CN114686495A - 人类免疫缺陷病毒抗原、载体、组合物、及其使用方法 - Google Patents
人类免疫缺陷病毒抗原、载体、组合物、及其使用方法 Download PDFInfo
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Abstract
本文描述了合成的HIV包膜蛋白、载体及其组合物,以及用于诱导针对人类免疫缺陷病毒(HIV)感染的保护性免疫的方法。编码该合成的HIV包膜蛋白的病毒表达载体可用于疫苗中以提供针对HIV的改善的保护性免疫。
Description
本申请是申请日为2016年12月15日,申请号为201680073839.5,题目为“人类免疫缺陷病毒抗原、载体、组合物、及其使用方法”的专利申请的分案申请。
背景技术
人类免疫缺陷病毒(HIV)影响全世界数百万人,并且即使在广泛的抗逆转录病毒治疗的时代,通过有效疫苗预防HIV仍然具有非常高的优先级。HIV-1是该病毒中最常见的并且致病的菌株,其中超过90%的HIV/AIDS病例来源于HIV-1组M的感染。该M组进一步细分为分枝或亚型。有效疫苗理想地能够引发强大的细胞应答和广泛中和性抗体两者,这些广泛中和性抗体能够中和来自不同分枝的HIV-1菌株。
HIV-1的高遗传变异性使得HIV-1疫苗的开发成为前所未有的挑战。为了改进潜在T-细胞表位的覆盖并改善细胞应答,其他人描述并且开发了来源于HIV组抗原(Gag)、聚合酶(Pol)、和包膜蛋白(Env)蛋白的“镶嵌(mosaic)”HIV-1 Gag、Pol和Env抗原,试图提供潜在T-细胞表位的最大覆盖(例如,巴鲁什(Barouch)等人,自然医学(Nat Med)2010,16:319-323)。这些镶嵌抗原在长度和结构域结构上与野生型,即天然存在的HIV-1抗原相似。
例如,在疫苗中描述并且使用的镶嵌HIV抗原包括巴鲁什(Barouch)等人(同上),以及WO 2010/059732中描述的那些,如:
(a)Gag镶嵌抗原,该Gag镶嵌抗原包括:
(a)(i)具有如在本文SEQ ID NO:1中所示的氨基酸序列的第一镶嵌Gag序列(“mos1Gag”),以及
(a)(ii)具有如在本文SEQ ID NO:2中所示的氨基酸序列的第二镶嵌Gag序列(“mos2Gag”);
(b)Pol镶嵌抗原,该Pol镶嵌抗原包括:
(b)(i)具有如在本文SEQ ID NO:3中所示的氨基酸序列的第一镶嵌Pol序列(“mos1Pol”),以及
(b)(ii)具有如在本文SEQ ID NO:4中所示的氨基酸序列的第二镶嵌Pol序列(“mos2Pol”);以及
(c)Env镶嵌抗原,该Env镶嵌抗原包括:
(c)(i)具有如在本文SEQ ID NO:5中所示的氨基酸序列的第一镶嵌Env序列(“mos1Env”),以及
(c)(ii)具有如在本文SEQ ID NO:6中所示的氨基酸序列的第二镶嵌Env序列(“mos2Env”)。
将编码这些抗原的序列克隆在载体,例如,如重组腺病毒载体(例如重组腺病毒血清型26(rAd26))中,并且这些重组载体先前用作疫苗以产生对这些抗原的免疫应答(参见例如巴鲁什等人,同上;以及WO 2010/059732)。例如,典型地将mos1Gag和mos1Pol镶嵌抗原序列组合到Gag和Pol的融合蛋白(“mos1GagPol”)中,并且将其编码序列克隆进入第一Ad26载体(“rAd26.mos1GagPol”)中;并且将mos2Gag和mos2Pol抗原序列组合到Gag和Pol的另一个融合蛋白(“mos2GagPol”)中,并且将其编码序列克隆进入第二Ad26载体(“rAd26.mos2GagPol”)中。典型地将编码mos1Env和mos2Env的构建体克隆进入分开的Ad26载体(分别为“rAd26.mos1Env”和“rAd26.mos2Env”)中。
一组如上所述的这样的镶嵌抗原给出了M组HIV-1分离株的良好的全局覆盖,其中编码镶嵌1抗原序列的rAd26载体(例如,rAd26.mos1GagPol和rAd26.mos1Env)有利于分枝B和CRF01 HIV-1亚型,并且编码镶嵌2抗原序列的rAd26载体(例如,rAd26.mos2GagPol和rAd26.mos2Env)有利于分枝C菌株。在rAd26载体中表达的镶嵌HIV-1Gag、Pol和Env抗原可以用于提高猕猴中抗原特异性T淋巴细胞应答的宽度和深度,而与共有序列或天然序列HIV-1抗原相比不会损害细胞应答和体液应答的大小(巴鲁什等人,同上;以及WO 2010/059732)。
然而,在对上述这些疫苗组分的进一步开发努力后,发现rAd26.mos2Env在非人类灵长动物中显示出非最佳的细胞表面表达和免疫应答,但是此外与其他rAd26载体(如rAd26.mos1Env)相比,其在制造过程期间显示出迄今未报告的、意想不到的和不可预测的非最佳遗传稳定性。因此,包含rAd26.mos2Env的疫苗可以导致针对分枝C HIV-1亚型的非最佳免疫应答,因为该mos2Env镶嵌抗原有利于分枝C HIV-1菌株。因此,对于抗HIV的疫苗中的mos2Env抗原的替代物存在需要,该替代物可用于诱导针对HIV-1分枝C的改善的免疫应答。
发明内容
本发明涉及新颖的合成的人类免疫缺陷病毒(HIV)包膜蛋白,当与先前描述的mos2Env抗原相比时这些包膜蛋白具有改进的细胞表面表达和遗传稳定性。本发明还涉及以下组合物和方法,这些组合物和方法使用此类新颖的合成的HIV包膜蛋白和/或其编码序列以诱导抗HIV-1,特别是HIV-1分枝C的增加的免疫应答,优选地当这些组合物与其他HIV抗原组合使用时。
在一个概述方面中,本发明涉及一种核酸,该核酸编码合成的HIV包膜蛋白,该合成的HIV包膜蛋白包含SEQ ID NO:8的、或具有一个或多个选自下组的突变的SEQ ID NO:8的氨基酸序列,该组由以下各项组成:(i)I529P(即,在SEQ ID NO:8的位置529处的Ile取代为Pro),(ii)K480E(即,在SEQ ID NO:8的位置480处的Lys取代为Glu),以及(iii)EK479-480RRRR(即,在SEQ ID NO:8的位置479-480处的Glu-Lys被四个连续Arg残基替换)、I529P、A471C(即,在SEQ ID NO:8的位置471处的Ala取代为Cys)以及T575C(即,在SEQ ID NO:8的位置575处的Thr取代为Cys)的组合。在一个实施例中,该合成的HIV包膜蛋白进一步包含信号序列,例如具有选自下组的氨基酸序列的信号序列,该组由以下各项组成:SEQ ID NO:9-12。在一个实施例中,该信号序列具有SEQ ID NO:9的氨基酸序列。
在某些实施例中,该合成的HIV包膜蛋白进一步包括跨膜结构域,优选地是具有SEQ ID NO:13的氨基酸序列的跨膜结构域。
在某些实施例中,该合成的HIV包膜蛋白进一步包括细胞质结构域的片段,优选地是包括SEQ ID NO:14的氨基酸序列、或其氨基酸1-4(即,NRVR)的细胞质结构域的片段。在其中该合成的HIV包膜蛋白进一步包括跨膜结构域和细胞质结构域的片段的实施例中,优选的是该蛋白还包括被融合到SEQ ID NO:8的羧基-末端(C-末端)和该跨膜区域的氨基-末端(N-末端)的SEQ ID NO:37的氨基酸序列。
在另一个实施例中,该合成的HIV包膜蛋白包括三聚结构域,例如,包括SEQ IDNO:15(GCN4)或SEQ ID NO:16(foldon结构域)的氨基酸序列的三聚结构域。在一个优选实施例中,该三聚结构域包括SEQ ID NO:15的氨基酸序列。具有三聚结构域的这些实施例对于基于本文提供的胞外结构域序列(如包含SEQ ID NO:8的氨基酸序列的胞外结构域序列)的可溶性(即,非膜结合的)的合成的HIV包膜蛋白是有用的,其中该三聚结构域位于该合成的HIV包膜蛋白的C-末端。
在又其他的实施例中,该合成的HIV包膜蛋白包括具有以下突变:EK479-480RRRR、I529P、A471C和T575C的SEQ ID NO:8。6个连续精氨酸残基(SEQ ID NO:8的天然序列中的位置478和481已经是Arg残基)的引入产生另外的优化的弗林蛋白酶(furin)切割位点,从而获得改进的加工的(即切割的)胞外结构域。I529P、A471C和T575C这三种突变被称为SOSIP突变,其中最后两个突变导致在新产生的半胱氨酸残基之间引入可能的二硫键。总的来说,这些突变导致可溶性的、三聚的、合成的HIV包膜蛋白,而不需要三聚结构域。
在一个优选实施例中,本发明涉及一种核酸,该核酸编码合成的HIV包膜蛋白,该合成的HIV包膜蛋白包括SEQ ID NO:17、SEQ ID NO:18的氨基酸序列,或SEQ ID NO:19的aa1-686。最优选地,由该核酸编码的该合成的HIV包膜蛋白包括SEQ ID NO:18的氨基酸序列或由SEQ ID NO:18的氨基酸序列组成。
在另一概述方面中,本发明涉及一种载体,该载体包括编码根据本发明的实施例的合成的HIV包膜蛋白的核酸。在一个实施例中,该载体是病毒载体。在一个优选实施例中,该病毒载体是腺病毒载体。在一个优选实施例中,该腺病毒载体是腺病毒26载体。
本发明的另一个概述方面涉及一种组合物,优选地是疫苗组合物,所述组合物包含免疫原性(immunogenically)有效量的根据本发明的实施例的载体、和运载体,其中编码该合成的HIV包膜蛋白的核酸可操作地连接至启动子序列。在一个实施例中,该组合物包含一种腺病毒载体,优选地是腺病毒26载体,所述腺病毒载体编码包括SEQ ID NO:18的氨基酸序列的合成的HIV包膜蛋白。
在另一概述方面中,本发明涉及一种用于在对其有需要的受试者体内诱导针对人类免疫缺陷病毒(HIV)的免疫应答的疫苗组合。该疫苗组合包括第一组合物,该第一组合物包括免疫原性有效量的载体,优选地是腺病毒载体,更优选地是腺病毒26载体,该载体编码具有SEQ ID NO:18的氨基酸序列的合成的HIV包膜蛋白;第二组合物,该第二组合物包括免疫原性有效量的第二载体,优选地是第二腺病毒载体,更优选地是第二腺病毒26载体,该第二载体编码包含SEQ ID NO:5的氨基酸序列的HIV抗原性多肽;以及任选地至少一种另外的组合物,该另外的组合物包括免疫有效量的至少一种选自由以下各项组成的组:载体,该载体编码具有选自由SEQ ID NO:1-4、28和29组成的组的氨基酸序列的抗原性多肽,和包含免疫原性有效量的分离的HIV抗原性多肽的多肽,该分离的HIV抗原性多肽包括但不限于具有SEQ ID NO:7的氨基酸序列的残基30-708的多肽或具有SEQ ID NO:36的残基30-724的多肽,其中该第一组合物、第二组合物和任选的另外的组合物是存在于同一组合物或一种或多种不同组合物中。
本发明的又另一个概述方面涉及在对其有需要的受试者体内诱导针对人类免疫缺陷病毒(HIV)的免疫应答的方法,这些方法包括向该受试者给予根据本发明的实施例的组合物或疫苗组合。本发明还涉及诱导针对HIV的免疫应答的多种方法,这些方法包括使用根据本发明的实施例的组合物或疫苗组合来引发并增强该免疫应答。
本发明的又另外的方面涉及一种合成的HIV包膜蛋白,该合成的HIV包膜蛋白包括SEQ ID NO:8的、或具有一个或多个选自下组的突变的SEQ ID NO:8的氨基酸序列,该组由以下各项组成:(i)I529P,(ii)K480E,(iii)EK479-480RRRR、I529P、A471C和T575C的组合。在一个实施例中,这些合成的HIV包膜蛋白包括具有EK479-480RRRR、I529P、A471C和T575C的突变的SEQ ID NO:8。在另一个实施例中,这些合成的HIV包膜蛋白包括SEQ ID NO:18的氨基酸序列的残基30-704或30-711。在又另一个实施例中,这些合成的HIV包膜蛋白包括SEQ ID NO:19的氨基酸序列的残基30-686。
本发明的另一方面涉及一种细胞,优选地是分离的细胞,所述细胞包括根据本发明的实施例的载体。
附图说明
当连同附图一起阅读时,会更好地理解先前概述以及以下本发明的详述。应理解的是本发明不限于附图中示出的准确实施例。
在这些附图中:
图1A-1C是HIV包膜蛋白结构的示意性表示;图1A示出了全长HIV包膜蛋白;图1B示出根据本发明的实施例的可溶性单链HIV包膜蛋白结构,其中该跨膜结构域(TM)被GCN4三聚结构域替换,并且该弗林蛋白酶切割位点是突变的(sC4);图1C示出根据本发明的实施例的膜结合HIV包膜蛋白的结构,该结构包括跨膜结构域和细胞质结构域的片段(C4D7);
图2示出了可溶性sC1包膜蛋白的表达水平,该sC1包膜蛋白基于具有另外的C-末端三聚结构域的mos2Env镶嵌抗原序列、和根据本发明的实施例的可溶性合成的HIV包膜蛋白(sC4);表达通过使用针对gp120的多克隆抗体的定量蛋白质印迹法测量;将编码sC1或sC4的质粒瞬时表达两次,并且每次转染通过光密度测定法定量两次;相比于显示出相对高的表达水平的sC4合成的HIV包膜蛋白,该sC1蛋白显示出非常低的表达水平;
图3A和3B示出在如通过ELISA测定而确定的可溶性CD4存在(浅灰色)和不存在(深灰色)的情况下,合成的HIV包膜蛋白与单克隆抗体17b(mAb17b)的结合;图3A示出sC1的结合;图3B示出sC4的结合;
图4是来自sC1蛋白和sC4合成的HIV包膜蛋白的天然聚丙烯酰胺凝胶电泳的蛋白质印迹的图像;
图5示出了使用抗gp120多克隆抗体(GP120)通过表达这些蛋白质的细胞的FACS分析,并且通过结合至广泛中和性抗体PG9(PG9)和PG16(PG16)的膜结合的C1、C1D7、C4和C4D7合成的HIV包膜蛋白的相对细胞表面表达水平,该广泛中和性抗体PG9和PG16是四级结构依赖性的并且优先结合正确折叠的Env三聚体;
图6是在多次病毒传代后腺病毒载体的稳定性的图示,这些腺病毒载体含有编码本发明的合成的HIV包膜蛋白的序列,这些序列包括全长C4(FLC4)、C4D7和sC4;在PER.C6细胞中产生重组腺病毒26载体;在用于转染和噬斑纯化的最初3次传代后,选择5个噬菌斑并以T25形式扩增10代,导致总病毒传代数(vpn)为13;示出了如通过E1转基因盒聚合酶链式反应(PCR)测定的vpn 3、5、10和13之后的稳定性;例如,3/5是指在5个测试的噬菌斑中的3个噬菌斑是稳定的,并且5/5是指在5个测试的噬菌斑中的5个噬菌斑是稳定的;并且
图7A和7B示出了在兔子中的基于TZM-bl细胞的中和测定中针对HIV-1包膜假型病毒颗粒(EVP)的病毒中和效价;在第1周、第8周、第14周和第20周,针对EVP VSV-G(阴性对照)和MW965.26(Tier 1A分枝C)测量高腺病毒载体给药组的log10-转化的IC50值;每个点表示单独的兔的log10-转化的IC50值,组平均值由水平线表示;HD:测试的最高稀释度(上部实线);LD:测试的最低稀释度(下部实线);LOB:背景的限值,编译的阴性样品的95百分位值(虚线);在相应的线处设置超过LD或HD阈值的Log10 IC50值;对每个时间点使用联合分级的Dunn方法与对照进行单向非参数比较;这些图中示出了以下统计显著差异:*=P<0.05,**=P<0.01,以及***=P<0.001;图7A示出了VSV-G(阴性对照)的结果;并且图7B示出了MW965.26(Tier 1A分枝C)的结果。
具体实施方式
在背景和整个说明书中引用或描述了各种出版物、文章和专利;这些参考文献中的每一篇均通过引用以其整体结合在此。包括在本说明书中的文件、法案、材料、装置、物品或类似物的讨论用于提供本发明的背景的目的。这种讨论不承认任何或所有这些事项形成关于所披露或要求保护的任何发明的现有技术的一部分。
除非另外指明,本文所用的所有科学技术术语具有如本发明所属领域的普通技术人员通常理解的相同含义。否则,本文使用的某些术语具有如说明书中示出的含义。本文引用的所有专利、公开专利申请和出版物如同完全列出一样通过引用结合在此。必须注意,除非上下文另外明确指示,否则如在此和所附权利要求中所使用,单数形式“一个/一种(a/an)”和“该”包括复数指示物。
如在此所使用,“受试者”是指将向其给予或已经给予根据本发明的实施例的载体、组合物或组合疫苗的任何动物,优选地是哺乳动物,最优选地是人类。如在此所用的术语“哺乳动物”涵盖任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、兔、豚鼠、猴、人等,更优选地是人。
本发明总体上涉及合成的HIV包膜蛋白、编码这些合成的HIV的包膜蛋白的核酸和载体、以及用编码这些合成的HIV的包膜蛋白的载体或这些合成的HIV的包膜蛋白单独地或与一种或多种另外的编码一种或多种另外的HIV抗原性多肽的载体组合地,和/或与一种或多种另外的分离的HIV抗原性多肽组合地诱导针对HIV的免疫应答的方法。
人类免疫缺陷病毒(HIV)是慢病毒属(Lentivirinae)的成员,其是逆转录病毒科(Retroviridae)的一部分。两种HIV感染人类:HIV-1和HIV-2。HIV-1是最常见的HIV病毒的菌株,并且已知比HIV-2更致病。如在此所使用,术语“人类免疫缺陷病毒”和“HIV”是指但不限于HIV-1和HIV-2。
HIV被分类为具有高度遗传趋异的多个分枝。如在此所使用,术语“HIV分枝”或“HIV亚型”是指根据它们的遗传相似性程度进行分类的相关人类免疫缺陷病毒。目前存在三组HIV-1分离株:M、N和O。M组(主要菌株)由至少从A至J的十个分枝组成。O组(外部菌株)可以由相似数目的分枝组成。N组是未分类于M或O组中的新HIV-1分离株。
如在此所使用,术语“HIV抗原性多肽”、“HIV抗原蛋白”、和“HIV免疫原”是指能够在受试者中诱导针对HIV的免疫应答,例如体液和/或细胞介导的应答的多肽。该抗原性多肽可以是HIV的蛋白质、其片段或表位、或其多个HIV蛋白或部分的组合,其可以在受试者中诱导针对HIV的免疫应答或产生免疫,例如保护性免疫。
优选地,抗原性多肽能够在宿主中产生保护性免疫应答,例如诱导针对病毒性疾病或感染的免疫应答,和/或在受试者中产生针对病毒性疾病或感染的免疫(即接种),其保护受试者免受病毒性疾病或感染。例如,该抗原性多肽可以包含来自猿猴免疫缺陷病毒(SIV)或HIV的蛋白质或其片段,如HIV或SIV包膜gp160蛋白,HIV或SIV基质/衣壳蛋白,以及HIV或SIV gag、pol和env基因产物。
HIV抗原性多肽可以是任何HIV-1或HIV-2抗原或其片段。HIV抗原的实例包括但不限于gag、pol、和env基因产物,这些基因产物编码结构蛋白和必需酶。Gag、pol、和env基因产物被合成为多蛋白,这些多蛋白被进一步加工成多个其他蛋白产物。该gag基因的初级蛋白产物是病毒结构蛋白gag多蛋白,其被进一步加工成MA、CA、SP1、NC、SP2以及P6蛋白产物。该pol基因编码病毒酶(Pol,聚合酶),并且该初级蛋白产物被进一步加工成RT、RNase H、IN、以及PR蛋白产物。该env基因编码结构蛋白,尤其病毒体包膜的糖蛋白。该env基因的初级蛋白产物是gp160,gp160被进一步加工成gp120和gp41。HIV抗原的其他实例包括基因调节蛋白Tat和Rev;辅助蛋白Nef、Vpr、Vif和Vpu;衣壳蛋白、核衣壳蛋白、以及p24病毒蛋白。
在某些实施例中,该HIV抗原性多肽包括HIV Gag、Env、或Pol抗原、或任何抗原部分或其表位或组合,优选地是HIV-1Gag、Env、或Pol抗原或任何抗原部分或其表位或组合。
HIV抗原性多肽还可以是镶嵌HIV抗原。如在此所使用,“镶嵌抗原”是指自天然序列的片段组装的重组蛋白。镶嵌抗原类似于天然抗原,但被优化以最大化在天然序列中发现的潜在T细胞表位的覆盖,这提高了免疫应答的宽度和覆盖。用于本发明的镶嵌HIV抗原优选地是镶嵌Gag、Pol、和/或Env抗原,并且更优选地是镶嵌HIV-1 Gag、Pol/和/或Env抗原。如在此所使用,“镶嵌HIV Gag、Pol、和/或Env抗原”尤其是指包含来源于HIV的一个或多个Gag、Pol和/或Env多蛋白序列的多个表位的镶嵌抗原。
在一个实施例中,用于本发明的镶嵌HIV抗原是具有来源于gag基因产物的序列的表位的镶嵌HIV Gag抗原(SEQ ID NO:1、2中提供了实例);是具有来源于pol基因产物的序列的表位的镶嵌HIV Pol抗原(SEQ ID NO:3、4中提供了实例);或是具有来源于env基因产物的序列的表位的镶嵌HIV Env抗原(SEQ ID NO:5、6中提供了实例;还有例如在SEQ ID N:8、17、18、19中的本发明的新颖抗原可以被认为是镶嵌HIV Env抗原)。在某些实施例中,用于本发明的镶嵌HIV抗原可以包括来源于gag、pol、和/或env基因产物的表位的组合。说明性的和非限制的实例包括具有来源于env和pol基因产物的序列的表位的镶嵌Env-Pol抗原;具有来源于gag和pol基因产物的序列的表位的镶嵌Gag-Pol抗原;以及具有来源于gag和env基因产物的序列的表位的镶嵌Gag-Env抗原。gag、pol、和env基因产物的序列可以来源于一种或多种分枝。
可以用于本发明中的镶嵌HIV Gag、Pol和/或Env抗原的实例包括描述于例如US20120076812;巴鲁什等人,自然医学(Nat Med)2010,16:319-323;以及巴鲁什等人,细胞(Cell)155:1-9,2013中的那些,所有这些文献都以其整体通过引用结合在此。优选地,用于本发明的镶嵌HIV Gag、Pol、和/或Env抗原包括但不限于mos1Gag(SEQ ID NO:1)、mos2Gag(SEQ ID NO:2)、mos1Pol(SEQ ID NO:3)、mos2Pol(SEQ ID NO:4)、mos1Env(SEQ ID NO:5)、mos2Env(SEQ ID NO:6)、mos1GagPol(SEQ ID NO:28)、mos2GagPol(SEQ ID NO:29)、以及其组合。
如本文所使用,术语“HIV包膜蛋白”、“env蛋白”、和“Env”各自是指在HIV病毒体的包膜上表达,并且使得HIV靶向并附着于HIV感染的细胞的质膜上的蛋白质或其片段或衍生物,这些蛋白质或片段或衍生物可以在对其有需要的受试者中诱导针对HIV的免疫应答或产生针对HIV的免疫。该HIV env基因编码前体蛋白gp160,该前体蛋白gp160被蛋白质裂解地切割成两种成熟的包膜糖蛋白,即gp120和gp41。该切割反应由宿主细胞蛋白酶(弗林蛋白酶)在逆转录病毒包膜糖蛋白前体中的高度保守的序列处介导。更具体地,gp160三聚化为(gp160)3,并且然后经历切割成为两个非共价缔合的gp120和gp41。病毒进入随后由gp120/gp41异源二聚体的三聚体介导。Gp120是受体结合片段,并且结合到靶细胞上的CD4受体上,该靶细胞具有这样的受体如,例如T-辅助细胞。非共价结合至gp120的Gp41是融合片段并且提供HIV进入细胞的第二步骤。Gp41最初埋在该病毒包膜内,但当gp120与CD4受体结合时,gp120改变其构象,从而导致gp41暴露,其中它可以帮助与宿主细胞融合。Gp140是三聚gp160,即(gp160)3的未切除的胞外结构域,其被用作天然状态的切割的病毒刺突的替代物。
根据本发明的实施例,“HIV包膜蛋白”可以是gp160、gp140、gp120、gp41蛋白,其组合,融合物,截短物或衍生物。例如,“HIV包膜蛋白”可以包括与gp41蛋白非共价缔合的gp120蛋白。它还可以包括稳定的三聚gp140蛋白,该三聚gp140蛋白可以具有或可以被修饰以包括三聚结构域,该三聚结构域稳定gp140的三聚体。三聚结构域的实例包括但不限于T4-fibritin“foldon”三聚结构域;来源于GCN4的卷曲螺旋三聚结构域;以及作为三聚体标签的大肠杆菌天冬氨酸转氨甲酰酶的催化亚基。“HIV包膜蛋白”还可以是截短的HIV包膜蛋白,该截短的HIV包膜蛋白包括但不局限于包含在胞外结构域(即,延伸至细胞外空间的结构域)中的C-末端截短、在gp41中的截短物(如在gp41的跨膜结构域中的截短物,或在gp41的细胞质结构域中的截短物)的包膜蛋白。“HIV包膜蛋白”可以进一步是天然存在的HIV包膜蛋白的衍生物,该HIV包膜蛋白的衍生物具有例如在弗林蛋白酶切割位点中的序列突变、和/或所谓的SOSIP突变。
优选地,“HIV包膜蛋白”是“合成的HIV包膜蛋白。”如在此所使用,术语“合成的HIV包膜蛋白”是指非天然存在的HIV包膜蛋白,其在对其有需要的受试者中针对一种或多种天然存在的HIV菌株诱导免疫应答或产生免疫。镶嵌HIV Env蛋白是合成的HIV Env蛋白的实例,并且本发明提供了新颖的合成的HIV Env抗原,例如包含SEQ ID NO:8、17、18、或19的那些。
合成的HIV包膜蛋白及其编码序列
本发明的实施例涉及新颖的合成的HIV包膜蛋白和编码这些的核酸分子。
在一个实施例中,本发明涉及合成的HIV包膜蛋白,该合成的HIV包膜蛋白包含SEQID NO:8的、或具有一种或多种选自下组的突变的SEQ ID NO:8的氨基酸序列,该组由以下各项组成:(i)I529P,(ii)K480E,以及(iii)EK479-480RRRR、I529P、A471C和T575C的组合。SEQ ID NO:8包括合成的成熟gp120和合成的截短gp41,该合成的截短gp41不具有跨膜区域,也不具有细胞质结构域。SEQ ID NO:8是非天然存在的序列,其包含来自该mos2Env镶嵌抗原(SEQ ID NO:6)的序列和其他HIV包膜蛋白序列的嵌合体。包含SEQ ID NO:8的新颖的合成的Env抗原的序列被优化以提供针对HIV分枝C的广泛覆盖和增强的T-细胞应答(当与该mos2Env抗原(SEQ ID NO:6)相比时)。在某些实施例中,另外的氨基酸可以添加至SEQ IDNO:8中或本文所定义的它的变体之一中。
在某些实施例中,该合成的HIV包膜蛋白进一步包括信号序列。该合成的HIV包膜蛋白使用信号序列合成,所述信号序列在其转运到内质网(ER)的腔内期间从新生多肽链切割。原则上,可以使用任何已知的信号序列。优选地使用HIV Env信号序列或其变体。本领域中已经使用针对HIV Env蛋白的不同信号序列(参见例如,WO 2014/107744)。在某些实施例中,该信号序列包括SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11或SEQ ID NO:12。在一个优选实施例中,该信号序列包括SEQ ID NO:9。
