

<213> Human Immunodeficiency Virus

<400> 17

Met Thr Val Met Gly Ile Arg Lys Asn Cys Gln Arg Trp Leu Thr Trp

1 5 10 15

Gly Thr Met Leu Leu Gly Met Leu Met Ile Cys Ser Ala Glu Asp Leu

20 25 30

Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys Glu Ala Asn Thr

35 40 45

Thr Leu Phe Cys Ala Ser Glu Ala Lys Ala Tyr Ser Thr Glu Ala His

50 55 60

Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp Pro Asn Pro Gln

65 70 75 80

Glu Val Val Leu Glu Asn Val Thr Glu Asn Phe Asn Met Trp Lys Asn

85 90 95

Asn Met Val Glu Gln Met Gln Glu Asp Val Ile Ser Leu Trp Asp Glu

100 105 110

Ser Leu Lys Pro Cys Ala Lys Leu Thr Pro Leu Cys Val Thr Leu Asn

115 120 125

Cys Thr Asp Val Glu Ser Asn Thr Thr Asn Ser Ser Ser Asn Thr Thr

130 135 140

Ala Ile Pro Ser Gly Glu Ile Lys Asn Cys Ser Phe Tyr Ile Thr Thr

145 150 155 160

Gln Ile Arg Asn Lys Val Arg Lys Glu His Ala Leu Phe Asp Arg Leu

165 170 175

Asp Val Val Pro Ile Asp Asn Asn Ser Ser Thr Tyr Met Leu Ile Asn

180 185 190

Cys Asn Thr Ser Val Ile Thr Gln Ala Cys Pro Lys Ile Ser Phe Glu

195 200 205

Pro Ile Pro Ile His Tyr Cys Thr Pro Ala Gly Phe Ala Leu Leu Lys

210 215 220

Cys Asn Asn Lys Thr Phe Asn Gly Thr Gly Pro Cys Thr Asn Val Ser

225 230 235 240

Thr Val Gln Cys Thr His Gly Ile Lys Pro Val Val Ser Thr Gln Leu

245 250 255

Leu Leu Asn Gly Ser Leu Ala Glu Glu Asp Ile Val Ile Arg Ser Glu

260 265 270

Asn Phe Thr Asn Asn Ala Lys Thr Ile Ile Val Gln Leu Asn Glu Thr

275 280 285

Val Lys Ile Glu Cys Ile Arg Pro Asn Asn Asn Thr Arg Arg Ser Ile

290 295 300

His Leu Ala Gly Gly Arg Ala Leu Tyr Thr Thr Gly Glu Ile Ile Gly

305 310 315 320

Asp Ile Arg Gln Ala His Cys Asn Val Ser Lys Trp Asn Glu Thr Leu

325 330 335

Lys Arg Val Ala Ile Lys Leu Lys Asp Gln Phe Lys Asn Lys Thr Ile

340 345 350

Val Phe Lys Pro Pro Ser Gly Gly Asp Pro Glu Ile Val Met Leu Thr

355 360 365

Phe Asn Cys Gly Gly Glu Phe Phe Tyr Cys Asn Thr Thr Lys Leu Phe

370 375 380

Asn Tyr Thr Trp Thr Asn Asp Asn Trp Ser Asn Ser Thr Glu Pro Asp

385 390 395 400

Gly His Ile Thr Leu Pro Cys Arg Ile Lys Gln Ile Ile Asn Arg Trp

405 410 415

Gln Glu Val Gly Arg Ala Met Tyr Ala Pro Pro Ile Lys Gly Gln Ile

420 425 430

Asn Cys Thr Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly

435 440 445

Asn Thr Thr Asn Gly Ser Glu Ile Phe Arg Pro Gly Gly Gly Asp Met

450 455 460

Arg Asp Asn Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile

465 470 475 480

Glu Pro Leu Gly Ile Ala Pro Thr Lys Ala Lys Arg Arg Val Val Gln

485 490 495

Arg Glu Lys Arg Ala Val Gly Thr Ile Gly Ala Leu Phe Leu Gly Phe

500 505 510

Leu Gly Ala Ala Gly Ser Thr Met Gly Ala Ala Ser Leu Thr Leu Thr

515 520 525

Val Gln Ala Arg Leu Leu Leu Ser Gly Ile Val Gln Gln Gln Asn Asn

530 535 540

Leu Leu Lys Ala Ile Glu Ala Gln Gln His Met Leu Gln Leu Thr Val

545 550 555 560