在某些实施例中,该合成的HIV包膜蛋白进一步包括跨膜结构域。该跨膜结构域将合成的HIV包膜蛋白锚定到该ER膜上,并且有助于膜组装和HIV包膜的功能。优选地,该跨膜结构域包括SEQ ID NO:13。
在另一个实施例中,该合成的HIV包膜蛋白包括具有截短的细胞质结构域的gp41。该gp41在其羧基末端具有异常长的细胞质结构域,通常约150个氨基酸(爱德华兹(Edwards)等人,病毒学杂志(J.Virology),2002,76:2683-2691)。据报道该细胞质结构域的截短诱导HIV-1Env蛋白的胞外结构域中的保守区域的暴露(Id.)。本发明的合成的HIV包膜中的截短的细胞质结构域可以在从一个至约140个氨基酸的范围内,如全长细胞质结构域的1、2、3、4、5、6、7、8、9、10、15、20、30、40、50、60、70、80、90、100、110、120、130、或140个氨基酸。在某些实施例中,通过给定的氨基酸直到C-末端之后的截短,该截短的细胞质结构域来源于SEQ ID NO:17的氨基酸704-862(即,来源于本发明的C4分子的细胞质结构域)。在一个优选实施例中,该合成的HIV包膜蛋白包括截短的细胞质结构域,该截短的细胞质结构域具有HIV gp41细胞质结构域的1至10个氨基酸残基,更优选地4至8个氨基酸残基,并且最优选地7个氨基酸残基。合成的HIV包膜蛋白的细胞质结构域或其片段位于该细胞外结构域(细胞外结构域(ectodomain))的C-末端,并且当该合成的HIV包膜蛋白还包括跨膜结构域时,该细胞质结构域或其片段位于该跨膜结构域的C-末端。参见,例如,图1A和1C。在一个特定实施例中,该合成的HIV包膜蛋白包括具有截短的细胞质结构域的gp41,该截短的细胞质结构域具有SEQ ID NO:14的氨基酸序列或其片段,如其残基1-4(即NRVR)。已经描述了并且可使用其他截短的细胞质结构域(例如Schiernle等人,美国科学院院刊(PNAS),1997;亚伯拉罕(Abrahamyan)等人,病毒学杂志(J Virol)2005)。
在其中该合成的HIV包膜蛋白进一步包括跨膜结构域和细胞质结构域的片段的实施例中,优选的是该蛋白还包括SEQ ID NO:37的氨基酸序列,该SEQ ID NO:37包含SEQ IDNO:18的残基655-682,其中SEQ ID NO:37的氨基酸序列被融合到SEQ ID NO:8的C-末端和该跨膜结构域的N-末端。
在本发明的一个特别优选的实施例中,该合成的HIV包膜蛋白进一步包括跨膜结构域,例如具有SEQ ID NO:13的氨基酸序列的那些和截短的细胞质结构域或细胞质结构域的片段例如具有SEQ ID NO:14的氨基酸序列或SEQ ID NO:14的残基1-4(即,NRVR)的那些。最优选地,该合成的HIV包膜蛋白包括SEQ ID NO:18的氨基酸序列,具有或没有信号序列(即,SEQ ID NO:18的氨基酸残基1-29)或由其组成。
在另一个实施例中,该合成的HIV包膜蛋白包括替代Env跨膜区域的三聚结构域。该三聚结构域增加了Env三聚结构的稳定性。优选地,该合成的HIV包膜蛋白包括gp140多肽,该gp140多肽被修饰以包括稳定gp140的三聚体的三聚结构域。三聚结构域的实例包括但不限于T4-fibritin“foldon”三聚结构域,如包含SEQ ID:16的氨基酸序列的那些;来源于GCN4的卷曲螺旋三聚结构域,如包含SEQ ID:15的氨基酸序列的那些;作为三聚体标签的大肠杆菌天冬氨酸转氨甲酰酶的催化亚基;或基于软骨基质蛋白的三聚基序。如果存在时,该三聚结构域通常位于该细胞外结构域的C-末端(参见图1B)。在某些优选实施例中,其中该合成的HIV包膜蛋白包括三聚结构域,该合成的HIV包膜蛋白包括SEQ ID NO:19的氨基酸序列,具有或没有信号序列(即,SEQ ID NO:19的氨基酸残基1-29)。具有三聚结构域的这些实施例主要用于该合成的HIV包膜蛋白的可溶性胞外结构域变体。在本发明的此类可溶性变体的某些实施例中,有可能对该弗林蛋白酶切割位点进行突变(例如在SEQ ID NO:8的位置480处的Lys突变为Glu)以使这个切割位点失活,从而使得该蛋白质将是一条单链;它与三聚结构域,尤其是与SEQ ID NO:19的GCN4三聚结构域良好地结合。
不使用三聚结构域的该合成的HIV包膜蛋白的此类可溶性细胞外结构域的可替代版本也是本发明的实施例,并且可以通过将优化该弗林蛋白酶切割位点的突变(在位置479-480处的Gly-Lys二肽被四个Arg残基替换)以及所谓的SOSIP突变(在位置529处的I>P突变,并且在位置471和575之间通过置换在SEQ ID NO:8中各自具有Cys残基的那些位置上的相应Ala和Thr而引入二硫键)进行合并来从SEQ ID NO:8制备。这产生一种蛋白质,该蛋白质具有以下突变的组合的SEQ ID NO:8的氨基酸序列:EK479-480RRRR、I529P、A471C和T575C。
进一步增加本发明的合成的HIV包膜蛋白(包含SEQ ID NO:8)的三聚体含量的一种可能的修饰是位置529处的Ile到Pro的修饰。这对于可溶性变体和膜结合变体两者都可以是有效的。
载体
本发明的另一个概述方面涉及包含编码合成的HIV包膜蛋白的核酸的载体。根据本发明的实施例,这些载体可以包含本文所述的任何合成的HIV包膜蛋白。在本发明的一个优选实施例中,该载体包含编码以下合成的HIV包膜蛋白的核酸,该HIV包膜蛋白包括SEQID NO:8、SEQ ID NO:17、SEQ ID NO:18、或SEQ ID NO:19的氨基酸序列,并且更优选地是SEQ ID NO:18的氨基酸序列。
根据本发明的实施例,编码该合成的HIV包膜蛋白的核酸可操作地连接至启动子,这意味着该核酸在启动子的控制下。该启动子可以是同源启动子(即,来源于相同的作为载体的遗传来源)或异源启动子(即,来源于不同载体或遗传来源)。适合的启动子的实例包括巨细胞病毒(CMV)启动子和劳氏肉瘤病毒(RSV)启动子。优选地,该启动子位于表达盒内的核酸的上游。可以可操作地连接至编码该合成的HIV包膜蛋白的核酸的示例性CMV启动子序列示于SEQ ID NO:24中。
根据本发明的实施例,载体可以是表达载体。表达载体包括但不限于用于重组蛋白表达的载体和用于将核酸递送至受试者中用于在该受试者的组织中表达的载体,例如病毒载体。适合用于本发明的病毒载体的实例包括但不限于腺病毒载体、腺相关病毒载体、痘病毒载体、MVA载体、肠系病毒载体、委内瑞拉马脑炎病毒载体、塞姆利基森林病毒载体、烟草花叶病毒载体、慢病毒载体等。该载体还可以是非病毒载体。非病毒载体的实例包括但不限于质粒、细菌人工染色体、酵母人工染色体、噬菌体等。
在本发明的某些实施例中,该载体是腺病毒载体。根据本发明的腺病毒属于腺病毒科,并且优选地是属于哺乳动物腺病毒(Mastadenovirus)属的一种。它可以是人类腺病毒,但还可以是感染其他物种的腺病毒,包括但不限于牛腺病毒(例如牛腺病毒3、BAdV3)、犬腺病毒(例如CAdV2)、猪腺病毒(例如PAdV3或PAdV5)、或猿猴腺病毒(其包括猴腺病毒和猿腺病毒,如黑猩猩腺病毒或大猩猩腺病毒)。优选地,该腺病毒是人类腺病毒(HAdV、或AdHu)、或猿猴腺病毒如黑猩猩或大猩猩腺病毒(ChAd、AdCh、或SAdV)。在本发明中,人类腺病毒是指如果称为Ad而不指明物种,例如该简短符号“Ad26”表示与HadV26相同,该HadV26是人腺病毒血清型26。还如在此所使用的,符号“rAd”是指重组腺病毒,例如,“rAd26”是指重组人类腺病毒26。
已使用人腺病毒进行大多数高级研究,并且根据本发明的某些方面,人腺病毒是优选的。在某些优选实施例中,根据本发明的重组腺病毒是基于人腺病毒。在优选的实施例中,该重组腺病毒基于人腺病毒血清型5、11、26、34、35、48、49、50、52等。根据本发明的一个特别优选的实施例,腺病毒是人腺病毒血清型26。这种血清型的优点是在人群体中的低血清阳性率和/或低预先存在的中和抗体效价,以及在临床试验中用于人类受试者的经验。
猿猴腺病毒总体上也具有在人群体中的低血清阳性率和/或低预先存在的中和抗体效价,并且已经报道了大量使用黑猩猩腺病毒载体的工作(例如,US6083716;WO 2005/071093;WO 2010/086189;WO 2010085984;法里纳(Farina)等人,2001,病毒学杂志(JVirol)75:11603-13[13];科恩(Cohen)等人,2002,普通病毒学杂志(J Gen Virol)83:151-55[69];科宾格(Kobinger)等人,2006,病毒学(Virology)346:394-401[70];Tatsis等人,2007,分子治疗(Molecular Therapy)15:608-17[71];还参见由Bangari和Mittal,2006,疫苗(Vaccine)24:849-62[72]的综述;以及由拉莎诺(Lasaro)和埃特尔(Ertl),2009,分子治疗(Mol Ther)17:1333-39[73]的综述)。因此,在其他的实施例中,根据本发明的重组腺病毒是基于猿猴腺病毒,例如黑猩猩腺病毒。在某些实施例中,该重组腺病毒是基于猿猴腺病毒类型1、7、8、21、22、23、24、25、26、27.1、28.1、29、30、31.1、32、33、34、35.1、36、37.2、39、40.1、41.1、42.1、43、44、45、46、48、49、50或SA7P。
优选地,该腺病毒载体是复制缺陷型重组病毒载体,如rAd26、rAd35、rAd48、rAd5HVR48等。
在本发明的一个优选实施例中,这些腺病毒载体包括来自罕见血清型的衣壳蛋白,包括Ad26。在典型实施例中,该载体是rAd26病毒。“腺病毒衣壳蛋白”是指在腺病毒(例如,Ad26、Ad35、rAd48、rAd5HVR48载体)的衣壳上的蛋白质,该腺病毒衣壳蛋白参与确定特定的腺病毒的血清型和/或趋向性。腺病毒衣壳蛋白典型地包括纤维、五邻体蛋白和/或六邻体蛋白。如在此所使用的用于特定腺病毒的“衣壳蛋白”(如“Ad26衣壳蛋白”)可以是例如包括至少一部分Ad26衣壳蛋白的嵌合的衣壳蛋白。在某些实施例中,该衣壳蛋白是Ad26的整个衣壳蛋白。在某些实施例中,该六邻体、五邻体和纤维都是Ad26的。
本领域的普通技术人员将认识到来源于多个血清型的元件可以被组合在单一的重组腺病毒载体中。因此,可以产生组合了来自不同血清型的所希望性质的嵌合腺病毒。因此,在一些实施例中,本发明的嵌合腺病毒可以将第一血清型的预先存在的免疫性的缺失与以下特征相结合:如温度稳定性、组装、锚定、产量、重定向或改善的感染、靶细胞中DNA的稳定性等。
在某些实施例中,本发明中有用的重组腺病毒载体主要或完全来源于Ad26(即,该载体是rAd26)。在某些实施例中,该腺病毒是复制缺陷的,例如,因为它包含基因组的E1区域中的缺失。对于来源于非类群C的腺病毒(如Ad26或Ad35)的腺病毒,典型地是将腺病毒的E4-orf6编码序列与人类亚群C(如Ad5)的腺病毒的E4-orf6交换。这允许在表达Ad5的E1基因的熟知的补充细胞系中此类腺病毒的繁殖,如例如293细胞或PER.C6细胞等(参见,例如哈文格(Havenga)等人,2006,普通病毒学杂志(J Gen Virol)87:2135-43;WO 03/104467)。然而,这样的腺病毒将不能在不表达Ad5的E1基因的非补充细胞中复制。
重组腺病毒载体的制备在本领域中是熟知的。例如在WO 2007/104792中和在阿宾克(Abbink)等人,(2007)病毒学(Virol)81(9):4654-63中描述了rAd26载体的制备。Ad26的示例性基因组序列发现于GenBank登录号EF 153474中和WO 2007/104792的SEQ ID NO:1中。用于本发明的载体的实例例如包括描述于WO2012/082918中的那些,将其披露内容以其整体通过引用结合在此。
典型地,使用核酸来产生本发明中有用的载体,该核酸包括整个重组腺病毒基因组(例如,质粒、粘粒、或杆状病毒载体)。因此,本发明还提供了分离的核酸分子,这些分离的核酸分子编码本发明的这些腺病毒载体。本发明的这些核酸分子可以处于RNA形式或处于通过克隆获得或合成产生的DNA形式。该DNA可以是双链或单链的。
本发明中有用的这些腺病毒载体典型地是复制缺陷的。在这些实施例中,该病毒通过使对病毒复制关键的区域(例如E1区域)缺失或失活而变得复制缺陷。可以通过在所述区域内例如插入感兴趣的基因,如编码合成的HIV包膜蛋白的基因(通常连接至启动子),或编码HIV抗原性多肽的基因(通常连接至启动子)来使这些区域基本上缺失或失活。在一些实施例中,本发明的这些载体可以包含其他区域如E2、E3或E4区域中的缺失,或这些区域中的一个或多个内的连接至启动子的异源基因的插入。对于E2-和/或E4-突变的腺病毒,一般使用E2-和/或E4补充细胞系来产生重组腺病毒。该腺病毒的E3区域中的突变不需要被细胞系补充,因为对于复制E3是需要的。
通常使用包装细胞系来生产足够量的用于在本发明中使用的腺病毒载体。包装细胞是包含在复制缺陷型载体中缺失或失活的那些基因的细胞,因此允许了该病毒在该细胞中复制。适合用于在该E1区域具有缺失的腺病毒的包装细胞系包括,例如,PER.C6、911、293、以及E1 A549。
根据本发明的实施例,并且如以上所指出的,本文所述的任何合成的HIV包膜蛋白可以在本发明的这些载体中表达。鉴于遗传密码的简并性,技术人员将充分意识到可以根据本领域中完全常规的方法来设计编码相同蛋白质的若干种核酸序列。编码该合成的HIV包膜蛋白的核酸可以任选地是密码子优化的,以确保在所治疗的宿主(例如,人类)中的适当的表达。密码子优化是广泛应用于本领域中的技术。SEQ ID NO:25、26和27中提供了一些编码本发明的合成的HIV包膜蛋白的序列的非限制性实例。典型地,编码该合成的HIV包膜蛋白的核酸被克隆入该腺病毒基因组的E1和/或E3区域。
在本发明的一个优选实施例中,该载体是腺病毒载体,并且更优选地是rAd26载体,最优选地是在该腺病毒基因组的E1区域内具有至少一个缺失的rAd26载体,例如如在阿宾克(Abbink),病毒学杂志(J Virol),2007.81(9):第4654-63页中描述的,将其通过引用结合在此。
本发明还提供了细胞,优选地是包含本文所述的任何载体的分离的细胞。这些细胞可以用于生产重组蛋白质,或用于生产病毒颗粒。
因此,本发明的实施例还涉及制造合成的HIV抗原性多肽的方法。该方法包括用表达载体转染宿主细胞,所述表达载体包含可操作地连接至启动子的编码该合成的HIV抗原性多肽的核酸;在适合于表达该合成的HIV抗原性多肽的条件下培养该转染的细胞,并从该细胞分离该合成的HIV抗原性多肽。可以通过本领域中已知的任何方法(包括亲和层析等)从该细胞中分离或收集该合成的HIV抗原性多肽。鉴于本披露,用于重组蛋白表达的技术将是本领域普通技术人员所熟知的。
本发明还包括用于生产编码本发明的合成的HIV抗原性多肽的载体的方法,该方法包括培养包含该载体的细胞以在所述培养期间繁殖和增殖该载体,并从该细胞培养物(例如,从细胞、从培养基或两者)中分离编码本发明的合成的HIV抗原性多肽的载体。可以根据本领域已知的方法进一步纯化该载体。
在某些实施例中,本发明提供了根据本发明的实施例的载体,该载体包含编码合成的HIV抗原性多肽的核酸,并且在某些示例性实施例中,该核酸具有选自下组的核苷酸序列,该组以下各项组成:SEQ ID NO:25、26和27。
组合物
在另一个概述方面中,本发明涉及包含载体和运载体的组合物,该载体包含编码合成的HIV包膜蛋白的核酸。根据本发明的实施例,本文所述的任何载体可以包括在该组合物中。优选地,该载体是病毒载体,更优选地是腺病毒载体,并且甚至更优选地是腺病毒26载体。在一个优选实施例中,组合物包含腺病毒载体,优选地是编码合成的HIV包膜蛋白的腺病毒26载体,该合成的HIV包膜蛋白包含SEQ ID NO:8、SEQ ID NO:18、或SEQ ID NO:19的氨基酸序列,并且更优选地是SEQ ID NO:18的氨基酸序列。
在一个方面,本发明提供了包含一种或多种载体的组合疫苗,这些载体一起包含编码以下各项的核酸序列:(i)合成的HIV包膜蛋白,其包含SEQ ID NO:8(例如SEQ ID NO:18或19)的氨基酸序列,和(ii)第二HIV包膜蛋白,其包含SEQ ID NO:5的氨基酸序列。这些载体可以各自在单独的组合物中,或可被结合在单一的组合物中。旨在向一个受试者给予在一个或多个载体中的这两种核酸,这将导致对HIV的免疫应答,其比给予任一单独的载体时将获得的免疫应答更广泛。这两种核酸序列还可以存在于单一的载体上。
根据本发明的实施例,组合物包含免疫原性有效量的载体,如病毒载体。如在此所使用的,“免疫原性有效量”或“免疫有效量”是指足以在对其有需要的受试者中诱导所需免疫效应或免疫应答的组合物的量。在一个实施例中,免疫原性有效量是指足以在对其有需要的受试者中诱导免疫应答的量。在另一个实施例中,免疫原性有效量是指足以在对其有需要的受试者中产生免疫,例如,提供对抗疾病例如病毒感染的保护效应的量。免疫原性有效量可以根据多种因素而变化,诸如受试者的身体状况、年龄、体重、健康等;具体应用,是否诱导免疫应答或提供保护性免疫;给予的特定重组载体;由所给予的重组载体编码的免疫原或抗原性多肽;给予的特异性抗原性多肽;以及需要免疫的具体疾病,例如病毒感染。考虑到本披露,通过本领域普通技术人员可以容易地确定免疫原性有效量。
作为一般指导,当参考重组病毒载体如腺病毒载体使用时,免疫原性有效量可以在从约108个病毒颗粒至约1012个病毒颗粒,例如108、109、1010、1011、或1012个病毒颗粒的范围内。免疫原性有效量可以以单一组合物或多个组合物,例如1、2、3、4、5、6、7、8、9或10个组合物(例如,片剂,胶囊或注射剂)给予,其中所述多个胶囊或注射剂的给予共同以免疫有效量提供给受试者。一般而言,当参考多肽(如分离的抗原性多肽)使用时,免疫原性有效量可以在从例如约0.3至约3000微克(μg)的范围内,例如1-1000μg,例如10-500μg,例如约10、50、100、150、200、250、300、350、400、450或500μg。作为非限制性实例,有可能将编码本发明的合成的HIV Env抗原(具有SEQ ID NO:8)的载体的给予与Env多肽,例如250μg的具有SEQID NO:7的氨基酸30-708的HIV分枝C Env三聚体蛋白的给予进行合并。在所谓的初免-加强方案中,还有可能向受试者给予免疫原性有效量,并且随后向同一受试者给予另一剂量的免疫原性有效量。初免-加强方案的一般概念是疫苗领域的技术人员熟知的。如果需要,可以任选地向该方案中加入另外的加强给予。
本发明的组合物进一步包括运载体。运载体可以包括一种或多种药学上可接受的赋形剂,如粘合剂、崩解剂、蓬松剂、助悬剂、乳化剂、润湿剂、润滑剂、调味剂、甜味剂、防腐剂、染料、增溶剂以及涂层。该运载体或其它物质的确切性质可以取决于给药途径,例如肌内、皮下、口服、静脉内、皮肤、粘膜内(例如,肠)、鼻内或腹膜内途径。对于液体可注射制剂(例如,悬浮液和溶液),适合的运载体和添加剂包括水、乙二醇、油、醇、防腐剂、着色剂等。对于固体口服制剂(例如散剂、胶囊、囊片、软胶囊和片剂),适合的运载体和添加剂包括淀粉、糖、稀释剂、粒化剂、润滑剂、粘合剂、崩解剂等。对于鼻喷雾剂/吸入剂混合物,该水性溶液/悬浮液可以包括作为适合的运载体和添加剂的水、乙二醇、油、软化剂、稳定剂、润湿剂、防腐剂、芳香剂、调味剂等。
本发明的组合物可以配制成适合于给予受试者以便于给予并改善功效的任何物质,包括但不限于口服(肠内)给予和肠胃外注射。肠胃外注射包括静脉内注射或输注、动脉内注射、皮下注射、肌内注射以及关节内注射。还可以配制本发明的组合物用于其它给药途径,包括经粘膜、眼、直肠、长效植入、舌下给药、舌下、从口腔粘膜绕过门脉循环、吸入或鼻内。
根据本发明的某些实施例中,组合物包含免疫原性有效量的纯化的或部分纯化的腺病毒载体(如腺病毒26载体),该腺病毒载体包含编码本发明的合成的HIV包膜蛋白的核酸。所述组合物可以根据本领域熟知的方法被配制成疫苗(也称为“免疫原性组合物”)。
本发明的组合物可以进一步任选地包括佐剂以增强免疫应答。术语“佐剂”和“免疫刺激剂”在此可互换地使用,并且被定义为引起免疫系统刺激的一种或多种物质。在本文中,佐剂用于增强对这些载体的免疫应答,这些载体编码本发明的合成的HIV包膜蛋白和/或与编码本发明的合成的HIV包膜蛋白的载体组合使用的HIV抗原多肽。
适合用于本发明的佐剂应当是在人中潜在安全的、耐受性良好的并且有效的佐剂,如例如QS-21、Detox-PC、MPL-SE、MoGM-CSF、TiterMax-G、CRL-1005、GERBU、TER酰胺、PSC97B、Adjumer、PG-026、GSK-I、GcMAF、B-alethine、MPC-026、Adjuvax、CpG ODN、Betafectin、铝盐(例如AdjuPhos)、Adjuplex、以及MF59。鉴于本披露,可以通过本领域技术人员熟知的技术确定制剂中每种组分的最佳比例。
在一个优选实施例中,该佐剂是铝盐,如AdjuPhos。
免疫原性组合物的制备和使用是本领域技术人员所熟知的。液体药物组合物一般包括液体载体例如水、石油、动物或植物油、矿物油或合成油。还可以包括生理盐水溶液、右旋糖或其他糖溶液或二醇,例如乙二醇、丙二醇或聚乙二醇。
例如,重组腺病毒载体可以储存于缓冲液中,该缓冲液还可以用于腺病毒世界标准(Adenovirus World Standard)(霍根森(Hoganson)等人,2002,生物工艺杂志(Bioprocessing J)1:43-8):20mM Tris pH 8,25mM NaCl,2.5%甘油。适用于向人类给予的另一种有用的腺病毒配制品缓冲液是20mM Tris、2mM MgCl2、25mM NaCl、蔗糖10%w/v、聚山梨酯-80 0.02%w/v。适用于重组腺病毒的另一种配制品缓冲液包括10-25mM柠檬酸盐缓冲剂pH 5.9-6.2,4-6%(w/w)羟丙基-β-环糊精(HBCD)、70-100mM NaCl、0.018-0.035%(w/w)聚山梨酯-80、以及任选地包括0.3-0.45%(w/w)乙醇。显而易见地,可以使用许多其他缓冲液,并且已知针对存储和针对纯化载体的药用给药的适合的配制品的若干实例。
根据本发明的实施例,本发明的组合物可以与一种或多种编码一种或多种另外的HIV抗原性多肽的另外的载体,和/或一种或多种分离的HIV抗原性多肽一起使用。这些另外的载体和/或HIV抗原性多肽可以存在于包含本发明的合成的HIV Env蛋白的同一组合物中。它们还可以存在于一种或多种不同的组合物中,所述不同的组合物可以与包含本发明的合成的HIV包膜蛋白的组合物在疫苗组合中一起使用。优选地,该一种或多种另外的载体是病毒载体,如腺病毒载体,并且最优选地是腺病毒26载体。鉴于本披露,该一种或多种另外的载体可以编码任何本领域技术人员已知的HIV抗原性多肽。
在一个实施例中,组合物或疫苗组合进一步包含第二腺病毒载体,优选地是腺病毒26载体,所述载体编码包含SEQ ID NO:5的氨基酸序列的HIV抗原性多肽。此类实施例的优点是增加免疫应答的宽度(覆盖来自分枝B和C的菌株)。
在另一个实施例中,本发明的组合物或疫苗组合进一步包含编码HIV抗原性多肽的腺病毒载体,优选地是腺病毒26载体,该HIV抗原性多肽包含SEQ ID NO:28(mos1GagPol)的氨基酸序列。
在另一个实施例中,本发明的组合物或疫苗组合进一步包含编码HIV抗原性多肽的腺病毒载体,优选地是腺病毒26载体,该HIV抗原性多肽包含SEQ ID NO:29(mos2GagPol)的氨基酸序列。
在一个具体实施例中,本发明的组合物或疫苗组合进一步包含第二腺病毒载体,优选地是腺病毒26载体,该第二腺病毒载体编码包含SEQ ID NO:5的氨基酸序列的HIV抗原性多肽;以及一种或多种另外的腺病毒载体,优选地是腺病毒26载体,该一种或多种另外的载体编码一种或多种包含选自由SEQ ID NO:28或SEQ ID NO:29组成的组的氨基酸序列的HIV抗原性多肽。例如,根据本发明的实施例的组合物或疫苗组合可以包含四种腺病毒载体,优选地是腺病毒26载体,其中第一载体编码包含SEQ ID NO:8(例如SEQ ID NO:18)的氨基酸序列的合成的HIV包膜蛋白;第二载体编码包含SEQ ID NO:5的氨基酸序列的HIV抗原性多肽;第三载体编码包含SEQ ID NO:28的氨基酸序列的合成的HIV包膜蛋白;并且第四载体编码包含SEQ ID NO:29的氨基酸序列的合成的HIV包膜蛋白。
在一些实施例中,该组合物或疫苗组合进一步包含一种或多种分离的HIV抗原性多肽。鉴于本披露,本领域技术人员已知的任何HIV抗原性多肽可以被进一步包括在本发明的组合物或疫苗组合中,包括但不限于HIV包膜蛋白(例如,gp160、gp140、gp120、或gp41),优选地是稳定化的三聚gp140蛋白,如稳定化的分枝C或分枝A gp140蛋白。在一个优选实施例中,该分离的HIV抗原性多肽是一种稳定化的HIV分枝C三聚gp140蛋白,如包含SEQ IDNO:7的氨基酸序列的残基30-708的蛋白(SEQ ID NO:7的残基1-29在该信号序列中)。可以使用的替代的或另外的HIV Env多肽(除了分枝C gp140蛋白或单独的)是镶嵌Env三聚体蛋白,该镶嵌Env三聚体蛋白例如具有如SEQ ID NO:36的氨基酸30-724中所披露的氨基酸序列(对应于WO 2014/107744的SEQ ID NO:2,SEQ ID NO:36的残基1-29在该信号序列中)。
根据本发明的一个具体实施例,HIV抗原性蛋白质可以是本发明的合成的HIV包膜蛋白。因此,本发明的合成的包膜蛋白可以以分离的和/或纯化的形式在对其有需要的受试者中使用从而例如针对HIV诱导免疫应答或提供保护性免疫。任何本文所述的包含SEQ IDN:8的氨基酸序列的合成的包膜蛋白可以用作处于分离和/或纯化形式的HIV抗原性蛋白。在一个优选实施例中,当以分离的形式作为HIV抗原性蛋白使用时,该合成的包膜蛋白包含SEQ ID NO:18的氨基酸序列的残基30-711或SEQ ID NO:19的氨基酸序列的残基30-686,并且更优选地包含SEQ ID NO:18的氨基酸序列的残基30-704。该分离的HIV抗原性多肽还可以包含具有以下突变:EK479-480RRRR、I529P、A471C和T575C的SEQ ID NO:8。
本发明的实施例还涉及组合物或疫苗组合,这些组合物或疫苗组合包含分离的合成的HIV包膜蛋白,该分离的合成的HIV包膜蛋白包含SEQ ID NO:8的氨基酸序列。可以使用任何本文所述的合成的HIV包膜蛋白。在本发明的具体实施例中,该分离的合成的HIV包膜蛋白包含SEQ ID NO:18的氨基酸序列的残基30-704或30-711,SEQ ID NO:19的氨基酸序列的残基30-686,或具有以下突变:EK479-480RRRR、I529P、A471C和T575C的SEQ ID NO:8的氨基酸序列。此类组合物或疫苗组合可以进一步包含一种或多种表达载体,例如,腺病毒载体,如腺病毒26载体,这些载体编码一种或多种另外的HIV抗原性多肽,如本发明的合成的HIV包膜蛋白,或其他HIV抗原性蛋白如列于SEQ ID NO:4、5、7、28或29中的那些或其片段。
本发明还涉及生产本发明的组合物或疫苗组合的方法。根据本发明的实施例,生产组合物或组合的方法包括将包含编码本发明的合成的HIV包膜蛋白的核酸的载体与运载体、以及任选的编码一种或多种另外的HIV抗原性多肽的一种或多种另外的载体和/或一种或多种分离的HIV抗原性多肽进行组合。本领域的普通技术人员将熟悉用于制备这样的组合物的常规技术。
疫苗和疫苗组合
根据本发明的实施例,组合物可以是疫苗。如在此所使用的,术语“疫苗”是指组合物,该组合物包含编码本发明的能够对受试者或接种疫苗的受试者提供保护性免疫或保护性免疫应答的合成的HIV包膜蛋白的表达载体,优选地是病毒载体。根据本发明的实施例,当向受试者给予该组合物时,该表达载体表达该编码的合成的HIV包膜蛋白,并且将该表达的合成的HIV包膜蛋白提供给受试者的免疫系统,从而诱导所需的应答以产生免疫,或诱导免疫应答。
因此,在另一概述方面中,本发明提供了用于在受试者中诱导针对人类免疫缺陷病毒(HIV)的免疫应答的疫苗。根据本发明的实施例,该疫苗包含组合物,该组合物包含免疫原性有效量的表达载体,该表达载体编码合成的HIV包膜蛋白,该合成的HIV包膜蛋白包含SEQ ID NO:8的氨基酸序列,并且优选地是SEQ ID NO:18的氨基酸序列。优选地,该表达载体是病毒载体,更优选地是腺病毒载体,并且最优选地是腺病毒26载体。
根据本发明的实施例,当参考本文所述的这些方法和组合物使用时,“诱导免疫应答”涵盖用于预防目的针对感染(如HIV感染)提供保护性免疫和/或接种受试者,以及用于治疗目的在对其有需要的受试者中引起针对感染(如HIV感染)的所希望的免疫应答或效应。优选地,本发明的这些方法是用于预防目的,如用于提供保护性免疫。该免疫应答可以是细胞免疫应答和/或体液免疫应答。
如在此所使用的,术语“保护性免疫”或“保护性免疫应答”是指该接种的受试者能够控制对其进行疫苗接种的致病因子的感染。通常,已经发展了“保护性免疫应答”的受试者仅发展轻度至中度的临床症状或根本没有症状。通常,对某种试剂具有“保护性免疫应答”或“保护性免疫”的受试者不会由于所述试剂的感染而死亡。
根据本发明的实施例,疫苗组合物可以进一步包含编码一种或多种另外的HIV抗原性多肽的一种或多种另外的载体,例如病毒载体,如腺病毒载体,优选地是腺病毒26载体,和/或一种或多种分离的HIV抗原性多肽。该合成的HIV包膜蛋白、另外的载体和/或一种或多种分离的HIV抗原性多肽可以被配制在该疫苗中的同一组合物或一种或多种不同组合物中。
本发明还涉及用于在对其有需要的受试者中使用一种或多种载体与分离的抗原性多肽组合来引发和加强对一种或多种HIV分枝的免疫应答的疫苗组合。因此,在另一概述方面中,本发明提供了用于在受试者中诱导针对HIV的免疫应答的疫苗组合。根据本发明的实施例,该疫苗组合包含:
(i)第一组合物,该第一组合物包含免疫原性有效量的表达载体、和运载体,该表达载体编码合成的HIV包膜蛋白,该合成的HIV包膜蛋白包含SEQ ID NO:8的、或具有一种或多种选自下组的突变的SEQ ID NO:8的氨基酸序列,该组由以下各项组成:(a)I529P,(b)K480E,以及(c)EK479-480RRRR、I529P、A471C和T575C的组合;和
(ii)第二组合物,该第二组合物包含免疫原性有效量的分离的HIV抗原性多肽和运载体,
其中该第一和第二组合物之一用于引发免疫并且另一种组合物用于加强免疫。
根据本发明的实施例,该疫苗组合任选地进一步包含免疫原性有效量的一种或多种另外的表达载体,所述表达载体编码一种或多种另外的HIV抗原性多肽。该一种或多种另外的表达载体可以包括在该第一组合物或该第二组合物中,或该一种或多种另外的表达载体可以包括在有待与该第一和/或第二组合物一起给予的一种或多种另外的组合物中。
如在此所使用的,术语“共递送”、“共给予”或“与……一起给予”是指同时给予两种或更多种组分,如病毒表达载体和分离的抗原性多肽,或多种病毒表达载体。“同时给予”可以是至少在同一天给予两种或更多种组分。当两种组分“一起给予”时,它们可以在短时间段内(例如24、20、16、12、8或4小时,或1小时或更短时间内)顺序地在分开的组合物中给予,或者它们可以同时在单一组合物中给予。
在本发明的疫苗组合的具体实施例中,该第一组合物包含腺病毒载体,优选地是腺病毒26载体,所述载体编码合成的HIV包膜蛋白,该合成的HIV包膜蛋白包含SEQ ID NO:18的氨基酸序列;并且该分离的HIV抗原性多肽包含SEQ ID NO:7的氨基酸序列的残基30-708或SEQ ID NO:36的残基30-724。在一个具体实施例中,该第一组合物进一步包含腺病毒载体,优选地是腺病毒26载体,所述载体编码包含SEQ ID NO:5的氨基酸序列的HIV抗原性多肽。在另一个具体实施例中,该第一组合物进一步包含一种或多种另外的腺病毒载体,优选地是腺病毒26载体,所述载体编码一种或多种另外的HIV抗原性多肽,该HIV抗原性多肽包含选自下组的氨基酸序列,该组由以下各项组成:SEQ ID NO:28和29。
本发明的另一个概述方面涉及试剂盒,该试剂盒包含根据本发明的实施例的疫苗组合。
在上文和下面的说明性实施例中详细讨论了可以在本发明的疫苗组合中使用的合成的HIV包膜蛋白、表达载体、另外的表达载体、由表达载体编码的HIV抗原性多肽、以及分离的HIV抗原性多肽等的其它实施例。
用于诱导针对HIV感染的保护性免疫的方法
本发明还涉及在对其有需要的受试者中诱导针对一种或多种HIV分枝的免疫应答的方法。本文所述的方法包括将一种或多种表达载体与一种或多种分离的抗原性多肽组合使用来引发和加强免疫应答的方法。
在一个概述方面中,在受试者中诱导针对人类免疫缺陷病毒(HIV)的免疫应答的方法包括向受试者给予包含免疫有效量的表达载体的组合物,该表达载体包含编码合成的HIV包膜蛋白的核酸,该合成的HIV包膜蛋白包含SEQ ID NO:8的氨基酸序列。本文所述的任何组合物可以用于在受试者中诱导针对HIV的免疫应答的方法。优选地,该组合物包括腺病毒载体,优选地是腺病毒26载体,所述载体包含编码合成的HIV包膜蛋白的核酸,该合成的HIV包膜蛋白包含SEQ ID NO:18的氨基酸序列。该组合物可以进一步包含编码一种或多种另外的HIV抗原性多肽的一种或多种另外的载体和/或一种或多种另外的分离的HIV抗原性多肽。
在另一概述方面中,在受试者中诱导针对人类免疫缺陷病毒(HIV)的免疫应答的方法包括:
(i)向该受试者给予第一组合物,该第一组合物包含免疫原性有效量的表达载体、和运载体,该表达载体编码镶嵌HIV包膜蛋白,该镶嵌HIV包膜蛋白具有SEQ ID NO:8的、或具有一种或多种选自下组的突变的SEQ ID NO:8的氨基酸序列,该组由以下各项组成:(a)I529P,(b)K480E,以及(c)EK479-480RRRR、I529P、A471C和T575C的组合;
(ii)向该受试者给予第二组合物,该第二组合物包含免疫原性有效量的分离的HIV抗原性多肽、和运载体;并且
(iii)任选地,向该受试者给予免疫原性有效量的一种或多种另外的表达载体,该一种或多种另外的表达载体编码一种或多种另外的HIV抗原性多肽,
其中步骤(i)和(ii)以任一顺序进行,其中步骤之一用于引发免疫并且另一步骤用于加强免疫。根据本发明的实施例,该任选的、有效量的一种或多种另外的表达载体与该第一组合物或该第二组合物一起给予。在一个优选实施例中,该任选的有效量的一种或多种另外的表达载体与该第一组合物一起给予。
在诱导免疫应答的方法的一个具体实施例中,该第一组合物包含一种腺病毒载体,优选地是腺病毒26载体,该腺病毒载体编码包含SEQ ID NO:8的氨基酸序列的合成的HIV包膜蛋白;和第二腺病毒载体,优选地是腺病毒26载体,该第二腺病毒载体编码包含SEQID NO:5的氨基酸序列的HIV抗原性多肽;该第二组合物包含分离的HIV抗原性多肽,该分离的HIV抗原性多肽具有SEQ ID NO:7的氨基酸序列的残基30-708或SEQ ID NO:36的残基30-724;并且该一种或多种另外的表达载体是腺病毒载体,优选地是腺病毒26载体,该腺病毒载体编码一种或多种另外的HIV抗原性多肽,该HIV抗原性多肽包含选自下组的氨基酸序列,该组由以下各项组成:SEQ ID NO:28和29;其中向该受试者一起给予该第一组合物与该一种或多种另外的表达载体一次或多次以用于引发免疫,并且向该受试者给予该第二组合物一次或多次以用于加强免疫。
通常肌内、皮内或皮下给予包含这些表达载体和/或抗原性多肽的免疫原性组合物。然而,也可以设想其它给药模式,如静脉内、直肠、皮肤、口服、鼻内等。免疫原性组合物的肌内给予可以通过使用针头注射这些表达载体(例如,腺病毒载体)和/或抗原性多肽的悬浮液来实现。一种替代方案是使用无针注射装置来给予该组合物(使用例如BiojectorTM)或含有该疫苗的冷冻干燥粉末。
对于肌内、静脉内、皮肤或皮下注射,或病痛部位的注射,该载体将处于肠胃外可接受的水性溶液形式,该水性溶液为无热原的并且具有适当的pH、等渗性以及稳定性。同样地,该分离的抗原性多肽将处于肠胃外可接受的溶液形式,该溶液具有适当的pH、等渗性以及稳定性。本领域普通技术人员完全能够使用例如等渗媒介物,如氯化钠注射液、林格氏注射液、乳酸盐林格氏注射液来制备适合的溶液。根据需要,可以包括防腐剂、稳定剂、缓冲剂、抗氧化剂和/或其他添加剂。还可以使用缓释配制品。
通常,根据本发明的实施例的疫苗组合物的给予将具有预防目的,以在感染或症状发展之前产生针对HIV抗原的免疫应答。在其他实施例中,这些表达载体(例如,腺病毒载体)、和/或HIV抗原性多肽可以被给予用于曝露后的预防用品。
向受试者给予包含这些表达载体(例如,腺病毒载体)和/或抗原性多肽的这些免疫原性组合物,在受试者中产生抗HIV免疫应答。足以诱导可检测的免疫应答的组合物的量被定义为“免疫原性有效剂量”或“免疫原性有效量。”在本发明的一个典型实施例中,该免疫应答是保护性免疫应答。
给予的实际量以及给予的速率和时程将取决于正治疗的疾病的性质和严重度。治疗处方(例如剂量等的决定)是在全科医生和其他医师、或在兽医环境中是兽医的职责范围内的,并且典型地考虑了有待治疗的失调、个体患者的状况、递送部位、给药方法以及医师已知的其他因素。以上提及的这些技术和方案的实例可以在雷明顿药学大全(Remington’sPharmaceutical Sciences),第16版,Osol,A.编著,1980中找到。
在产生腺病毒载体和任选将这种颗粒配制成组合物后,可以将这些载体给予个体,特别是人或其它灵长类动物。对非人哺乳动物的递送不需要用于治疗目的,而是可以用于在实验背景中使用,例如在对由本发明的这些腺病毒载体表达的合成的HIV包膜蛋白的免疫应答的机制的研究中使用。
在披露的方法的一个实施例中,使用编码一种或多种HIV抗原性多肽的一种或多种腺病毒载体来引发免疫应答。一种或多种分离的HIV抗原性多肽可以与一种或多种腺病毒载体一起用于引发免疫。引发免疫可以仅施用一次,但也可以任选地施用多次,例如,在时间0初次引发施用,随后是在约第4-14周,例如,第4、5、6、7、8、9、10、11、12、13或14周,或在初始引发施用之间、之后的任何时间另一次引发施用。可以将一种或多种分离的HIV抗原性多肽任选地与一种或多种另外的腺病毒或编码一种或多种另外的HIV抗原性多肽的其它载体一起使用以增强免疫应答。加强免疫也可以施用一次或多次,例如,首先在约第18-36周,例如,第18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、或36周,或在初始引发施用之间、之后的任何时间,随后在约第36-52周,例如,第36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59或60周,或在初始引发施用之间、之后的任何时间另一次加强施用。监测由免疫诱导的免疫应答。
这些披露的方法的实施例还考虑更短的初免-加强方案,意味着在初始引发施用之后的约22-26周施用该最终加强免疫。可以在第0周给予该引发免疫。该加强免疫可以施用多次,例如,首先在约第7-9周或第11-13周,或在约第4、5、6、7、8、9、10、11、12、13、或14周,或在初始引发施用之间、之后的任何时间,随后在约第22-26周、或在约第16、17、18、19、20、21、22、23、24、25、26、27、或28周,或在初始引发施用之间、之后的任何时间另一次加强施用。在某些实施例中,将一种或多种分离的HIV抗原性多肽与一种或多种腺病毒载体一起给予用于引发和/或加强免疫。
本领域技术人员容易理解,可以基于施用后测量的免疫应答来调整用于引发和加强施用的方案。例如,通常在给予引发组合物后数周或数月,例如,约2-3周或4周、或8周、或16周、或20周、或24周、或28周、或30周、或32周,或给予引发组合物后一至两年给予这些加强组合物。
根据本发明的实施例,佐剂可以与该分离的HIV抗原性多肽一起作为引发和/或加强免疫的一部分来给予。鉴于本披露,可以使用任何佐剂,并且在某些实施例中,该佐剂是铝盐,如AdjuPhos。
在本发明的一个优选实施例中,在本文披露的这些方法中使用的这些腺病毒载体包括rAd26载体。优选地,编码合成的HIV包膜蛋白(包含SEQ ID NO:18或SEQ ID NO:19的,最优选地是SEQ ID NO:18的氨基酸序列)的rAd26载体,单独地或与一种或多种另外的rAd26载体(编码一种或多种另外的HIV抗原性多肽,如具有SEQ ID NO:5的氨基酸序列的mos1Env)组合用于引发免疫应答,并且分离的HIV抗原性多肽(如包含SEQ ID NO:7的氨基酸序列的残基30-708或SEQ ID NO:36的残基30-724的那些)被用于加强免疫应答,或者反之亦然。
在一个示例性实施例中,编码包含SEQ ID NO:18的氨基酸序列的合成的HIV包膜蛋白的rAd26载体与编码具有SEQ ID NO:5的氨基酸序列的HIV抗原性多肽的rAd26载体组合用于引发免疫应答。一种或多种另外的rAd26载体还可以与其他rAd26载体一起给予以引发免疫应答,该一种或多种另外的rAd26载体编码一种或多种另外的具有选自由SEQ IDNOs:1-4、28和29组成的组的氨基酸序列的HIV抗原性多肽。在某些实施例中,在给予任何加强免疫之前给予该引发施用两次。然后给予分离的HIV抗原性多肽,如包含SEQ ID NO:7(优选地)的氨基酸序列的残基30-708的那些,或包含SEQ ID NO:36的氨基酸序列的残基30-724的那些,或这样的分离的HIV抗原性多肽的至少两种的组合,以加强免疫应答,并且优选地给予超过一次。优选地,在加强免疫中,进一步给予佐剂与该分离的HIV抗原性多肽。
在一个具体实施例中,通过给予在腺病毒载体(优选地是rAd26载体)上编码的四种HIV抗原来引发免疫应答,编码的这四种抗原为:(i)包含SEQ ID NO:18的氨基酸序列的合成的HIV包膜蛋白,(ii)具有SEQ ID NO:5的氨基酸序列的多肽,(iii)具有SEQ ID NO:28的氨基酸序列的多肽,以及(iv)具有SEQ ID NO:29的氨基酸序列的多肽。这四种抗原各自可以在单独的腺病毒载体(优选地是rAd26载体)上编码,以约1、2、3、4、5、6、7、8、9、或10x1010个病毒颗粒(vp),例如约5x1010 vp(对于所有载体一起)的总剂量给予。这些载体可以例如以1:1:1:1比率预先混合,。可以在初始引发施用后,例如,在初始引发施用后第8、9、10、11、12、13、14、15或16周时重复该引发施用。在此实施例中,通过将用于该引发施用的同一腺病毒载体疫苗与分离的HIV Env gp140蛋白(例如分枝C gp140蛋白(包含SEQ ID NO:7的氨基酸序列的残基30-708)或镶嵌gp140蛋白(包含SEQ ID NO:36的氨基酸序列的残基30-724),或者分枝C gp140蛋白和镶嵌gp140蛋白)一起,以约50-300μg蛋白的总剂量,例如分枝C gp140蛋白的50、100、150、200、250、或300微克或之间的任何量,或例如镶嵌gp140蛋白的50、100、150、200、250、或300微克或之间的任何量,或例如分枝C gp140蛋白和镶嵌gp140蛋白的组合(例如以1:1比率,混合在一起活单独地给予)的50、100、150、200、250、或300微克或之间的任何量给予来加强免疫应答。优选地,该gp140蛋白与佐剂,例如磷酸铝一起给予。可以在约第18、19、20、21、22、23、24、25、26、27、28、29或30周,或在该初始引发施用之间、之后的任何时间进行该腺病毒加上gp140蛋白给予以加强免疫应答。可以例如在约第42、43、44、45、46、47、48、49、50、51、52、53或54周,或在该初始引发施用之间、之后的任何时间重复该加强施用。通过肌内途径优选地进行根据这个实施例的所有给予。
实施例
实施例1是编码合成的HIV包膜蛋白的核酸,该合成的HIV包膜蛋白包含SEQ IDNO:8的、或具有一种或多种选自下组的突变的SEQ ID NO:8的氨基酸序列,该组由以下各项组成:(i)I529P,(ii)K480E,以及(iii)EK479-480RRRR、I529P、A471C和T575C的组合。
实施例2是根据实施例1所述的核酸,其中该合成的HIV包膜蛋白进一步包含信号序列,例如包含选自下组的氨基酸序列的信号序列,该组由以下各项组成:SEQ ID NO:9至12,优选地是SEQ ID NO:9。
实施例3是根据实施例1或2所述的核酸,其中该合成的HIV包膜蛋白进一步包含跨膜结构域,例如具有SEQ ID NO:13的氨基酸序列的跨膜结构域,优选地该合成的HIV包膜蛋白进一步包含融合到SEQ ID NO:8的C-末端和该跨膜结构域的N-末端的SEQ ID NO:37。
实施例4是根据实施例3所述的核酸,其中该合成的HIV包膜蛋白进一步包含一个细胞质结构域的片段,优选地是包含SEQ ID NO:14的氨基酸序列或其氨基酸残基1-4(即,NRVR)的细胞质结构域的片段。
实施例5是如以上实施例1-4中任一项所述的核酸,其中该合成的HIV包膜蛋白包含SEQ ID NO:18的氨基酸序列。
实施例6是根据实施例1或2所述的核酸,其中该合成的HIV包膜蛋白(a)进一步包含选自下组的三聚结构域,该组由以下各项组成:GCN4、fibritin(foldon结构域),例如具有SEQ ID NO:15或SEQ ID NO:16的,优选地是SEQ ID NO:15的氨基酸序列的三聚结构域,或(b)包含具有以下突变:EK479-480RRRR、I529P、A471C和T575C的组合的SEQ ID NO:8。
实施例7是根据实施例6所述的核酸,其中该合成的HIV包膜蛋白包含SEQ ID NO:19的氨基酸序列。
实施例8是根据实施例5所述的核酸,其中该合成的HIV包膜蛋白由SEQ ID NO:18的氨基酸序列组成。
实施例9是根据实施例7所述的核酸,其中该合成的HIV包膜蛋白由SEQ ID NO:19的氨基酸序列组成。
实施例10是一种载体,该载体包含实施例1-9中任一项所述的核酸,其中所述核酸可操作地连接至启动子序列。
实施例11是根据实施例10所述的载体,是病毒载体,优选地是腺病毒载体,并且更优选地是腺病毒26载体。
实施例12是分离的细胞,该分离的细胞包含实施例10或实施例11所述的载体。
实施例13是一种组合物,该组合物包含免疫原性有效量的实施例10或权利要求11所述的载体、和运载体。
实施例14是一种疫苗组合,该疫苗组合包括第一组合物,该第一组合物包括免疫原性有效量的腺病毒载体,优选地是腺病毒26载体,该载体编码具有SEQ ID NO:18的氨基酸序列的合成的HIV包膜蛋白;第二组合物,该第二组合物包括免疫原性有效量的第二腺病毒载体,优选地是第二腺病毒26载体,该第二腺病毒载体编码包含SEQ ID NO:5的氨基酸序列的HIV抗原性多肽;以及任选地至少一种另外的组合物,该另外的组合物包括免疫有效量的选自由以下各项组成的组的至少一种:一种载体,该载体编码具有选自由SEQ ID NO:1-4、28和29组成的组的氨基酸序列的抗原性多肽,和一种分离的HIV抗原性多肽,该分离的HIV抗原性多肽具有SEQ ID NO:7的氨基酸序列的残基30-708或具有SEQ ID NO:36的残基30-724,其中该第一组合物、第二组合物和另外的组合物是存在于同一组合物或一种或多种不同组合物中。
实施例15是一种在对其有需要的受试者中诱导针对人类免疫缺陷病毒(HIV)的免疫应答的方法,该方法包括向该受试者给予实施例13所述的组合物或实施例14所述的疫苗组合。
实施例16是实施例13所述的组合物或实施例14所述的疫苗组合,该组合物或疫苗组合包含一种腺病毒载体,优选地是腺病毒26载体,该腺病毒载体载体编码合成的HIV包膜蛋白,该合成的HIV包膜蛋白包含SEQ ID NO:18的氨基酸序列;第二腺病毒载体,优选地是腺病毒26载体,该第二腺病毒载体编码HIV抗原性多肽,该HIV抗原性多肽包含SEQ ID NO:5的氨基酸序列;一种或多种另外的腺病毒载体,该一种或多种另外的腺病毒载体编码一种或多种另外的抗原性多肽,该抗原性多肽包含选自下组的氨基酸序列,该组由以下各项组成:SEQ ID NO:1-4、28和29;以及分离的HIV抗原性多肽,该分离的HIV抗原性多肽包含SEQID NO:7的氨基酸序列的残基30-708或SEQ ID NO:36的残基30-724,用于诱导针对人类免疫缺陷病毒(HIV)的免疫应答。
实施例17是合成的HIV包膜蛋白,该合成的HIV包膜蛋白包含SEQ ID NO:8的、或具有一种或多种选自下组的突变的SEQ ID NO:8的氨基酸序列,该组由以下各项组成:(i)I529P,(ii)K480E,以及(iii)EK479-480RRRR、I529P、A471C和T575C的组合。
实施例18是实施例17所述的合成的HIV包膜蛋白,该合成的HIV包膜蛋白包含具有突变EK479-480RRRR、I529P、A471C和T575C的SEQ ID NO:8的氨基酸序列,或SEQ ID NO:18的氨基酸序列的残基30-704或SEQ ID NO:19的残基30-686。
实施例19是实施例13所述的组合物,该组合物进一步包含编码一种或多种另外的HIV抗原性多肽的一种或多种另外的表达载体(该表达载体)和/或一种或多种分离的HIV抗原性多肽。
实施例20是实施例13所述的组合物,该组合物包含腺病毒载体,优选地是腺病毒26载体,该载体编码由SEQ ID NO:18的氨基酸序列组成的合成的HIV包膜蛋白。
实施例21是根据实施例20所述的组合物,该组合物进一步包含第二腺病毒载体,优选地是腺病毒26载体,该第二腺病毒载体编码HIV抗原性多肽,该HIV抗原性多肽包含SEQID NO:5的氨基酸序列;以及任选地一种或多种另外的腺病毒载体,优选地是腺病毒26载体,该一种或多种另外的腺病毒载体编码一种或多种另外的HIV抗原性多肽,该HIV抗原性多肽包含SEQ ID NO:1-4、28和29的氨基酸序列。
实施例22是在对其有需要的受试者中产生针对人类免疫缺陷病毒(HIV)的免疫应答的方法,该方法包括向该受试者给予根据实施例19、20、或21中任一项所述的组合物。
实施例23是生产组合物或疫苗组合的方法,该方法包括将实施例10或实施例11所述的载体与运载体、以及任选地编码一个或多个另外的HIV抗原性多肽的一种或多种另外的载体和/或一种或多种分离的HIV抗原性多肽连同运载体一起进行组合。
实施例24是用于在受试者中诱导针对人类免疫缺陷病毒(HIV)的免疫应答的疫苗组合,该疫苗组合包含:
(i)第一组合物,该第一组合物包含免疫原性有效量的表达载体、和运载体,该表达载体编码合成的HIV包膜蛋白,该合成的HIV包膜蛋白包含SEQ ID NO:8的、或具有一种或多种选自下组的突变的SEQ ID NO:8的氨基酸序列,该组由以下各项组成:(i)I529P,(ii)K480E,以及(iii)EK479-480RRRR、I529P、A471C和T575C的组合;和
(ii)第二组合物,该第二组合物包含免疫原性有效量的分离的HIV抗原性多肽和运载体,
其中该第一和第二组合物之一用于引发免疫并且另一种组合物用于加强免疫,并且
其中该疫苗组合任选地进一步包含免疫原性有效量的一种或多种另外的表达载体,该一种或多种另外的表达载体编码一种或多种另外的HIV抗原性多肽,并且该一种或多种另外的表达载体包括在该第一或该第二组合物中,或一种或多种要与该第一或该第二组合物一起使用的另外的组合物中。
实施例25是根据实施例24所述的疫苗组合,其中该第一组合物包含腺病毒载体,优选地是腺病毒26载体,该腺病毒载体编码合成的HIV包膜蛋白,该合成的HIV包膜蛋白包含SEQ ID NO:18的氨基酸序列;该分离的HIV抗原性多肽包含SEQ ID NO:7的氨基酸序列的残基30-708,或SEQ ID NO:36的残基30-724;并且该一种或多种另外的表达载体是腺病毒载体,优选地是腺病毒26载体,该一种或多种另外的载体编码一种或多种另外的HIV抗原性多肽,该另外的HIV抗原性多肽包含选自下组的氨基酸序列,该组由以下各项组成:SEQ IDNO:1-5、28和29。
实施例26是用于在对其有需要的受试者中诱导针对人类免疫缺陷病毒(HIV)的免疫应答的方法,该方法包括:
(i)向该受试者给予第一组合物,该第一组合物包含免疫原性有效量的表达载体、和运载体,该表达载体编码合成的HIV包膜蛋白,该合成的HIV包膜蛋白包含SEQ ID NO:8的、或具有一种或多种选自下组的突变的SEQ ID NO:8的氨基酸序列,该组由以下各项组成:(i)I529P,(ii)K480E,以及(iii)EK479-480RRRR、I529P、A471C和T575C的组合;
(ii)向该受试者给予第二组合物,该第二组合物包含免疫原性有效量的分离的HIV抗原性多肽、和运载体;并且