Trp Gly Ile Lys Gln Leu Gln Ala Arg Val Leu Ala Val Glu Arg Tyr

565 570 575

Leu Arg Asp Gln Gln Leu Leu Gly Ile Trp Gly Cys Ser Gly Lys Leu

580 585 590

Ile Cys Thr Thr Ala Val Pro Trp Asn Ala Ser Trp Ser Asn Lys Ser

595 600 605

Ile Asn Glu Ile Trp Glu Asn Met Thr Trp Met Gln Trp Glu Arg Glu

610 615 620

Ile Asp Asn Tyr Thr Glu Leu Ile Tyr Ser Leu Leu Glu Lys Ser Gln

625 630 635 640

Asn Gln Gln Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Asn Trp

645 650 655

Ala Asn Leu Trp Asn Trp Phe Asp Ile Thr Asn Trp Leu Trp Tyr Ile

660 665 670

Lys Ile Phe Ile Met Ile Val Gly Gly Leu Ile Gly Leu Arg Ile Val

675 680 685

Phe Thr Val Phe Ser Ile Val Asn Arg Val Arg Gln Gly Tyr Ser Pro

690 695 700

Leu Ser Phe Gln Thr Arg Leu Pro Ala Gln Arg Gly Pro Asp Arg Pro

705 710 715 720

Glu Glu Thr Glu Glu Gly Gly Gly Glu Arg Asn Arg Gly Gly Ser Thr

725 730 735

Arg Leu Val His Gly Phe Leu Ala Leu Val Trp Asp Asp Leu Arg Ser

740 745 750

Leu Cys Leu Phe Ser Tyr Arg Arg Leu Ser Asp Leu Leu Ser Ile Val

755 760 765

Ala Arg Ile Val Glu Leu Leu Gly Arg Arg Gly Trp Glu Ala Leu Lys

770 775 780

Tyr Trp Trp Asn Leu Leu Gln Tyr Trp Arg Gln Glu Leu Lys Lys Ser

785 790 795 800

Ala Val Ser Leu Leu Asn Thr Thr Ala Ile Ala Val Ala Glu Gly Thr

805 810 815

Asp Arg Ile Ile Glu Val Ala Gln Ile Ile Gly Arg Ala Ile Leu His

820 825 830

Ile Pro Arg Arg Ile Arg Gln Gly Ala Glu Arg Ala Trp Leu

835 840 845

<210> 18

<211> 2541

<212> DNA

<213> Human Immunodeficiency Virus

<400> 18

atgacagtga tggggatcag gaagaattgt cagcgctggt tgacatgggg cacgatgctc 60

cttggaatgt taatgatctg tagtgctgaa gatttgtggg tcacagtcta ttatggggta 120

cctgtgtgga aagaagcaaa caccacctta ttttgtgcat cagaggctaa agcatatagc 180

acagaggcac ataatgtttg ggccacacat gcctgtgtac ccacagaccc taacccacaa 240

gaagtagtat tggaaaatgt gacagaaaat tttaatatgt ggaaaaataa catggtagaa 300

cagatgcagg aggatgtaat cagtttatgg gatgaaagcc taaagccatg tgccaaatta 360

accccactct gtgttacttt aaattgcact gatgtggagt ctaatactac taattccagt 420

agtaatacta ctgccattcc aagtggagaa ataaaaaact gctctttcta tataaccaca 480

caaataagaa ataaggtgcg aaaagaacat gcactttttg ataggcttga tgtagtacca 540

atagataata atagctctac atatatgttg ataaattgta atacctcagt cattacacag 600

gcctgtccaa agatatcctt tgaaccaatt cccatacatt attgtacccc ggctggtttt 660

gcgcttctaa agtgtaataa taagacattc aatggaacag gaccatgtac aaatgtcagt 720

acagtacaat gtacacatgg aattaagcca gtagtgtcaa ctcaactgct gctaaatggc 780

agtctagcag aagaagatat agtaattaga tctgaaaatt tcacgaacaa tgctaagacc 840

ataatagtac agctgaatga gactgtaaaa attgagtgta taagacccaa caacaataca 900

agaaggagta tacatttagc aggggggaga gcattatata caacaggaga aataatagga 960

gatataagac aagcacattg taatgttagt aagtggaatg aaacgttaaa acgggtagct 1020

ataaaattaa aagaccaatt taaaaataag acaatagtct ttaagccacc ctcaggaggg 1080

gatccagaaa ttgtaatgct cacatttaat tgtggagggg aatttttcta ctgtaataca 1140