(iii)任选地,向该受试者给予免疫原性有效量的一种或多种另外的表达载体,该一种或多种另外的表达载体编码一种或多种另外的HIV抗原性多肽,
其中步骤(i)和(ii)是以任一顺序进行,这些步骤之一用于引发免疫并且另一步骤用于加强免疫,并且优选地,该任选的、有效量的一种或多种另外的表达载体与该第一组合物一起给予。
实施例27是根据实施例26所述的方法,其中该第一组合物包含一种腺病毒载体,优选地是腺病毒26载体,该腺病毒载体编码合成的HIV包膜蛋白,该合成的HIV包膜蛋白具有SEQ ID NO:18的氨基酸序列;和第二腺病毒载体,优选地是腺病毒26载体,该第二腺病毒载体编码HIV抗原性多肽,该HIV抗原性多肽包含SEQ ID NO:5的氨基酸序列;该第二组合物包含分离的HIV抗原性多肽,该分离的HIV抗原性多肽具有SEQ ID NO:7的氨基酸序列的残基30-708、或SEQ ID NO:36的残基30-724;并且该任选的一种或多种另外的表达载体是腺病毒载体,优选地是腺病毒26载体,所述载体编码一种或多种另外的HIV抗原性多肽,该另外的HIV抗原性多肽包含选自下组的氨基酸序列,该组由以下各项组成:SEQ ID NO:28和29;其中向该受试者给予该第一组合物,任选地连同该一种或多种另外的表达载体一次或多次以用于引发免疫,并且向该受试者给予该第二组合物一次或多次以用于加强免疫。
实施例28是合成的HIV包膜蛋白,该合成的HIV包膜蛋白由SEQ ID NO:18或SEQ IDNO:19的氨基酸序列(具有或没有该信号序列)组成。
实施例29是一种疫苗组合,该疫苗组合包含一种或多种载体,这些载体一起包含编码以下各项的核酸序列:(i)包含SEQ ID NO:8的氨基酸序列的第一合成的HIV包膜蛋白和(ii)包含SEQ ID NO:5的氨基酸序列的第二HIV包膜蛋白。
实施例30是根据实施例29所述的疫苗组合,其中该第一合成的HIV包膜蛋白包含SEQ ID NO:18的氨基酸序列。
实施例31是一种疫苗组合,该疫苗组合包含以下组分:
(i)编码由SEQ ID NO:18的氨基酸序列组成的合成的HIV包膜蛋白的Ad26载体;和
(ii)编码由SEQ ID NO:5的氨基酸序列组成的HIV包膜蛋白的Ad26载体。
实施例32是根据实施例31所述的疫苗组合,该疫苗组合进一步包含以下组分:(iii)编码由SEQ ID NO:28的氨基酸序列组成的HIV抗原的Ad26载体。
实施例33是根据实施例31或32所述的疫苗组合,该疫苗组合进一步包含以下组分:(iv)编码由SEQ ID NO:29的氨基酸序列组成的HIV抗原的Ad26载体。
实施例34是根据实施例31-33中任一项所述的疫苗组合,该疫苗组合进一步包含以下组分:(v)分离的HIV抗原性多肽,该分离的HIV抗原性多肽具有SEQ ID NO:7的氨基酸序列的残基30-708、或SEQ ID NO:36的氨基酸序列的残基30-724,任选地进一步包含佐剂。
实施例35是一种在对其有需要的受试者中诱导针对人类免疫缺陷病毒(HIV)的免疫应答的方法,该方法包括:
(a)向该受试者给予:(i)编码包含SEQ ID NO:18的氨基酸序列的合成的HIV包膜蛋白的rAd26载体;(ii)编码包含SEQ ID NO:5的氨基酸序列的抗原的rAd26载体;(iii)编码包含SEQ ID NO:28的氨基酸序列的抗原的rAd26载体;以及(iv)编码包含SEQ ID NO:29的氨基酸序列的抗原的rAd26载体;优选地,其中以约1:1:1:1的比率,以约1-10x1010病毒颗粒(vp)(例如5x1010 vp)的总剂量给予这些rAd26载体;
(b)在步骤(a)之后的约第10-14周,例如在第12周重复步骤(a);
(c)向该受试者给予:(i)编码包含SEQ ID NO:18的氨基酸序列的合成的HIV包膜蛋白的rAd26载体;(ii)编码包含SEQ ID NO:5的氨基酸序列的抗原的rAd26载体;(iii)编码包含SEQ ID NO:28的氨基酸序列的抗原的rAd26载体;(iv)编码包含SEQ ID NO:29的氨基酸序列的抗原的rAd26载体;(v)具有SEQ ID NO:7的氨基酸30-708的序列的分离的HIVgp140蛋白;以及(vi)磷酸铝佐剂;优选地,其中以约1:1:1:1的比率、以约1-10x1010病毒颗粒(vp)(例如5x1010 vp)的总剂量给予这些rAd26载体,并且其中以约50-300微克(例如250微克)的剂量给予该分离的HIV gp140蛋白;在步骤(a)之后的约第20-28周,例如在第24周;以及(d)在步骤(a)之后的约第42-54周,例如在第48周重复步骤(c)。
实施例36是一种在对其有需要的受试者中诱导针对人类免疫缺陷病毒(HIV)的免疫应答的方法,该方法包括:
(a)向该受试者给予:(i)编码包含SEQ ID NO:18的氨基酸序列的合成的HIV包膜蛋白的rAd26载体;(ii)编码包含SEQ ID NO:5的氨基酸序列的抗原的rAd26载体;(iii)编码包含SEQ ID NO:28的氨基酸序列的抗原的rAd26载体;以及(iv)编码包含SEQ ID NO:29的氨基酸序列的抗原的rAd26载体;优选地,其中以约1:1:1:1的比率,以约1-10x1010病毒颗粒(vp)(例如5x1010 vp)的总剂量给予这些rAd26载体;
(b)在步骤(a)之后的约第10-14周,例如在第12周重复步骤(a);
(c)向该受试者给予:(i)编码包含SEQ ID NO:18的氨基酸序列的合成的HIV包膜蛋白的rAd26载体;(ii)编码包含SEQ ID NO:5的氨基酸序列的抗原的rAd26载体;(iii)编码包含SEQ ID NO:28的氨基酸序列的抗原的rAd26载体;(iv)编码包含SEQ ID NO:29的氨基酸序列的抗原的rAd26载体;(v)具有SEQ ID NO:7的氨基酸30-708的序列的分离的HIVgp140蛋白;(vi)具有SEQ ID NO:36的氨基酸30-724的序列的分离的HIV gp140蛋白;以及(vii)磷酸铝佐剂;优选地,其中以约1:1:1:1的比率、以约1-10x1010病毒颗粒(vp)(例如5x1010 vp)的总剂量给予这些rAd26载体,并且其中以约1:1的比率、以约50-300微克(例如250微克)的总剂量给予这些分离的HIV gp140蛋白;在步骤(a)之后的约第20-28周,例如在第24周;以及(d)在步骤(a)之后的约第42-54周,例如在第48周重复步骤(c)。
实例
实例1:HIV包膜抗原序列的设计
设计了几个HIV包膜抗原序列,其与镶嵌HIV抗原mos2Env(SEQ ID NO:6;先前也描述于WO 2010/059732中)具有序列相似性。这些新设计的膜结合的序列基于来自HIV包膜蛋白的完全天然野生型序列、或mos2Env序列和野生型HIV包膜蛋白序列的嵌合体(的组合)。除了全长包膜蛋白序列(参见图1A),还设计了具有细胞质结构域的C-末端截短的序列(参见例如,图1C)。还参见例如,Schiernle等人,美国科学院院刊(PNAS)1997;亚伯拉罕(Abrahamyan)等人,病毒学杂志(J Virol)2005;爱德华兹(Edwards)等人,病毒学杂志(J.Virology),2002,76:2683-2691。在跨膜(TM)区域之前,还通过C-末端截短来制备可溶性变体,该跨膜区域被三聚结构域(如GCN4三聚结构域)替换(参见例如,图1B)。这些可溶性变体通过弗林蛋白酶切割位点的突变进一步转化为单链变体,从而抑制该包膜蛋白的细胞外结构域加工成gp120和gp41亚基。
在产生的和测试的所有构建体中,基于C4的构建体具有最佳性质,例如良好的可制造性、折叠、免疫原性等,并且选择这些基于C4的构建体用于进一步研究。在进一步研究中还产生并测试了具有代替跨膜结构域的GCN4三聚结构域的C4构建体的可溶性变体(sC4,图1B)和包含细胞质结构域的7个氨基酸片段的变体(C4D7,图1C)。C4、sC4、以及C4D7的氨基酸序列分别示于SEQ ID NO:17、19、和18中。编码这些的序列分别示于SEQ ID NO:25、27、和26中。构建体C1具有基于mos2Env序列(SEQ ID NO:6)的细胞外结构域序列。还分别产生了具有代替跨膜结构域的GCN4三聚结构域的构建体C1的可溶性变体(sC1)和包含细胞质结构域的7个氨基酸片段的变体(C1D7),它们类似于如图1B和1C中示出的sC4和C4D7。出于比较目的,将构建体C1及其变体用于进一步研究中,因为它们基本上基于现有技术的mos2Env序列。C1、sC1以及C1D7的氨基酸序列分别示于SEQ ID NO:31、30、和32中。编码这些的核酸序列分别示于SEQ ID NO:34、33、和35中。测试的其他构建体不如基于构建体C4的那些最优,并且没有进入进一步发展。
实例2:合成的HIV包膜蛋白的表达和折叠
测量合成的HIV包膜蛋白的表达水平、折叠、和细胞表面表达。
表达水平
用编码如实例1所述的可溶性合成的HIV包膜蛋白sC1和sC4的质粒瞬时转染HEK293F细胞。使用定量蛋白印迹法(QWB)在上清液中测量该可溶性蛋白的表达水平。结果示于图2中。sC1的低表达水平(其基本上对应于具有添加的跨膜结构域的mos2Env)与我们最近对mos2Env的见解一致。如通过这些结果所证明的,本发明的sC4变体显示比该sC1变体(对照)显著更高的表达水平。
蛋白质折叠
通过测量可溶性合成的HIV包膜蛋白与已知结合该HIV包膜蛋白的共受体结合位点的抗体(MAb 17b)的结合来测试蛋白质折叠,该HIV包膜蛋白仅在结合CD4后通过酶联免疫吸附测定(ELISA)而暴露。具体地,在存在预先的sC4与CD4的结合以及不存在预先的sC4与CD4的结合的情况下,测试了纯化的sC4与MAb17b的结合。使用纯化的sC1作为对照。在没有预先的CD4结合到该包膜蛋白的情况下,MAb 17b与sC4的结合是部分解折叠的或预先触发的包膜蛋白(即,在不存在CD4结合时采取“开放”构象的不稳定Env)的指示。该ELISA测定的结果示于图3A和3B中。
如图3B中所示,在存在预先与CD4结合的情况下,sC4显示了与MAb 17b的强结合,但在不存在预先与CD4结合的情况下,sC4显示没有与MAb 17b的可检测的结合。相比之下,如在图3A中所示,在存在与不存在预先与CD4结合的情况下,sC1显示与MAb 17b的低得多的结合。结果表明,在不暴露预先与CD4结合的共受体结合位点的情况下,sC4具有正确的折叠模式。
还通过sC1和sC4的天然聚丙烯酰胺凝胶电泳(PAGE)来分析蛋白质折叠,以评价可溶性蛋白质变体的四级结构,以及原聚体之间可能的不正确的二硫键形成。在非变性凝胶上电泳后,通过蛋白印迹分析来检测凝胶中的蛋白质。如图4中的结果所示,大部分sC4以三聚体状态存在,这是正确的四级结构。
总之,蛋白质折叠实验的结果表明该sC4可溶性合成的HIV包膜蛋白具有希望的折叠特性(folding profile),这与现有的mos2Env抗原(由sC1表示)的折叠特性相比是被改进的。
细胞表面表达
还研究了HIV包膜蛋白C1(全长)、C4(全长,参见图1A)、C1D7和C4D7的膜结合变体的细胞表面表达。仅用编码eGFP的质粒(阴性对照,NC),或用编码eGFP的质粒连同编码HIV包膜蛋白变体的表达构建体瞬时转染HEK293T细胞。转染后两天,在暴露于针对gp120的多种多克隆和单克隆抗体、以及二级抗体后,对细胞进行荧光激活细胞分选(FACS)分析,并且然后检查包膜蛋白细胞表面表达水平。通过使用抗gp120多克隆抗体测定总表达水平,并通过评估广泛中和性抗体PG9和PG16(它们是四级结构依赖性的,并优先结合正确折叠的包膜三聚体)的相对结合,来评估这些包膜变体的质量。
细胞表面表达实验的结果示于图5中。如使用抗gp120抗体测量的截短变体C1D7和C4D7的表面表达水平分别远高于其全长对应物C1和C4的表面表达水平。这证实了来自Env的羧基-末端的144个残基的缺失增加了包膜表面表达水平。与全长C1相比,本发明的全长C4构建体还显示出提高的PG9和PG16结合,这表明该C4包膜序列在细胞表面上被适当地折叠(即,三聚体)。
结果还表明,C1D7变体,其基本上是具有添加的跨膜结构域和细胞质结构域的7个氨基酸的Mos2Env,可以在HEK293T细胞上进行表面表达。这与当转染至A549细胞时不能在表面上以可检测的水平表达的Ad26.mos2Env中的可溶性构建体形成对比。然而,与PG9和PG16的相对结合在背景之上几乎检测不到,这表明该C1D7包膜序列折叠不良,并且可能不作为细胞表面上的完整三聚体存在。
总的来说,与C1和C1D7相比,该C4D7包膜变体具有最佳的抗体结合特性,具有比其全长对应物C4更高的gp120表达,和大于15倍的增加的PG9和PG16结合(图5)。
实例3:编码HIV包膜序列的载体的稳定性
我们实验室中的先前工作(未公开)表明编码该mos2Env抗原序列的腺病毒26(Ad26)载体显示具有相对高的VP/IU比率(表明腺病毒产物批次的较低质量),并且此外这样的载体显示稳定性问题。因此,重要的是在腺病毒背景下测试本发明的合成的HIV包膜蛋白构建体的稳定性。
在PER.C6细胞中产生编码如以上实例1中所述的本发明的HIV抗原序列C4、C4D7和sC4的重组Ad26(rAd26)载体(分别称为“rAd26.C4”、“rAd26.C4D7”、和“rAd26.sC4”)。挑选载体克隆(噬菌斑)并按比例放大以产生研究批次。将最多5个病毒克隆(噬菌斑)按比例扩大至T25形式,并以T25形式连续传代10代(传代1-3是转染和噬斑纯化步骤,随后以T25形式传代10次,得到总共13次传代)。通过E1转基因盒PCR分析在病毒传代数(vpn)3、5、10和13时评估遗传稳定性,随后在vpn 13时测序。结果示于图6中。
编码全长C4(rAd26.C4)的rAd26载体显示差的生长特征,如通过在2-3天中没有完全细胞病变效应(CPE);遗传不稳定性,如通过E1转基因盒区域的缺失所确定的;或其组合所确定的(图6)。由于差的生长特征和观察到的遗传不稳定性,不进一步追踪该编码全长C4的载体。
相比之下,对于编码C4D7(rAd26.C4D7)和sC4(rAd26.sC4)的这些rAd26载体,所有繁殖的噬菌斑在实验过程中保持遗传稳定(图6)。因此,就腺病毒载体背景中的稳定性而言,这些新颖的sC4和C4D7构建体胜过原始mos2Env构建体。直到vpn 13的遗传稳定性试验代表了在载体的工业规模制备中使用的几个传代之外的繁殖。
实例4:腺病毒载体中的HIV包膜序列的表达和体内抗原性
在体内在载体转导的A549细胞(人细胞系)中单独地或与编码mos1Env(SEQ IDNO:5)的重组Ad26载体(下文称为“rAd26.mos1Env”)组合来评估rAd26.C4D7和rAd26.sC4的表达和抗原性(数据未显示)。流式细胞术分析证明所有抗原在用作为对照的这些单一包膜抗原的2x104个病毒颗粒(vp),或用通过腺病毒转导的2种组合的Env抗原的1x104 vp转导的细胞培养物中表达。所有转导物另外含有编码mos1GagPol(“rAd26.mos1GagPol”)和mos2GagPol(“rAd26.mos2GagPol”)的单剂量(1x104 vp)的腺病毒载体(巴鲁什等人,自然医学(Nat Med)2010,16:319-323),使得所评估的载体组合显示与用于临床前和临床用途的不同腺病毒载体相同的相对比例。优选地,将编码本发明的合成的HIV包膜蛋白的这些载体与编码用于临床用途的mos1GagPol和mos2GagPol抗原的载体进行组合。
rAd26.mos1Env和rAd26.C4D7的组合产生如通过单克隆抗体结合测定的评估表位的最大覆盖。特别地,通过用Ad26.C4D7转化而贡献的PG16表位的暴露有希望用于疫苗使用,因为PG16代表识别HIV-1Env的V1/V2环区域的广泛中和性单克隆抗体(沃克(Walker)等人,科学(Science),2009)。因此,与仅由mos1Env产生的免疫应答相比,来源于C4序列的本发明的合成的HIV包膜蛋白增加了针对该HIV包膜蛋白的免疫应答的宽度。在RV144研究中,针对包膜蛋白区域的疫苗诱导的抗体应答已经显示与来自HIV-1感染的保护相关(海恩斯(Haynes)等人,新英格兰医学杂志(N Engl J Med.)2012),因此本发明的合成的HIV包膜蛋白是包括在HIV疫苗方案中的物有希望的候选。
实例5:编码合成的HIV包膜蛋白的载体的免疫原性
在兔中测试Ad26载体背景下的本发明的合成的HIV包膜蛋白序列,以确定这些构建体是否是rAd26.mos2Env构建体的免疫原性替代物。
单独地,并与编码本发明的合成的HIV包膜蛋白的腺病毒载体(rAd26.C4D7和rAd26.sC4;包含SEQ ID NO:8,具体地分别是SEQ ID NO:18和19)组合地测试编码mos1Env的腺病毒载体(rAd26.mos1Env;SEQ ID NO:5)的免疫原性。在所有情况下,还给予编码mos1GagPol和mos2GagPol抗原的腺病毒26载体(分别是rAd26.mos1GagPol[SEQ ID NO:28]和rAd26.mos2GagPol[SEQ ID NO:29])。更确切地说,将rAd26.mos1Env单独的免疫原性(三价疫苗:rAd26.mos1GagPol、rAd26.mos2GagPol和rAd26.mos1Env)与rAd26.mos1Env和rAd26.C4D7或rAd26.sC4之一的组合的免疫原性进行比较(四价疫苗:给予任何rAd26.mos1GagPol、rAd26.mos2GagPol、rAd26.mos1Env和rAd26.C4D7;或给予rAd26.mos1GagPol、rAd26.mos2GagPol、rAd26.mos1Env和rAd26.sC4)。该三价疫苗(缺少编码本发明的合成的HIV包膜蛋白的任何载体)与该四价疫苗(包含编码本发明的合成的HIV包膜蛋白的载体)的比较允许确定本发明的HIV包膜蛋白是否有助于保护的宽度。
在疫苗方案中进行给予,其中这些Ad26载体在第0和6周作为双重引发来给予,并且分枝C gp140蛋白(三价Env gp140蛋白,其具有不带有残基1-29的信号肽序列的SEQ IDNO:7,还参见WO 2010/042942)在第12和18周作为双重加强来给予(参见例如,巴鲁什等人,2015,科学(Science)349:320-324)。表1描述了用于本研究的疫苗方案。空rAd26是指缺少编码HIV抗原蛋白的序列的任何基因的对照载体。每个组包括六只兔子。
表1:兔中的免疫原性研究中测试的疫苗方案
该三价Ad26疫苗(缺乏本发明的新颖Env抗原)与该四价Ad26疫苗(其包含新型sC4或C4D7 Env抗原)的比较允许测试新颖抗原是否有助于保护的宽度。使用建立的基于TZM-bl细胞的中和测定[Montefiori DC.方法分子生物学(Methods Mol Biol)2009,485:395-405;Sarzotti-Kelsoe M等人,免疫方法期刊(J Immunol Methods)2014,409:131-146]来测量候选疫苗的中和活性。
结果示于图7中,并且通过使用该三价疫苗(表1中的组1)作为对照组并与每种新颖四价疫苗(表1中的组2和组3)进行比较来统计分析这些结果。
总的来说,在兔中进行两次同源肌内免疫后,新颖C4-衍生的(即,编码包含SEQ IDNO:8的Env蛋白,是mos2Env的替代物)腺病毒构建体是免疫原性的。
兔免疫血清针对Tier 1B假病毒的中和能力不存在(数据未显示),这是不出乎意料的,因为已知此类病毒更难以中和。
兔免疫血清针对分枝B Tier 1A病毒的假病毒中和能力不受添加新组分的影响(数据未显示)。这证明新抗原不会不利地干扰该疫苗中存在的现有分枝B抗原的免疫原性(尽管这些新组分针对分枝C,但是这种不期望的干扰在其被测试前不能被先验排除)。
与三价(仅具有mos1Env)单独的免疫(组1)相比,在含有腺病毒的该四价新颖C4D7(四价,组2)中兔免疫血清针对分枝C Tier 1A病毒的假病毒中和能力显著增强(图7,B图)。此外,与三价(仅具有mos1Env)单独的免疫(组1)相比,在含有腺病毒的该四价新颖sC4(四价,组3)中兔免疫血清针对分枝C Tier 1A病毒的假病毒中和能力在第8周显著增强(图7,B图)。
总之,Ad26中编码的C4D7和sC4构建体是免疫原性的并且其添加扩大了疫苗的结合能力和中和能力,该疫苗具有mos1Env(主要是分枝B)作为唯一的朝向分枝C菌株的Ad26编码的Env组分(图7B)。
实例6:包括编码本发明的合成的HIV包膜蛋白的载体的疫苗方案的免疫原性
一种另外的兔研究评估了该四价载体组合Ad26.Mos4.HIV(由四种腺病毒载体:Ad26.Mos1GagPol[编码SEQ ID NO:28]、Ad26.Mos2GagPol[编码SEQ ID NO:29]、Ad26.Mos1Env[编码SEQ ID NO:5]和Ad26.Mos2SEnv[如以上使用的名称“C4D7”还被称为“Mos2S”;该载体以1:1:1:1混合,以5x109 vp的总剂量编码根据本发明的新颖SEQ ID NO:18]组成),在第0周和第6周肌内给予该四价载体组合作为双重引发免疫,在第13周和第19周与重组的HIV-1Env蛋白加强进行组合,使用分枝C gp140[具有SEQ ID NO:7的氨基酸残基30-708的序列]、镶嵌gp140[具有SEQ ID NO:36的氨基酸残基30-724的序列]、或分枝Cgp140和镶嵌gp140的组合。以10或50微克蛋白质组合免疫当天配制的250mcg磷酸铝佐剂的总剂量肌内施用这些蛋白质加强。
结果表明,所有测试的方案在所有动物中是免疫原性的,这诱导高抗体滴度和针对Tier 1Env假型病毒的中等中和活性。如果将镶嵌gp140单独地或与分枝C gp140组合用作疫苗抗原,则与单独用分枝C gp140加强的参照组相比,镶嵌gp140特异性ELISA滴度和分枝B假病毒识别在第15周显著增加。改善的总体效应大小是中度的,并且与单独的镶嵌gp140相比,用二价分枝C gp140-镶嵌gp140组合而增强的组更大。在研究的第21周,失去这些差异,并且针对接受二价分枝C gp140-镶嵌gp140加强或单价分枝C gp140加强的群体而测量的免疫应答在统计学上不可区分。
该二价蛋白质方案显示分枝C ELISA滴度和假病毒识别与分枝C gp140单独加强方案的可比较的诱导,这表明分枝B相关的免疫原镶嵌gp140的包含对分枝C抗原覆盖没有不利影响,同时在本研究的第15周显著增强了分枝B覆盖。
数据证实,编码根据本发明的合成的Env抗原的Ad26.Mos2SEnv载体可成功地用于疫苗方案中。
参考文献
1.巴鲁什等人,自然医学(Nat Med)2010,16:319-323
2.WO 2010/059732
3.Schiernle等人,美国科学院院刊(PNAS)94:8640-8645,1997
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8.WO 03/104467
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16.沃克LM、Phogat SK、陈慧(Chan-Hui)PY、瓦格纳(Wagner)D、彭(Phung)P、戈斯(Goss)JL等人,来自非洲供体的广泛并有效的中和性抗体揭示了新的HIV-1疫苗靶标(Broad and potent neutralizing antibodies from an African donor reveal a newHIV-1vaccine target),科学(Science)2009,326:285-289。
17.海恩斯BF、吉尔伯特(Gilbert)PB、麦克拉特(McElrath)MJ、佐拉(Zolla)-Pazner S、Tomaras GD、阿拉姆(Alam)SM等人,HIV-1疫苗效力试验的免疫相关分析(Immune-correlates analysis of an HIV-1vaccine efficacy trial),新英格兰医学杂志(N Engl J Med)2012,366:1275-1286。
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19.蒙特菲奥里(Montefiori)DC,在荧光素酶报道基因测定中测量HIV中和性(Measuring HIV neutralization in a luciferase reporter gene assay),分子生物学方法(Methods Mol Biol)2009,485:395-405。
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Lys Glu Pro Ile Val Gly Ala Glu Thr Phe Tyr Val Ala Gly Ala Ala
435 440 445
Asn Arg Glu Thr Lys Leu Gly Lys Ala Gly Tyr Val Thr Asp Arg Gly
450 455 460
Arg Gln Lys Val Val Ser Leu Thr Asp Thr Thr Asn Gln Lys Thr Ala
465 470 475 480
Leu Gln Ala Ile His Leu Ala Leu Gln Asp Ser Gly Leu Glu Val Asn
485 490 495
Ile Val Thr Ala Ser Gln Tyr Ala Leu Gly Ile Ile Gln Ala Gln Pro
500 505 510
Asp Lys Ser Glu Ser Glu Leu Val Ser Gln Ile Ile Glu Gln Leu Ile
515 520 525
Lys Lys Glu Lys Val Tyr Leu Ala Trp Val Pro Ala His Lys Gly Ile
530 535 540
Gly Gly Asn Glu Gln Val Asp Lys Leu Val Ser Arg Gly Ile Arg Lys
545 550 555 560
Val Leu Phe Leu Asp Gly Ile Asp Lys Ala Gln Glu Glu His Glu Lys
565 570 575
Tyr His Ser Asn Trp Arg Ala Met Ala Ser Glu Phe Asn Leu Pro Pro
580 585 590
Ile Val Ala Lys Glu Ile Val Ala Ser Cys Asp Lys Cys Gln Leu Lys
595 600 605
Gly Glu Ala Ile His Gly Gln Val Asp Cys Ser Pro Gly Ile Trp Gln
610 615 620
Leu Ala Cys Thr His Leu Glu Gly Lys Val Ile Leu Val Ala Val His
625 630 635 640
Val Ala Ser Gly Tyr Ile Glu Ala Glu Val Ile Pro Ala Glu Thr Gly
645 650 655
Gln Glu Thr Ala Tyr Phe Leu Leu Lys Leu Ala Gly Arg Trp Pro Val
660 665 670
Lys Thr Ile His Thr Ala Asn Gly Ser Asn Phe Thr Ser Ala Thr Val
675 680 685
Lys Ala Ala Cys Trp Trp Ala Gly Ile Lys Gln Glu Phe Gly Ile Pro
690 695 700
Tyr Asn Pro Gln Ser Gln Gly Val Val Ala Ser Ile Asn Lys Glu Leu
705 710 715 720
Lys Lys Ile Ile Gly Gln Val Arg Asp Gln Ala Glu His Leu Lys Thr
725 730 735
Ala Val Gln Met Ala Val Phe Ile His Asn Phe Lys Arg Lys Gly Gly
740 745 750
Ile Gly Glu Tyr Ser Ala Gly Glu Arg Ile Val Asp Ile Ile Ala Ser
755 760 765
Asp Ile Gln Thr Lys Glu Leu Gln Lys Gln Ile Thr Lys Ile Gln Asn
770 775 780
Phe Arg Val Tyr Tyr Arg Asp Ser Arg Asp Pro Leu Trp Lys Gly Pro
785 790 795 800
Ala Lys Leu Leu Trp Lys Gly Glu Gly Ala Val Val Ile Gln Asp Asn
805 810 815
Ser Asp Ile Lys Val Val Pro Arg Arg Lys Ala Lys Ile Ile Arg Asp
820 825 830
Tyr Gly Lys Gln Met Ala Gly Asp Asp Cys Val Ala Ser Arg Gln Asp
835 840 845
Glu Asp
850
<210> 5
<211> 685
<212> PRT
<213> 人工序列
<220>
<223> mos1Env 嵌合抗原序列
<400> 5
Met Arg Val Thr Gly Ile Arg Lys Asn Tyr Gln His Leu Trp Arg Trp
1 5 10 15
Gly Thr Met Leu Leu Gly Ile Leu Met Ile Cys Ser Ala Ala Gly Lys
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 Glu Asn Val Thr Glu Asn Phe Asn Met Trp Lys
85 90 95
Asn Asn Met Val Glu Gln Met His Glu Asp Ile Ile Ser Leu Trp Asp
100 105 110
Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
115 120 125
Asn Cys Thr Asp Asp Val Arg Asn Val Thr Asn Asn Ala Thr Asn Thr
130 135 140
Asn Ser Ser Trp Gly Glu Pro Met Glu Lys Gly Glu Ile Lys Asn Cys
145 150 155 160
Ser Phe Asn Ile Thr Thr Ser Ile Arg Asn Lys Val Gln Lys Gln Tyr
165 170 175
Ala Leu Phe Tyr Lys Leu Asp Val Val Pro Ile Asp Asn Asp Ser Asn
180 185 190
Asn Thr Asn Tyr Arg Leu Ile Ser Cys Asn Thr Ser Val Ile Thr Gln
195 200 205
Ala Cys Pro Lys Val Ser Phe Glu Pro Ile Pro Ile His Tyr Cys Ala
210 215 220
Pro Ala Gly Phe Ala Ile Leu Lys Cys Asn Asp Lys Lys Phe Asn Gly
225 230 235 240
Thr Gly Pro Cys Thr Asn Val Ser Thr Val Gln Cys Thr His Gly Ile
245 250 255
Arg Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu
260 265 270
Glu Glu Val Val Ile Arg Ser Glu Asn Phe Thr Asn Asn Ala Lys Thr
275 280 285
Ile Met Val Gln Leu Asn Val Ser Val Glu Ile Asn Cys Thr Arg Pro
290 295 300
Asn Asn Asn Thr Arg Lys Ser Ile His Ile Gly Pro Gly Arg Ala Phe
305 310 315 320
Tyr Thr Ala Gly Asp Ile Ile Gly Asp Ile Arg Gln Ala His Cys Asn
325 330 335
Ile Ser Arg Ala Asn Trp Asn Asn Thr Leu Arg Gln Ile Val Glu Lys
340 345 350
Leu Gly Lys Gln Phe Gly Asn Asn Lys Thr Ile Val Phe Asn His Ser
355 360 365
Ser Gly Gly Asp Pro Glu Ile Val Met His Ser Phe Asn Cys Gly Gly
370 375 380
Glu Phe Phe Tyr Cys Asn Ser Thr Lys Leu Phe Asn Ser Thr Trp Thr
385 390 395 400
Trp Asn Asn Ser Thr Trp Asn Asn Thr Lys Arg Ser Asn Asp Thr Glu
405 410 415
Glu His Ile Thr Leu Pro Cys Arg Ile Lys Gln Ile Ile Asn Met Trp
420 425 430
Gln Glu Val Gly Lys Ala Met Tyr Ala Pro Pro Ile Arg Gly Gln Ile
435 440 445
Arg Cys Ser Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly
450 455 460
Asn Asp Thr Ser Gly Thr Glu Ile Phe Arg Pro Gly Gly Gly Asp Met
465 470 475 480
Arg Asp Asn Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile
485 490 495
Glu Pro Leu Gly Val Ala Pro Thr Lys Ala Lys Arg Arg Val Val Gln
500 505 510
Ser Glu Lys Ser Ala Val Gly Ile Gly Ala Val Phe Leu Gly Phe Leu
515 520 525
Gly Ala Ala Gly Ser Thr Met Gly Ala Ala Ser Met Thr Leu Thr Val
530 535 540
Gln Ala Arg Leu Leu Leu Ser Gly Ile Val Gln Gln Gln Asn Asn Leu
545 550 555 560
Leu Arg Ala Ile Glu Ala Gln Gln His Leu Leu Gln Leu Thr Val Trp
565 570 575
Gly Ile Lys Gln Leu Gln Ala Arg Val Leu Ala Val Glu Arg Tyr Leu
580 585 590
Lys Asp Gln Gln Leu Leu Gly Ile Trp Gly Cys Ser Gly Lys Leu Ile
595 600 605
Cys Thr Thr Thr Val Pro Trp Asn Ala Ser Trp Ser Asn Lys Ser Leu
610 615 620
Asp Lys Ile Trp Asn Asn Met Thr Trp Met Glu Trp Glu Arg Glu Ile
625 630 635 640
Asn Asn Tyr Thr Ser Leu Ile Tyr Thr Leu Ile Glu Glu Ser Gln Asn
645 650 655
Gln Gln Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala
660 665 670
Ser Leu Trp Asn Trp Phe Asp Ile Ser Asn Trp Leu Trp
675 680 685
<210> 6
<211> 684
<212> PRT
<213> 人工序列
<220>
<223> mos2Env 嵌合抗原序列
<400> 6
Met Arg Val Arg Gly Ile Gln Arg Asn Trp Pro Gln Trp Trp Ile Trp
1 5 10 15
Gly Ile Leu Gly Phe Trp Met Ile Ile Ile Cys Arg Val Met Gly Asn
20 25 30
Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys Glu Ala Lys
35 40 45
Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Glu Lys 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 Met Val Leu Glu Asn Val Thr Glu Asn Phe Asn Met Trp Lys
85 90 95
Asn Asp Met Val Asp Gln Met His Glu Asp Ile Ile Arg Leu Trp Asp
100 105 110
Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
115 120 125
Glu Cys Arg Asn Val Arg Asn Val Ser Ser Asn Gly Thr Tyr Asn Ile
130 135 140
Ile His Asn Glu Thr Tyr Lys Glu Met Lys Asn Cys Ser Phe Asn Ala
145 150 155 160
Thr Thr Val Val Glu Asp Arg Lys Gln Lys Val His Ala Leu Phe Tyr
165 170 175
Arg Leu Asp Ile Val Pro Leu Asp Glu Asn Asn Ser Ser Glu Lys Ser
180 185 190
Ser Glu Asn Ser Ser Glu Tyr Tyr Arg Leu Ile Asn Cys Asn Thr Ser
195 200 205
Ala Ile Thr Gln Ala Cys Pro Lys Val Ser Phe Asp Pro Ile Pro Ile
210 215 220
His Tyr Cys Ala Pro Ala Gly Tyr Ala Ile Leu Lys Cys Asn Asn Lys
225 230 235 240
Thr Phe Asn Gly Thr Gly Pro Cys Asn Asn Val Ser Thr Val Gln Cys
245 250 255
Thr His Gly Ile Lys Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly
260 265 270
Ser Leu Ala Glu Glu Glu Ile Ile Ile Arg Ser Glu Asn Leu Thr Asn
275 280 285
Asn Ala Lys Thr Ile Ile Val His Leu Asn Glu Thr Val Asn Ile Thr
290 295 300
Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys Ser Ile Arg Ile Gly Pro
305 310 315 320
Gly Gln Thr Phe Tyr Ala Thr Gly Asp Ile Ile Gly Asp Ile Arg Gln
325 330 335
Ala His Cys Asn Leu Ser Arg Asp Gly Trp Asn Lys Thr Leu Gln Gly
340 345 350
Val Lys Lys Lys Leu Ala Glu His Phe Pro Asn Lys Thr Ile Asn Phe
355 360 365
Thr Ser Ser Ser Gly Gly Asp Leu Glu Ile Thr Thr His Ser Phe Asn
370 375 380
Cys Arg Gly Glu Phe Phe Tyr Cys Asn Thr Ser Gly Leu Phe Asn Gly
385 390 395 400
Thr Tyr Met Pro Asn Gly Thr Asn Ser Asn Ser Ser Ser Asn Ile Thr
405 410 415
Leu Pro Cys Arg Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly
420 425 430
Arg Ala Met Tyr Ala Pro Pro Ile Ala Gly Asn Ile Thr Cys Arg Ser
435 440 445
Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly Ser Asn Asn Gly
450 455 460
Val Pro Asn Asp Thr Glu Thr Phe Arg Pro Gly Gly Gly Asp Met Arg
465 470 475 480
Asn Asn Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Glu Val Lys
485 490 495
Pro Leu Gly Val Ala Pro Thr Glu Ala Lys Arg Arg Val Val Glu Ser
500 505 510
Glu Lys Ser Ala Val Gly Ile Gly Ala Val Phe Leu Gly Ile Leu Gly
515 520 525
Ala Ala Gly Ser Thr Met Gly Ala Ala Ser Ile Thr Leu Thr Val Gln
530 535 540
Ala Arg Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Ser Asn Leu Leu
545 550 555 560
Arg Ala Ile Glu Ala Gln Gln His Met Leu Gln Leu Thr Val Trp Gly
565 570 575
Ile Lys Gln Leu Gln Thr Arg Val Leu Ala Ile Glu Arg Tyr Leu Gln
580 585 590
Asp Gln Gln Leu Leu Gly Leu Trp Gly Cys Ser Gly Lys Leu Ile Cys
595 600 605
Thr Thr Ala Val Pro Trp Asn Thr Ser Trp Ser Asn Lys Ser Gln Thr
610 615 620
Asp Ile Trp Asp Asn Met Thr Trp Met Gln Trp Asp Lys Glu Ile Gly
625 630 635 640
Asn Tyr Thr Gly Glu Ile Tyr Arg Leu Leu Glu Glu Ser Gln Asn Gln
645 650 655
Gln Glu Lys Asn Glu Lys Asp Leu Leu Ala Leu Asp Ser Trp Lys Asn
660 665 670
Leu Trp Asn Trp Phe Asp Ile Thr Asn Trp Leu Trp
675 680
<210> 7
<211> 708
<212> PRT
<213> 人工序列
<220>
<223> 稳定化的进化枝 C gp140三聚体: 具有切割突变的C97ZA012-gp140-折叠子(foldon)
<400> 7
Met Arg Val Arg Gly Ile Gln Arg Asn Cys Gln His Leu Trp Arg Trp
1 5 10 15
Gly Thr Leu Ile Leu Gly Met Leu Met Ile Cys Ser Ala Ala Glu Asn
20 25 30
Leu Trp Val Gly Asn Met Trp Val Thr Val Tyr Tyr Gly Val Pro Val
35 40 45
Trp Thr Asp Ala Lys Thr Thr Leu Phe Cys Ala Ser Asp Thr Lys Ala
50 55 60
Tyr Asp Arg Glu Val His Asn Val Trp Ala Thr His Ala Cys Val Pro
65 70 75 80
Thr Asp Pro Asn Pro Gln Glu Ile Val Leu Glu Asn Val Thr Glu Asn
85 90 95
Phe Asn Met Trp Lys Asn Asp Met Val Asp Gln Met His Glu Asp Ile
100 105 110
Ile Ser Leu Trp Asp Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro
115 120 125
Leu Cys Val Thr Leu His Cys Thr Asn Ala Thr Phe Lys Asn Asn Val
130 135 140
Thr Asn Asp Met Asn Lys Glu Ile Arg Asn Cys Ser Phe Asn Thr Thr
145 150 155 160
Thr Glu Ile Arg Asp Lys Lys Gln Gln Gly Tyr Ala Leu Phe Tyr Arg
165 170 175
Pro Asp Ile Val Leu Leu Lys Glu Asn Arg Asn Asn Ser Asn Asn Ser
180 185 190
Glu Tyr Ile Leu Ile Asn Cys Asn Ala Ser Thr Ile Thr Gln Ala Cys
195 200 205
Pro Lys Val Asn Phe Asp Pro Ile Pro Ile His Tyr Cys Ala Pro Ala
210 215 220
Gly Tyr Ala Ile Leu Lys Cys Asn Asn Lys Thr Phe Ser Gly Lys Gly
225 230 235 240
Pro Cys Asn Asn Val Ser Thr Val Gln Cys Thr His Gly Ile Lys Pro
245 250 255
Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu Lys Glu
260 265 270
Ile Ile Ile Arg Ser Glu Asn Leu Thr Asp Asn Val Lys Thr Ile Ile
275 280 285
Val His Leu Asn Lys Ser Val Glu Ile Val Cys Thr Arg Pro Asn Asn
290 295 300
Asn Thr Arg Lys Ser Met Arg Ile Gly Pro Gly Gln Thr Phe Tyr Ala
305 310 315 320
Thr Gly Asp Ile Ile Gly Asp Ile Arg Gln Ala Tyr Cys Asn Ile Ser
325 330 335
Gly Ser Lys Trp Asn Glu Thr Leu Lys Arg Val Lys Glu Lys Leu Gln
340 345 350
Glu Asn Tyr Asn Asn Asn Lys Thr Ile Lys Phe Ala Pro Ser Ser Gly
355 360 365
Gly Asp Leu Glu Ile Thr Thr His Ser Phe Asn Cys Arg Gly Glu Phe
370 375 380
Phe Tyr Cys Asn Thr Thr Arg Leu Phe Asn Asn Asn Ala Thr Glu Asp
385 390 395 400
Glu Thr Ile Thr Leu Pro Cys Arg Ile Lys Gln Ile Ile Asn Met Trp
405 410 415
Gln Gly Val Gly Arg Ala Met Tyr Ala Pro Pro Ile Ala Gly Asn Ile
420 425 430
Thr Cys Lys Ser Asn Ile Thr Gly Leu Leu Leu Val Arg Asp Gly Gly
435 440 445
Glu Asp Asn Lys Thr Glu Glu Ile Phe Arg Pro Gly Gly Gly Asn Met
450 455 460
Lys Asp Asn Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Ile Glu Leu
465 470 475 480
Lys Pro Leu Gly Ile Ala Pro Thr Gly Ala Lys Glu Arg Val Val Glu
485 490 495
Arg Glu Glu Arg Ala Val Gly Ile Gly Ala Val Phe Leu Gly Phe Leu
500 505 510
Gly Ala Ala Gly Ser Thr Met Gly Ala Ala Ser Leu Thr Leu Thr Val
515 520 525
Gln Ala Arg Gln Leu Leu Ser Ser Ile Val Gln Gln Gln Ser Asn Leu
530 535 540
Leu Arg Ala Ile Glu Ala Gln Gln His Met Leu Gln Leu Thr Val Trp
545 550 555 560
Gly Ile Lys Gln Leu Gln Thr Arg Val Leu Ala Ile Glu Arg Tyr Leu
565 570 575
Lys Asp Gln Gln Leu Leu Gly Ile Trp Gly Cys Ser Gly Lys Leu Ile
580 585 590
Cys Thr Thr Asn Val Pro Trp Asn Ser Ser Trp Ser Asn Lys Ser Gln
595 600 605
Thr Asp Ile Trp Asn Asn Met Thr Trp Met Glu Trp Asp Arg Glu Ile
610 615 620
Ser Asn Tyr Thr Asp Thr Ile Tyr Arg Leu Leu Glu Asp Ser Gln Thr
625 630 635 640
Gln Gln Glu Lys Asn Glu Lys Asp Leu Leu Ala Leu Asp Ser Trp Lys
645 650 655
Asn Leu Trp Ser Trp Phe Asp Ile Ser Asn Trp Leu Trp Tyr Ile Lys
660 665 670
Ser Arg Ile Glu Gly Arg Gly Ser Gly Gly Tyr Ile Pro Glu Ala Pro
675 680 685
Arg Asp Gly Gln Ala Tyr Val Arg Lys Asp Gly Glu Trp Val Leu Leu
690 695 700
Ser Thr Phe Leu
705
<210> 8
<211> 625
<212> PRT
<213> 人工序列
<220>
<223> C4片段:没有信号肽和跨膜结构域的gp120-截短的 gp41
<400> 8