acaaaactgt ttaattatac ttggactaat gataattgga gtaacagtac tgagccagac 1200

ggacacatca cactcccatg cagaataaaa caaattataa acaggtggca ggaagtagga 1260

agagcaatgt atgcccctcc catcaaggga caaattaact gtacatcaaa tattacaggg 1320

ctgctattaa caagagatgg tggtaacacc acgaatgggt ccgaaatctt cagacctgga 1380

ggaggagata tgagagacaa ttggagaagt gaattatata aatataaagt agtaaaaatt 1440

gagccactag gaatagcacc caccaaggca aagagaagag tggtgcagag agaaaaaaga 1500

gcagtgggaa caataggagc tctgttcctc gggttcttgg gagcagcagg aagcactatg 1560

ggcgcggcgt cactgacgct gacggtacag gccagactat tactgtctgg tatagtgcaa 1620

cagcagaaca atctgctgaa agctattgag gcgcaacagc acatgttgca actcacagtc 1680

tggggcatca agcagctcca ggcaagagtc ctcgctgtgg aaagatacct aagggatcaa 1740

cagctcctag ggatttgggg ttgctctgga aaactcatct gcaccactgc tgtgccttgg 1800

aatgctagtt ggagtaataa atccataaat gagatttggg aaaacatgac ctggatgcag 1860

tgggagagag aaattgacaa ttacacagaa ttaatatact ctttacttga aaaatcgcag 1920

aaccagcaag aaaagaatga gcaagaatta ttggaattgg ataactgggc aaatttgtgg 1980

aattggtttg acataacaaa ctggctgtgg tacataaaga tattcataat gatagtagga 2040

ggcttaatag gtttaagaat agtttttact gtattttcta tagtgaatag agttaggcag 2100

ggatactcac cattgtcatt ccagacccgc ctcccagctc agaggggacc cgacaggccc 2160

gaagaaaccg aagaaggagg tggagaaaga aacagaggtg gatccactcg attagtgcat 2220

ggattcttag cactcgtctg ggacgacctg cggagcctgt gccttttcag ctaccgccgc 2280

ttgagcgact tactctcgat tgtagcgaga attgtggaac ttctgggacg cagggggtgg 2340

gaagctctca agtattggtg gaatctccta cagtattgga ggcaggaact aaagaagagt 2400

gctgttagtc tgcttaatac caccgctata gcagtagctg agggaacaga tagaattata 2460

gaagtagcac aaataattgg tagagctatc ctccacatac ctagaagaat cagacagggc 2520

gcagaaagag cttggctata a 2541

Claims (10)

1.一种针对HIV的IgG抗体，由轻链和重链组成；

所述重链的重链可变区包括三个可变区区段，第一个可变区区段的中的CDR1、CDR2和CDR3依次如序列表的序列1中第46-57位、第75-77位、第114-121位所示，第二个可变区区段的中的CDR1、CDR2和CDR3依次如序列表的序列1中第172-179位、第197-204位、第243-257位所示，第三个可变区区段的中的CDR1、CDR2和CDR3依次如序列表的序列1中第309-306位、第334-341位、第380-394位所示；

所述轻链的轻链可变区中的CDR1、CDR2和CDR3依次如序列表的序列3中第46-51位、第69-71位、第108-112位所示。

2.如权利要求1所述的针对HIV的IgG抗体，其特征在于：

所述重链的重链可变区中，第一个可变区区段如序列表的序列1中第20-131位所示，第二个可变区区段如序列表的序列1中第147-268位所示,第三个可变区区段如序列表的序列1中第284-405位所示。

3.如权利要求1所述的针对HIV的IgG抗体，其特征在于：所述重链的重链可变区如序列表的序列1中第20-405位所示。

4.如权利要求1至3中任一所述的针对HIV的IgG抗体，其特征在于：所述轻链的轻链可变区如序列表的序列3中第20-122位所示。

5.如权利要求4所述的针对HIV的IgG抗体，其特征在于：所述重链如序列表的序列1中第20-735位所示或者所述重链如序列表的序列1所示；所述轻链如序列表的序列3中第20-229位所示或者所述重链如序列表的序列3所示。

6.编码权利要求1所述的针对HIV的IgG抗体的基因。

7.如权利要求6所述的基因，其特征在于：

编码所述重链的基因为如下(1)或(2)：

(1)序列表的序列2自5’末端第946-3093位核苷酸所示的DNA分子；

(2)序列表的序列2自5’末端第889-3096位核苷酸所示的DNA分子；

编码所述轻链的基因为如下(3)或(4)：

(3)序列表的序列4自5’末端第946-1575位核苷酸所示的DNA分子；

(4)序列表的序列4自5’末端第889-1578位核苷酸所示的DNA分子。

8.权利要求1或2或3或4或5所述的针对HIV的IgG抗体在制备药物中的应用；所述药物的功能为抑制HIV和/或中和HIV和/或预防艾滋病和/或治疗艾滋病。

9.一种药物，其活性成分为权利要求1或2或3或4或5所述的针对HIV的IgG抗体；所述药物的功能为抑制HIV和/或中和HIV和/或预防艾滋病和/或治疗艾滋病。

10.权利要求6或7所述基因在制备药物中的应用；所述药物的功能为抑制HIV和/或中和HIV和/或预防艾滋病和/或治疗艾滋病。