Met Gly Asn Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys
1 5 10 15
Asp Ala Lys Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Glu
20 25 30
Lys Glu Val His Asn Val Trp Ala Thr His Ala Cys Val Pro Thr Asp
35 40 45
Pro Asn Pro Gln Glu Ile Val Leu Gly Asn Val Thr Glu Asn Phe Asn
50 55 60
Met Trp Lys Asn Asp Met Val Asp Gln Met His Glu Asp Ile Ile Ser
65 70 75 80
Leu Trp Asp Ala Ser Leu Glu Pro Cys Val Lys Leu Thr Pro Leu Cys
85 90 95
Val Thr Leu Asn Cys Arg Asn Val Arg Asn Val Ser Ser Asn Gly Thr
100 105 110
Tyr Asn Ile Ile His Asn Glu Thr Tyr Lys Glu Met Lys Asn Cys Ser
115 120 125
Phe Asn Ala Thr Thr Val Val Glu Asp Arg Lys Gln Lys Val His Ala
130 135 140
Leu Phe Tyr Arg Leu Asp Ile Val Pro Leu Asp Glu Asn Asn Ser Ser
145 150 155 160
Glu Lys Ser Ser Glu Asn Ser Ser Glu Tyr Tyr Arg Leu Ile Asn Cys
165 170 175
Asn Thr Ser Ala Ile Thr Gln Ala Cys Pro Lys Val Ser Phe Asp Pro
180 185 190
Ile Pro Ile His Tyr Cys Ala Pro Ala Gly Tyr Ala Ile Leu Lys Cys
195 200 205
Asn Asn Lys Thr Phe Asn Gly Thr Gly Pro Cys Asn Asn Val Ser Thr
210 215 220
Val Gln Cys Thr His Gly Ile Lys Pro Val Val Ser Thr Gln Leu Leu
225 230 235 240
Leu Asn Gly Ser Leu Ala Glu Glu Glu Ile Ile Ile Arg Ser Glu Asn
245 250 255
Leu Thr Asn Asn Ala Lys Thr Ile Ile Val His Leu Asn Glu Thr Val
260 265 270
Asn Ile Thr Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys Ser Ile Arg
275 280 285
Ile Gly Pro Gly Gln Thr Phe Tyr Ala Thr Gly Asp Ile Ile Gly Asp
290 295 300
Ile Arg Gln Ala His Cys Asn Leu Ser Arg Asp Gly Trp Asn Lys Thr
305 310 315 320
Leu Gln Gly Val Lys Lys Lys Leu Ala Glu His Phe Pro Asn Lys Thr
325 330 335
Ile Lys Phe Ala Pro His Ser Gly Gly Asp Leu Glu Ile Thr Thr His
340 345 350
Thr Phe Asn Cys Arg Gly Glu Phe Phe Tyr Cys Asn Thr Ser Asn Leu
355 360 365
Phe Asn Glu Ser Asn Ile Glu Arg Asn Asp Ser Ile Ile Thr Leu Pro
370 375 380
Cys Arg Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Arg Ala
385 390 395 400
Ile Tyr Ala Pro Pro Ile Ala Gly Asn Ile Thr Cys Arg Ser Asn Ile
405 410 415
Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly Ser Asn Asn Gly Val Pro
420 425 430
Asn Asp Thr Glu Thr Phe Arg Pro Gly Gly Gly Asp Met Arg Asn Asn
435 440 445
Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Glu Val Lys Pro Leu
450 455 460
Gly Val Ala Pro Thr Glu Ala Lys Arg Arg Val Val Glu Arg Glu Lys
465 470 475 480
Arg Ala Val Gly Ile Gly Ala Val Phe Leu Gly Ile Leu Gly Ala Ala
485 490 495
Gly Ser Thr Met Gly Ala Ala Ser Ile Thr Leu Thr Val Gln Ala Arg
500 505 510
Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Ser Asn Leu Leu Arg Ala
515 520 525
Ile Glu Ala Gln Gln His Met Leu Gln Leu Thr Val Trp Gly Ile Lys
530 535 540
Gln Leu Gln Thr Arg Val Leu Ala Ile Glu Arg Tyr Leu Gln Asp Gln
545 550 555 560
Gln Leu Leu Gly Leu Trp Gly Cys Ser Gly Lys Leu Ile Cys Thr Thr
565 570 575
Ala Val Pro Trp Asn Thr Ser Trp Ser Asn Lys Ser Gln Thr Asp Ile
580 585 590
Trp Asp Asn Met Thr Trp Met Gln Trp Asp Lys Glu Ile Gly Asn Tyr
595 600 605
Thr Gly Glu Ile Tyr Arg Leu Leu Glu Glu Ser Gln Asn Gln Gln Glu
610 615 620
Lys
625
<210> 9
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 信号序列
<400> 9
Met Arg Val Arg Gly Met Leu Arg Asn Trp Gln Gln Trp Trp Ile Trp
1 5 10 15
Ser Ser Leu Gly Phe Trp Met Leu Met Ile Tyr Ser Val
20 25
<210> 10
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 信号序列
<400> 10
Met Arg Val Thr Gly Ile Arg Lys Asn Tyr Gln His Leu Trp Arg Trp
1 5 10 15
Gly Thr Met Leu Leu Gly Ile Leu Met Ile Cys Ser Ala
20 25
<210> 11
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 信号序列
<400> 11
Met Arg Val Arg Gly Ile Gln Arg Asn Trp Pro Gln Trp Trp Ile Trp
1 5 10 15
Gly Ile Leu Gly Phe Trp Met Ile Ile Ile Cys Arg Val
20 25
<210> 12
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 信号序列
<400> 12
Met Arg Val Arg Gly Ile Gln Arg Asn Cys Gln His Leu Trp Arg Trp
1 5 10 15
Gly Thr Leu Ile Leu Gly Met Leu Met Ile Cys Ser Ala
20 25
<210> 13
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 跨膜结构域
<400> 13
Ile Phe Ile Met Ile Val Gly Gly Leu Ile Gly Leu Arg Ile Ile Phe
1 5 10 15
Ala Val Leu Ser Ile Val
20
<210> 14
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 截短的细胞质区域
<400> 14
Asn Arg Val Arg Gln Gly Tyr
1 5
<210> 15
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> GCN4三聚结构域
<400> 15
Met Lys Gln Ile Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile Tyr
1 5 10 15
His Ile Glu Asn Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu Val
20 25 30
<210> 16
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 折叠子三聚结构域
<400> 16
Gly Ser Gly Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly Gln Ala Tyr
1 5 10 15
Val Arg Lys Asp Gly Glu Trp Val Leu Leu Ser Thr Phe Leu
20 25 30
<210> 17
<211> 862
<212> PRT
<213> 人工序列
<220>
<223> C4 序列
<400> 17
Met Arg Val Arg Gly Met Leu Arg Asn Trp Gln Gln Trp Trp Ile Trp
1 5 10 15
Ser Ser Leu Gly Phe Trp Met Leu Met Ile Tyr Ser Val Met Gly Asn
20 25 30
Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys Asp Ala Lys
35 40 45
Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Glu Lys 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 Ile Val Leu Gly Asn Val Thr Glu Asn Phe Asn Met Trp Lys
85 90 95
Asn Asp Met Val Asp Gln Met His Glu Asp Ile Ile Ser Leu Trp Asp
100 105 110
Ala Ser Leu Glu Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
115 120 125
Asn Cys Arg Asn Val Arg Asn Val Ser Ser Asn Gly Thr Tyr Asn Ile
130 135 140
Ile His Asn Glu Thr Tyr Lys Glu Met Lys Asn Cys Ser Phe Asn Ala
145 150 155 160
Thr Thr Val Val Glu Asp Arg Lys Gln Lys Val His Ala Leu Phe Tyr
165 170 175
Arg Leu Asp Ile Val Pro Leu Asp Glu Asn Asn Ser Ser Glu Lys Ser
180 185 190
Ser Glu Asn Ser Ser Glu Tyr Tyr Arg Leu Ile Asn Cys Asn Thr Ser
195 200 205
Ala Ile Thr Gln Ala Cys Pro Lys Val Ser Phe Asp Pro Ile Pro Ile
210 215 220
His Tyr Cys Ala Pro Ala Gly Tyr Ala Ile Leu Lys Cys Asn Asn Lys
225 230 235 240
Thr Phe Asn Gly Thr Gly Pro Cys Asn Asn Val Ser Thr Val Gln Cys
245 250 255
Thr His Gly Ile Lys Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly
260 265 270
Ser Leu Ala Glu Glu Glu Ile Ile Ile Arg Ser Glu Asn Leu Thr Asn
275 280 285
Asn Ala Lys Thr Ile Ile Val His Leu Asn Glu Thr Val Asn Ile Thr
290 295 300
Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys Ser Ile Arg Ile Gly Pro
305 310 315 320
Gly Gln Thr Phe Tyr Ala Thr Gly Asp Ile Ile Gly Asp Ile Arg Gln
325 330 335
Ala His Cys Asn Leu Ser Arg Asp Gly Trp Asn Lys Thr Leu Gln Gly
340 345 350
Val Lys Lys Lys Leu Ala Glu His Phe Pro Asn Lys Thr Ile Lys Phe
355 360 365
Ala Pro His Ser Gly Gly Asp Leu Glu Ile Thr Thr His Thr Phe Asn
370 375 380
Cys Arg Gly Glu Phe Phe Tyr Cys Asn Thr Ser Asn Leu Phe Asn Glu
385 390 395 400
Ser Asn Ile Glu Arg Asn Asp Ser Ile Ile Thr Leu Pro Cys Arg Ile
405 410 415
Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Arg Ala Ile Tyr Ala
420 425 430
Pro Pro Ile Ala Gly Asn Ile Thr Cys Arg Ser Asn Ile Thr Gly Leu
435 440 445
Leu Leu Thr Arg Asp Gly Gly Ser Asn Asn Gly Val Pro Asn Asp Thr
450 455 460
Glu Thr Phe Arg Pro Gly Gly Gly Asp Met Arg Asn Asn Trp Arg Ser
465 470 475 480
Glu Leu Tyr Lys Tyr Lys Val Val Glu Val Lys Pro Leu Gly Val Ala
485 490 495
Pro Thr Glu Ala Lys Arg Arg Val Val Glu Arg Glu Lys Arg Ala Val
500 505 510
Gly Ile Gly Ala Val Phe Leu Gly Ile Leu Gly Ala Ala Gly Ser Thr
515 520 525
Met Gly Ala Ala Ser Ile Thr Leu Thr Val Gln Ala Arg Gln Leu Leu
530 535 540
Ser Gly Ile Val Gln Gln Gln Ser Asn Leu Leu Arg Ala Ile Glu Ala
545 550 555 560
Gln Gln His Met Leu Gln Leu Thr Val Trp Gly Ile Lys Gln Leu Gln
565 570 575
Thr Arg Val Leu Ala Ile Glu Arg Tyr Leu Gln Asp Gln Gln Leu Leu
580 585 590
Gly Leu Trp Gly Cys Ser Gly Lys Leu Ile Cys Thr Thr Ala Val Pro
595 600 605
Trp Asn Thr Ser Trp Ser Asn Lys Ser Gln Thr Asp Ile Trp Asp Asn
610 615 620
Met Thr Trp Met Gln Trp Asp Lys Glu Ile Gly Asn Tyr Thr Gly Glu
625 630 635 640
Ile Tyr Arg Leu Leu Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu
645 650 655
Lys Asp Leu Leu Ala Leu Asp Ser Trp Asn Asn Leu Trp Asn Trp Phe
660 665 670
Ser Ile Ser Lys Trp Leu Trp Tyr Ile Lys Ile Phe Ile Met Ile Val
675 680 685
Gly Gly Leu Ile Gly Leu Arg Ile Ile Phe Ala Val Leu Ser Ile Val
690 695 700
Asn Arg Val Arg Gln Gly Tyr Ser Pro Leu Ser Leu Gln Thr Leu Thr
705 710 715 720
Gln Asn Pro Gly Gly Leu Asp Arg Leu Gly Arg Ile Glu Glu Glu Gly
725 730 735
Gly Glu Gln Asp Lys Asp Arg Ser Ile Arg Leu Val Asn Gly Phe Phe
740 745 750
Ala Leu Phe Trp Asp Asp Leu Arg Ser Leu Cys Leu Phe Ser Tyr His
755 760 765
Arg Leu Arg Asp Phe Ile Leu Ile Val Ala Arg Ala Val Glu Leu Leu
770 775 780
Gly Arg Ser Ser Leu Arg Gly Leu Gln Arg Gly Trp Glu Ile Leu Lys
785 790 795 800
Tyr Leu Gly Ser Leu Leu Gln Tyr Trp Gly Leu Glu Leu Lys Lys Ser
805 810 815
Ala Ile Asn Leu Leu Asp Thr Ile Ala Ile Ala Val Ala Glu Gly Thr
820 825 830
Asp Arg Ile Ile Glu Leu Ile Gln Arg Ile Cys Arg Ala Ile Cys Asn
835 840 845
Ile Pro Arg Arg Ile Arg Gln Gly Phe Glu Ala Ala Leu Gln
850 855 860
<210> 18
<211> 711
<212> PRT
<213> 人工序列
<220>
<223> C4D7 序列
<400> 18
Met Arg Val Arg Gly Met Leu Arg Asn Trp Gln Gln Trp Trp Ile Trp
1 5 10 15
Ser Ser Leu Gly Phe Trp Met Leu Met Ile Tyr Ser Val Met Gly Asn
20 25 30
Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys Asp Ala Lys
35 40 45
Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Glu Lys 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 Ile Val Leu Gly Asn Val Thr Glu Asn Phe Asn Met Trp Lys
85 90 95
Asn Asp Met Val Asp Gln Met His Glu Asp Ile Ile Ser Leu Trp Asp
100 105 110
Ala Ser Leu Glu Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
115 120 125
Asn Cys Arg Asn Val Arg Asn Val Ser Ser Asn Gly Thr Tyr Asn Ile
130 135 140
Ile His Asn Glu Thr Tyr Lys Glu Met Lys Asn Cys Ser Phe Asn Ala
145 150 155 160
Thr Thr Val Val Glu Asp Arg Lys Gln Lys Val His Ala Leu Phe Tyr
165 170 175
Arg Leu Asp Ile Val Pro Leu Asp Glu Asn Asn Ser Ser Glu Lys Ser
180 185 190
Ser Glu Asn Ser Ser Glu Tyr Tyr Arg Leu Ile Asn Cys Asn Thr Ser
195 200 205
Ala Ile Thr Gln Ala Cys Pro Lys Val Ser Phe Asp Pro Ile Pro Ile
210 215 220
His Tyr Cys Ala Pro Ala Gly Tyr Ala Ile Leu Lys Cys Asn Asn Lys
225 230 235 240
Thr Phe Asn Gly Thr Gly Pro Cys Asn Asn Val Ser Thr Val Gln Cys
245 250 255
Thr His Gly Ile Lys Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly
260 265 270
Ser Leu Ala Glu Glu Glu Ile Ile Ile Arg Ser Glu Asn Leu Thr Asn
275 280 285
Asn Ala Lys Thr Ile Ile Val His Leu Asn Glu Thr Val Asn Ile Thr
290 295 300
Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys Ser Ile Arg Ile Gly Pro
305 310 315 320
Gly Gln Thr Phe Tyr Ala Thr Gly Asp Ile Ile Gly Asp Ile Arg Gln
325 330 335
Ala His Cys Asn Leu Ser Arg Asp Gly Trp Asn Lys Thr Leu Gln Gly
340 345 350
Val Lys Lys Lys Leu Ala Glu His Phe Pro Asn Lys Thr Ile Lys Phe
355 360 365
Ala Pro His Ser Gly Gly Asp Leu Glu Ile Thr Thr His Thr Phe Asn
370 375 380
Cys Arg Gly Glu Phe Phe Tyr Cys Asn Thr Ser Asn Leu Phe Asn Glu
385 390 395 400
Ser Asn Ile Glu Arg Asn Asp Ser Ile Ile Thr Leu Pro Cys Arg Ile
405 410 415
Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Arg Ala Ile Tyr Ala
420 425 430
Pro Pro Ile Ala Gly Asn Ile Thr Cys Arg Ser Asn Ile Thr Gly Leu
435 440 445
Leu Leu Thr Arg Asp Gly Gly Ser Asn Asn Gly Val Pro Asn Asp Thr
450 455 460
Glu Thr Phe Arg Pro Gly Gly Gly Asp Met Arg Asn Asn Trp Arg Ser
465 470 475 480
Glu Leu Tyr Lys Tyr Lys Val Val Glu Val Lys Pro Leu Gly Val Ala
485 490 495
Pro Thr Glu Ala Lys Arg Arg Val Val Glu Arg Glu Lys Arg Ala Val
500 505 510
Gly Ile Gly Ala Val Phe Leu Gly Ile Leu Gly Ala Ala Gly Ser Thr
515 520 525
Met Gly Ala Ala Ser Ile Thr Leu Thr Val Gln Ala Arg Gln Leu Leu
530 535 540
Ser Gly Ile Val Gln Gln Gln Ser Asn Leu Leu Arg Ala Ile Glu Ala
545 550 555 560
Gln Gln His Met Leu Gln Leu Thr Val Trp Gly Ile Lys Gln Leu Gln
565 570 575
Thr Arg Val Leu Ala Ile Glu Arg Tyr Leu Gln Asp Gln Gln Leu Leu
580 585 590
Gly Leu Trp Gly Cys Ser Gly Lys Leu Ile Cys Thr Thr Ala Val Pro
595 600 605
Trp Asn Thr Ser Trp Ser Asn Lys Ser Gln Thr Asp Ile Trp Asp Asn
610 615 620
Met Thr Trp Met Gln Trp Asp Lys Glu Ile Gly Asn Tyr Thr Gly Glu
625 630 635 640
Ile Tyr Arg Leu Leu Glu Glu Ser Gln Asn Gln Gln Glu Lys Asn Glu
645 650 655
Lys Asp Leu Leu Ala Leu Asp Ser Trp Asn Asn Leu Trp Asn Trp Phe
660 665 670
Ser Ile Ser Lys Trp Leu Trp Tyr Ile Lys Ile Phe Ile Met Ile Val
675 680 685
Gly Gly Leu Ile Gly Leu Arg Ile Ile Phe Ala Val Leu Ser Ile Val
690 695 700
Asn Arg Val Arg Gln Gly Tyr
705 710
<210> 19
<211> 704
<212> PRT
<213> 人工序列
<220>
<223> sC4 序列
<400> 19
Met Arg Val Arg Gly Met Leu Arg Asn Trp Gln Gln Trp Trp Ile Trp
1 5 10 15
Ser Ser Leu Gly Phe Trp Met Leu Met Ile Tyr Ser Val Met Gly Asn
20 25 30
Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys Asp Ala Lys
35 40 45
Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Glu Lys 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 Ile Val Leu Gly Asn Val Thr Glu Asn Phe Asn Met Trp Lys
85 90 95
Asn Asp Met Val Asp Gln Met His Glu Asp Ile Ile Ser Leu Trp Asp
100 105 110
Ala Ser Leu Glu Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
115 120 125
Asn Cys Arg Asn Val Arg Asn Val Ser Ser Asn Gly Thr Tyr Asn Ile
130 135 140
Ile His Asn Glu Thr Tyr Lys Glu Met Lys Asn Cys Ser Phe Asn Ala
145 150 155 160
Thr Thr Val Val Glu Asp Arg Lys Gln Lys Val His Ala Leu Phe Tyr
165 170 175
Arg Leu Asp Ile Val Pro Leu Asp Glu Asn Asn Ser Ser Glu Lys Ser
180 185 190
Ser Glu Asn Ser Ser Glu Tyr Tyr Arg Leu Ile Asn Cys Asn Thr Ser
195 200 205
Ala Ile Thr Gln Ala Cys Pro Lys Val Ser Phe Asp Pro Ile Pro Ile
210 215 220
His Tyr Cys Ala Pro Ala Gly Tyr Ala Ile Leu Lys Cys Asn Asn Lys
225 230 235 240
Thr Phe Asn Gly Thr Gly Pro Cys Asn Asn Val Ser Thr Val Gln Cys
245 250 255
Thr His Gly Ile Lys Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly
260 265 270
Ser Leu Ala Glu Glu Glu Ile Ile Ile Arg Ser Glu Asn Leu Thr Asn
275 280 285
Asn Ala Lys Thr Ile Ile Val His Leu Asn Glu Thr Val Asn Ile Thr
290 295 300
Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys Ser Ile Arg Ile Gly Pro
305 310 315 320
Gly Gln Thr Phe Tyr Ala Thr Gly Asp Ile Ile Gly Asp Ile Arg Gln
325 330 335
Ala His Cys Asn Leu Ser Arg Asp Gly Trp Asn Lys Thr Leu Gln Gly
340 345 350
Val Lys Lys Lys Leu Ala Glu His Phe Pro Asn Lys Thr Ile Lys Phe
355 360 365
Ala Pro His Ser Gly Gly Asp Leu Glu Ile Thr Thr His Thr Phe Asn
370 375 380
Cys Arg Gly Glu Phe Phe Tyr Cys Asn Thr Ser Asn Leu Phe Asn Glu
385 390 395 400
Ser Asn Ile Glu Arg Asn Asp Ser Ile Ile Thr Leu Pro Cys Arg Ile
405 410 415
Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly Arg Ala Ile Tyr Ala
420 425 430
Pro Pro Ile Ala Gly Asn Ile Thr Cys Arg Ser Asn Ile Thr Gly Leu
435 440 445
Leu Leu Thr Arg Asp Gly Gly Ser Asn Asn Gly Val Pro Asn Asp Thr
450 455 460
Glu Thr Phe Arg Pro Gly Gly Gly Asp Met Arg Asn Asn Trp Arg Ser
465 470 475 480
Glu Leu Tyr Lys Tyr Lys Val Val Glu Val Lys Pro Leu Gly Val Ala
485 490 495
Pro Thr Glu Ala Lys Arg Arg Val Val Glu Arg Glu Glu Arg Ala Val
500 505 510
Gly Ile Gly Ala Val Phe Leu Gly Ile Leu Gly Ala Ala Gly Ser Thr
515 520 525
Met Gly Ala Ala Ser Ile Thr Leu Thr Val Gln Ala Arg Gln Leu Leu
530 535 540
Ser Gly Ile Val Gln Gln Gln Ser Asn Leu Leu Arg Ala Ile Glu Ala
545 550 555 560
Gln Gln His Met Leu Gln Leu Thr Val Trp Gly Ile Lys Gln Leu Gln
565 570 575
Thr Arg Val Leu Ala Ile Glu Arg Tyr Leu Gln Asp Gln Gln Leu Leu
580 585 590
Gly Leu Trp Gly Cys Ser Gly Lys Leu Ile Cys Thr Thr Ala Val Pro
595 600 605
Trp Asn Thr Ser Trp Ser Asn Lys Ser Gln Thr Asp Ile Trp Asp Asn
610 615 620
Met Thr Trp Met Gln Trp Asp Lys Glu Ile Gly Asn Tyr Thr Gly Glu
625 630 635 640
Ile Tyr Arg Leu Leu Glu Glu Ser Gln Asn Gln Gln Glu Lys Met Lys
645 650 655
Gln Ile Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile Tyr His Ile
660 665 670
Glu Asn Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu Val Gly Ser
675 680 685
Gly Ala Pro Thr Lys Ala Lys Arg Arg Val Val Gln Arg Glu Lys Arg
690 695 700
<210> 20
<211> 4050
<212> DNA
<213> 人工序列
<220>
<223> 编码mos1GagPol的核苷酸序列
<400> 20
atgggagcca gagccagcgt gctgtccgga ggggagctgg accgctggga gaagatcagg 60
ctgaggcctg gagggaagaa gaagtacagg ctgaagcaca tcgtgtgggc cagcagagag 120
ctggaacggt ttgccgtgaa ccctggcctg ctggaaacca gcgagggctg taggcagatt 180
ctgggacagc tgcagcccag cctgcagaca ggcagcgagg aactgcggag cctgtacaac 240
accgtggcca ccctgtactg cgtgcaccag cggatcgaga tcaaggacac caaagaagcc 300
ctggaaaaga tcgaggaaga gcagaacaag agcaagaaga aagcccagca ggctgccgct 360
gacacaggca acagcagcca ggtgtcccag aactacccca tcgtgcagaa catccaggga 420
cagatggtgc accaggccat cagccctcgg accctgaacg cctgggtgaa ggtggtggag 480
gaaaaggcct tcagccctga ggtgatcccc atgttctctg ccctgagcga gggagccaca 540
ccccaggacc tgaacaccat gctgaacacc gtgggagggc accaggctgc catgcagatg 600
ctgaaagaga caatcaacga ggaagctgcc gagtgggaca gggtccaccc agtgcacgct 660
ggacctatcg ctcctggcca gatgagagag cccagaggca gcgatattgc tggcaccacc 720
tccacactgc aggaacagat cggctggatg accaacaacc ctcccatccc tgtgggagag 780
atctacaagc ggtggatcat tctgggactg aacaagatcg tgcggatgta cagccctgtg 840
agcatcctgg acatcaggca gggacccaaa gagcccttca gggactacgt ggaccggttc 900
tacaagaccc tgagagccga gcaggccagc caggacgtga agaactggat gaccgagaca 960
ctgctggtgc agaacgccaa ccctgactgc aagaccatcc tgaaagccct gggacctgct 1020
gccaccctgg aagagatgat gacagcctgc cagggagtgg gaggacctgg ccacaaggcc 1080
agggtgctgg ccgaggccat gagccaggtg accaactctg ccaccatcat gatgcagaga 1140
ggcaacttcc ggaaccagag aaagaccgtg aagtgcttca actgtggcaa agagggacac 1200
attgccaaga actgcagggc tcccaggaag aaaggctgct ggaagtgcgg aaaagaaggc 1260
caccagatga aggactgcac cgagaggcag gccaacttcc tgggcaagat ctggcctagc 1320
aacaagggca ggcctggcaa cttcctgcag aacagacccg agcccaccgc tcctcccgag 1380
gaaagcttcc ggtttggcga ggaaaccacc acccctagcc agaagcagga acccatcgac 1440
aaagagatgt accctctggc cagcctgaag agcctgttcg gcaacgaccc cagcagccag 1500
atggctccca tcagcccaat cgagacagtg cctgtgaagc tgaagcctgg catggacgga 1560
cccagggtga agcagtggcc tctgaccgag gaaaagatca aagccctgac agccatctgc 1620
gaggaaatgg aaaaagaggg caagatcacc aagatcggac ccgagaaccc ctacaacacc 1680
cctgtgttcg ccatcaagaa gaaagacagc accaagtgga ggaaactggt ggacttcaga 1740
gagctgaaca agcggaccca ggacttctgg gaggtgcagc tgggcatccc tcaccctgct 1800
ggcctgaaga aaaagaaaag cgtgaccgtg ctggctgtgg gagatgccta cttcagcgtg 1860
cctctggacg agggcttccg gaagtacaca gccttcacca tccccagcac caacaacgag 1920
acacctggca tcagatacca gtacaacgtg ctgcctcagg gctggaaagg cagccctgcc 1980
atcttccagt gcagcatgac cagaatcctg gaacccttca gagccaagaa ccctgagatc 2040
gtgatctacc agtatatggc tgccctctac gtgggcagcg acctggaaat cggacagcac 2100
agagccaaaa tcgaagaact ccgcgagcac ctgctgaagt ggggattcac cacccctgac 2160
aagaagcacc agaaagagcc tcccttcctg tggatgggct acgagctgca ccctgacaag 2220
tggaccgtgc agcccatcca gctgccagag aaggactcct ggaccgtgaa cgacatccag 2280
aaactggtcg gcaagctgaa ctgggccagc cagatctacc ctggcatcaa agtcagacag 2340
ctgtgtaagc tgctgagggg agccaaagca ctgaccgaca tcgtgcctct gacagaagaa 2400
gccgagctgg aactggccga gaacagagag atcctgaaag aacccgtgca cggagtgtac 2460
tacgacccct ccaaggacct gattgccgag atccagaaac agggacacga ccagtggacc 2520
taccagatct atcaggaacc tttcaagaac ctgaaaacag gcaagtacgc caagatgcgg 2580
acagcccaca ccaacgacgt gaagcagctg accgaagccg tgcagaaaat cgccatggaa 2640
agcatcgtga tctggggaaa gacacccaag ttcaggctgc ccatccagaa agagacatgg 2700
gaaacctggt ggaccgacta ctggcaggcc acctggattc ccgagtggga gttcgtgaac 2760
accccacccc tggtgaagct gtggtatcag ctggaaaagg accctatcgc tggcgtggag 2820
acattctacg tggctggagc tgccaacaga gagacaaagc tgggcaaggc tggctacgtg 2880
accgacagag gcagacagaa aatcgtgagc ctgaccgaaa ccaccaacca gaaaacagcc 2940
ctgcaggcca tctatctggc actgcaggac agcggaagcg aggtgaacat cgtgacagcc 3000
agccagtatg ccctgggcat catccaggcc cagcctgaca agagcgagag cgagctggtg 3060
aaccagatca tcgagcagct gatcaagaaa gaacgggtgt acctgagctg ggtgccagcc 3120
cacaagggca tcggagggaa cgagcaggtg gacaagctgg tgtccagcgg aatccggaag 3180
gtgctgttcc tggacggcat cgataaagcc caggaagagc acgagaagta ccacagcaat 3240
tggagagcca tggccagcga cttcaacctg cctcccgtgg tggccaaaga aatcgtggcc 3300
agctgcgacc agtgccagct gaaaggcgag gccatgcacg gacaggtgga ctgctcccct 3360
ggcatctggc agctggcatg cacccacctg gaaggcaaga tcattctggt ggccgtgcac 3420
gtggccagcg gatacatcga agccgaagtg atccctgccg agacagggca ggaaacagcc 3480
tacttcatcc tgaagctggc tggcagatgg cctgtgaagg tgatccacac agccaacggc 3540
agcaacttca cctctgctgc cgtgaaggct gcctgttggt gggctggcat tcagcaggaa 3600
tttggcatcc cctacaatcc ccagtctcag ggagtggtgg ccagcatgaa caaagagctg 3660
aagaagatca tcggacaggt cagggatcag gccgagcacc tgaaaactgc cgtccagatg 3720
gccgtgttca tccacaactt caagcggaag ggagggatcg gagggtactc tgctggcgag 3780
cggatcatcg acatcattgc caccgatatc cagaccaaag agctgcagaa acagatcatc 3840
aagatccaga acttcagggt gtactacagg gacagcaggg accccatctg gaagggacct 3900
gccaagctgc tgtggaaagg cgaaggagcc gtcgtcatcc aggacaacag cgacatcaag 3960
gtggtgccca gacggaaggt gaaaatcatc aaggactacg gcaaacagat ggctggagcc 4020
gactgtgtcg ctggcaggca ggacgaggac 4050
<210> 21
<211> 4023
<212> DNA
<213> 人工序列
<220>
<223> 编码mos2GagPol的核苷酸序列
<400> 21
atgggagcca gagccagcat cctgcgagga gggaagctgg acaagtggga gaagatcagg 60
ctgaggcctg gagggaagaa acactacatg ctgaagcacc tggtctgggc cagcagagag 120
ctggaacggt ttgccctcaa tcctggcctg ctggaaacca gcgagggctg caagcagatc 180
atcaagcagc tgcagcctgc cctgcagaca ggcaccgagg aactgcggag cctgttcaac 240
accgtggcca ccctgtactg cgtgcatgcc gagatcgaag tgagggacac caaagaagcc 300
ctggacaaga tcgaggaaga gcagaacaag agccagcaga aaacccagca ggccaaagaa 360
gccgacggca aggtctccca gaactacccc atcgtgcaga acctgcaggg acagatggtg 420
caccagccca tcagccctcg gacactgaat gcctgggtga aggtgatcga ggaaaaggcc 480
ttcagccctg aggtgatccc catgttcaca gccctgagcg agggagccac accccaggac 540
ctgaacacca tgctgaacac cgtgggaggg caccaggctg ccatgcagat gctgaaggac 600
accatcaacg aggaagctgc cgagtgggac aggctgcacc ctgtgcacgc tggacctgtg 660
gctcctggcc agatgagaga gcccagaggc agcgatattg ctggcaccac ctccaatctg 720
caggaacaga tcgcctggat gaccagcaac cctcccatcc ctgtgggaga catctacaag 780
cggtggatca tcctgggact gaacaagatc gtgcggatgt acagccctac ctccatcctg 840
gacatcaagc agggacccaa agagcctttc agggactacg tggaccggtt cttcaagacc 900
ctgagagccg agcaggccac ccaggacgtg aagaactgga tgaccgacac cctgctggtg 960
cagaacgcca accctgactg caagaccatc ctgagagccc tgggacctgg agccaccctg 1020
gaagagatga tgacagcctg ccagggagtg ggaggaccct ctcacaaggc tagggtgctg 1080
gccgaggcca tgagccagac caacagcacc atcctgatgc agcggagcaa cttcaagggc 1140
agcaagcgga tcgtgaagtg cttcaactgt ggcaaagagg gacacattgc cagaaactgt 1200
agggcaccca ggaagaaagg ctgctggaag tgcggaaaag aaggccacca gatgaaggac 1260
tgcaccgaga ggcaggccaa cttcctgggc aagatctggc ctagccacaa gggcagacct 1320
ggcaacttcc tgcagagcag acccgagccc accgctcctc cagccgagag cttccggttc 1380
gaggaaacca cccctgctcc caagcaggaa cctaaggaca gagagcctct gaccagcctg 1440
agaagcctgt tcggcagcga ccctctgagc cagatggctc ccatctcccc tatcgagaca 1500
gtgcctgtga agctgaagcc tggcatggac ggacccaagg tgaaacagtg gcctctgacc 1560
gaggaaaaga tcaaagccct ggtggagatc tgtaccgaga tggaaaaaga gggcaagatc 1620
agcaagatcg gacccgagaa cccctacaac acccctatct tcgccatcaa gaagaaagac 1680
agcaccaagt ggaggaaact ggtggacttc agagagctga acaagcggac ccaggacttc 1740
tgggaggtgc agctgggcat ccctcaccct gctggcctga agaaaaagaa aagcgtgacc 1800
gtgctggccg tgggagatgc ctacttcagc gtgcctctgg acgaggactt cagaaagtac 1860
acagccttca ccatccccag catcaacaac gagacacctg gcatcagata ccagtacaac 1920
gtgctgcctc agggatggaa gggctctcct gcaatcttcc agagcagcat gaccaagatc 1980
ctggaaccct tccggaagca gaaccctgac atcgtgatct accagtacat ggcagccctg 2040
tacgtcggca gcgacctgga aatcggacag caccggacca agatcgaaga actcaggcag 2100
cacctgctgc ggtggggatt caccacccct gacaagaagc accagaaaga gcctcccttc 2160
ctgtggatgg gctacgagct gcacccagac aagtggaccg tgcagcccat cgtgctgcct 2220
gagaaggact cctggaccgt gaacgacatc cagaaactgg tcggcaagct gaactgggcc 2280
agccagatct acgctggcat caaagtgaag cagctgtgta agctcctgag aggcaccaaa 2340
gccctgaccg aggtggtgcc actgacagag gaagccgagc tggaactggc cgagaacaga 2400
gagatcctga aagaacccgt gcacggagtg tactacgacc ccagcaagga cctgattgcc 2460
gagatccaga agcagggaca gggacagtgg acctaccaga tctaccagga acccttcaag 2520
aacctgaaaa caggcaagta cgccaggatg aggggagccc acaccaacga cgtcaaacag 2580
ctgaccgaag ccgtgcagaa gatcgccacc gagagcatcg tgatttgggg aaagacaccc 2640
aagttcaagc tgcccatcca gaaagagaca tgggaggcct ggtggaccga gtactggcag 2700
gccacctgga ttcccgagtg ggagttcgtg aacaccccac ccctggtgaa gctgtggtat 2760
cagctggaaa aagaacccat cgtgggagcc gagacattct acgtggctgg agctgccaac 2820
agagagacaa agctgggcaa ggctggctac gtgaccgaca gaggcaggca gaaagtggtg 2880
tccctgaccg ataccaccaa ccagaaaaca gccctgcagg ccatccacct ggctctgcag 2940
gactctggcc tggaagtgaa catcgtgaca gccagccagt atgccctggg catcattcag 3000
gcacagcctg acaagagcga gagcgagctg gtgtctcaga tcattgagca gctgatcaag 3060
aaagaaaagg tgtacctggc ctgggtgcca gcccacaagg ggatcggagg gaacgagcag 3120
gtggacaagc tggtgtccag gggcatccgg aaggtgctgt ttctggacgg catcgacaaa 3180
gcccaggaag agcacgagaa gtaccacagc aattggagag ccatggccag cgagttcaac 3240
ctgcctccca tcgtggccaa agaaatcgtg gcctcttgcg acaagtgcca gctgaaaggc 3300
gaggccattc acggacaggt ggactgcagc ccaggcatct ggcagctggc ctgcacccac 3360
ctggaaggca aggtgatcct ggtggccgtg cacgtggcct ctggatacat cgaagccgaa 3420
gtgatccctg ccgagacagg ccaggaaaca gcctacttcc tgctgaagct ggctggcagg 3480
tggcctgtga aaaccatcca cacagccaac ggcagcaact tcacctctgc caccgtgaag 3540
gctgcctgtt ggtgggctgg cattaagcag gaatttggca tcccctacaa ccctcagtct 3600
cagggagtgg tggcctccat caacaaagag ctgaagaaga tcatcggaca ggtcagggat 3660
caggccgagc atctgaaaac agccgtccag atggccgtgt tcatccacaa cttcaagcgg 3720
aagggaggga tcggagagta ctctgctggc gagaggatcg tggacattat cgccagcgat 3780
atccagacca aagaactgca gaagcagatc acaaagatcc agaacttcag ggtgtactac 3840
agggacagca gagatcccct gtggaaggga cctgccaagc tgctgtggaa aggcgaagga 3900
gccgtcgtca tccaggacaa cagcgacatc aaggtggtgc ccagacggaa ggccaagatc 3960
atcagagact acggcaaaca gatggctggc gacgactgcg tcgcctctag gcaggacgag 4020
gac 4023
<210> 22
<211> 2055
<212> DNA
<213> 人工序列
<220>
<223> 编码mos1Env的核苷酸序列
<400> 22
atgcgggtga ccggcatccg gaagaactac cagcacctgt ggcggtgggg caccatgctg 60
ctgggcatcc tgatgatttg ctctgccgcc ggaaagctgt gggtgaccgt gtactacggc 120
gtgcccgtgt ggaaagaggc caccaccacc ctgttctgcg ccagcgacgc caaggcctac 180
gacaccgagg tgcacaacgt gtgggccacc cacgcctgcg tgcccaccga ccccaacccc 240
caggaagtgg tcctggaaaa cgtgaccgag aacttcaaca tgtggaagaa caacatggtg 300
gagcagatgc acgaggacat catcagcctg tgggaccaga gcctgaagcc ctgcgtgaag 360
ctgacccccc tgtgcgtgac cctgaactgc accgacgacg tgcggaacgt gaccaacaac 420
gccaccaaca ccaacagcag ctggggcgag cctatggaaa agggcgagat caagaactgc 480
agcttcaaca tcaccacctc catccggaac aaggtgcaga agcagtacgc cctgttctac 540
aagctggacg tggtgcccat cgacaacgac agcaacaaca ccaactaccg gctgatcagc 600
tgcaacacca gcgtgatcac ccaggcctgc cccaaggtgt ccttcgagcc catccccatc 660
cactactgcg cccctgccgg cttcgccatc ctgaagtgca acgacaagaa gttcaacggc 720
accggcccct gcaccaacgt gagcaccgtg cagtgcaccc acggcatccg gcccgtggtg 780
tccacccagc tgctgctgaa cggcagcctg gccgaggaag aggtggtgat cagaagcgag 840
aatttcacca acaatgccaa gaccatcatg gtgcagctga acgtgagcgt ggagatcaac 900
tgcacccggc ccaacaacaa cacccggaag agcatccaca tcggccctgg cagggccttc 960
tacacagccg gcgacatcat cggcgacatc cggcaggccc actgcaacat cagccgggcc 1020
aactggaaca acaccctgcg gcagatcgtg gagaagctgg gcaagcagtt cggcaacaac 1080
aagaccatcg tgttcaacca cagcagcggc ggagaccccg agatcgtgat gcacagcttc 1140
aactgtggcg gcgagttctt ctactgcaac agcaccaagc tgttcaacag cacctggacc 1200
tggaacaact ccacctggaa taacaccaag cggagcaacg acaccgaaga gcacatcacc 1260
ctgccctgcc ggatcaagca gattatcaat atgtggcagg aggtcggcaa ggccatgtac 1320
gcccctccca tccggggcca gatccggtgc agcagcaaca tcaccggcct gctgctgacc 1380
cgggacggcg gcaacgatac cagcggcacc gagatcttcc ggcctggcgg cggagatatg 1440
cgggacaact ggcggagcga gctgtacaag tacaaggtgg tgaagatcga gcccctgggc 1500
gtggctccca ccaaggccaa gcggcgggtg gtgcagagcg agaagagcgc cgtgggcatc 1560
ggcgccgtgt ttctgggctt cctgggagcc gccggaagca ccatgggagc cgccagcatg 1620
accctgaccg tgcaggcccg gctgctgctg tccggcatcg tgcagcagca gaacaacctg 1680
ctccgggcca tcgaggccca gcagcacctg ctgcagctga ccgtgtgggg catcaagcag 1740
ctgcaggcca gggtgctggc cgtggagaga tacctgaagg atcagcagct cctggggatc 1800
tggggctgca gcggcaagct gatctgcacc accaccgtgc cctggaacgc cagctggtcc 1860
aacaagagcc tggacaagat ctggaacaat atgacctgga tggaatggga gcgcgagatc 1920
aacaattaca ccagcctgat ctacaccctg atcgaggaaa gccagaacca gcaggaaaag 1980
aacgagcagg aactgctgga actggacaag tgggccagcc tgtggaactg gttcgacatc 2040
agcaactggc tgtgg 2055
<210> 23
<211> 2052
<212> DNA
<213> 人工序列
<220>
<223> 编码mos2Env的核苷酸序列
<400> 23
atgagagtgc ggggcatcca gcggaactgg ccccagtggt ggatctgggg catcctgggc 60
ttttggatga tcatcatctg ccgggtgatg ggcaacctgt gggtgaccgt gtactacggc 120
gtgcccgtgt ggaaagaggc caagaccacc ctgttctgcg ccagcgacgc caaggcctac 180
gagaaagagg tgcacaacgt gtgggccacc cacgcctgcg tgcccaccga ccccaacccc 240
caggaaatgg tcctggaaaa cgtgaccgag aacttcaaca tgtggaagaa cgacatggtg 300
gaccagatgc acgaggacat catccggctg tgggaccaga gcctgaagcc ctgcgtgaag 360
ctgacccccc tgtgcgtgac cctggaatgc cggaacgtga gaaacgtgag cagcaacggc 420
acctacaaca tcatccacaa cgagacctac aaagagatga agaactgcag cttcaacgcc 480
accaccgtgg tggaggaccg gaagcagaag gtgcacgccc tgttctaccg gctggacatc 540
gtgcccctgg acgagaacaa cagcagcgag aagtccagcg agaacagctc cgagtactac 600
cggctgatca actgcaacac cagcgccatc acccaggcct gccccaaggt gtccttcgac 660
cccatcccca tccactactg cgcccctgcc ggctacgcca tcctgaagtg caacaacaag 720
accttcaacg gcaccggccc ctgcaacaac gtgagcaccg tgcagtgcac ccacggcatc 780
aagcccgtgg tgtccaccca gctgctgctg aacggcagcc tggccgagga agagatcatc 840
atccggtccg agaacctgac caacaacgcc aagaccatca tcgtgcacct gaatgagacc 900
gtgaacatca cctgcacccg gcccaacaac aacacccgga agagcatccg gatcggccct 960
ggccagacct tttacgccac cggcgacatc atcggcgaca tccggcaggc ccactgcaac 1020
ctgagccggg acggctggaa caagaccctg cagggcgtga agaagaagct ggccgagcac 1080
ttccccaata agaccatcaa cttcaccagc agcagcggcg gagacctgga aatcaccacc 1140
cacagcttca actgcagggg cgagttcttc tactgcaata cctccggcct gttcaatggc 1200
acctacatgc ccaacggcac caacagcaac agcagcagca acatcaccct gccctgccgg 1260
atcaagcaga tcatcaatat gtggcaggag gtcggcaggg ccatgtacgc ccctcccatc 1320
gccggcaata tcacctgccg gtccaacatc accggcctgc tgctgaccag ggacggcggc 1380
agcaacaacg gcgtgcctaa cgacaccgag accttccggc ctggcggcgg agatatgcgg 1440
aacaactggc ggagcgagct gtacaagtac aaggtggtgg aggtgaagcc cctgggcgtg 1500
gctcctaccg aggccaagcg gcgggtggtg gagagcgaga agagcgccgt gggcatcggc 1560
gccgtgtttc tgggcattct gggagccgcc ggaagcacca tgggagccgc cagcatcacc 1620
ctgaccgtgc aggcccggca gctgctgtcc ggcatcgtgc agcagcagag caacctgctg 1680
agagccatcg aggcccagca gcacatgctg cagctgaccg tgtggggcat caagcagctg 1740
cagacccggg tgctggccat cgagagatac ctgcaggatc agcagctcct gggcctgtgg 1800
ggctgcagcg gcaagctgat ctgcaccacc gccgtgccct ggaacaccag ctggtccaac 1860
aagagccaga ccgacatctg ggacaacatg acctggatgc agtgggacaa agagatcggc 1920
aactacaccg gcgagatcta caggctgctg gaagagagcc agaaccagca ggaaaagaac 1980
gagaaggacc tgctggccct ggacagctgg aagaacctgt ggaactggtt cgacatcacc 2040
aactggctgt gg 2052
<210> 24
<211> 829
<212> DNA
<213> 人工序列
<220>
<223> 用于表达Ad26载体中的抗原的CMV启动子
<400> 24
tcaatattgg ccattagcca tattattcat tggttatata gcataaatca atattggcta 60
ttggccattg catacgttgt atccatatca taatatgtac atttatattg gctcatgtcc 120
aacattaccg ccatgttgac attgattatt gactagttat taatagtaat caattacggg 180
gtcattagtt catagcccat atatggagtt ccgcgttaca taacttacgg taaatggccc 240
gcctggctga ccgcccaacg acccccgccc attgacgtca ataatgacgt atgttcccat 300
agtaacgcca atagggactt tccattgacg tcaatgggtg gagtatttac ggtaaactgc 360
ccacttggca gtacatcaag tgtatcatat gccaagtacg ccccctattg acgtcaatga 420
cggtaaatgg cccgcctggc attatgccca gtacatgacc ttatgggact ttcctacttg 480
gcagtacatc tacgtattag tcatcgctat taccatggtg atgcggtttt ggcagtacat 540
caatgggcgt ggatagcggt ttgactcacg gggatttcca agtctccacc ccattgacgt 600
caatgggagt ttgttttggc accaaaatca acgggacttt ccaaaatgtc gtaacaactc 660
cgccccattg acgcaaatgg gcggtaggcg tgtacggtgg gaggtctata taagcagagc 720
tcgtttagtg aaccgtcaga tcgcctggag acgccatcca cgctgttttg acctccatag 780
aagacaccgg gaccgatcca gcctccgcgg ccgggaacgg tgcattgga 829
<210> 25
<211> 2586
<212> DNA
<213> 人工序列
<220>
<223> 编码C4的核苷酸序列
<400> 25
atgagagtgc ggggcatgct gagaaactgg cagcagtggt ggatctggtc cagcctgggc 60
ttctggatgc tgatgatcta cagcgtgatg ggcaacctgt gggtcaccgt gtactacggc 120
gtgcccgtgt ggaaggacgc caagaccacc ctgttttgcg cctccgatgc caaggcctac 180
gagaaagagg tgcacaacgt ctgggccacc cacgcctgtg tgcccaccga ccccaatccc 240
caggaaatcg tcctgggcaa cgtgaccgag aacttcaaca tgtggaagaa cgacatggtc 300
gatcagatgc acgaggacat catctccctg tgggacgcct ccctggaacc ctgcgtgaag 360
ctgacccctc tgtgcgtgac cctgaactgc cggaacgtgc gcaacgtgtc cagcaacggc 420
acctacaaca tcatccacaa cgagacatac aaagagatga agaactgcag cttcaacgct 480
accaccgtgg tcgaggaccg gaagcagaag gtgcacgccc tgttctaccg gctggacatc 540
gtgcccctgg acgagaacaa cagcagcgag aagtcctccg agaacagctc cgagtactac 600
agactgatca actgcaacac cagcgccatc acccaggcct gccccaaggt gtccttcgac 660
cctatcccca tccactactg cgcccctgcc ggctacgcca tcctgaagtg caacaacaag 720
accttcaatg gcaccggccc ctgcaacaat gtgtccaccg tgcagtgcac ccacggcatc 780
aagcccgtgg tgtctaccca gctgctgctg aacggcagcc tggccgagga agagatcatt 840
atcagaagcg agaacctgac caacaacgcc aaaaccatca tcgtccacct gaacgaaacc 900
gtgaacatca cctgtacccg gcctaacaac aacacccgga agtccatccg gatcggccct 960
ggccagacct tttacgccac cggcgatatt atcggcgaca tccggcaggc ccactgcaat 1020
ctgagccggg acggctggaa caagacactg cagggcgtca agaagaagct ggccgaacac 1080
ttccctaaca agactatcaa gttcgcccct cactctggcg gcgacctgga aatcaccacc 1140
cacaccttca actgtcgggg cgagttcttc tactgcaata cctccaacct gttcaacgag 1200
agcaacatcg agcggaacga cagcatcatc acactgcctt gccggatcaa gcagattatc 1260
aatatgtggc aggaagtggg cagagccatc tacgcccctc caatcgccgg caacatcaca 1320
tgccggtcca atatcaccgg cctgctgctc accagagatg gcggctccaa caatggcgtg 1380
ccaaacgaca ccgagacatt cagacccggc ggaggcgaca tgcggaacaa ttggcggagc 1440
gagctgtaca agtacaaggt ggtggaagtg aagcccctgg gcgtggcccc taccgaggcc 1500
aagagaagag tggtcgaacg cgagaagcgg gccgtgggaa tcggagccgt gtttctggga 1560
atcctgggag ccgctggctc taccatgggc gctgcctcta tcaccctgac agtgcaggcc 1620
agacagctgc tcagcggcat cgtgcagcag cagagcaacc tgctgagagc cattgaggcc 1680
cagcagcaca tgctgcagct gaccgtgtgg ggcattaagc agctccagac acgggtgctg 1740
gccatcgaga gatacctgca ggatcagcag ctcctgggcc tgtggggctg tagcggcaag 1800
ctgatctgta ccaccgccgt gccctggaat acctcttgga gcaacaagag ccagaccgac 1860
atctgggaca acatgacctg gatgcagtgg gacaaagaaa tcggcaacta taccggcgag 1920
atctatagac tgctggaaga gtcccagaac cagcaggaaa agaacgagaa ggacctgctg 1980
gccctggatt cttggaacaa tctgtggaac tggttcagca tctccaagtg gctgtggtac 2040
atcaagatct tcatcatgat cgtgggcggc ctgatcggcc tgcggatcat ctttgccgtg 2100
ctgagcatcg tgaaccgcgt gcggcaggga tacagccctc tgagcctgca gaccctgact 2160
cagaaccctg gcggactgga cagactgggc cggattgagg aagaaggcgg cgagcaggac 2220
aaggatcgga gcatcaggct ggtcaacggc ttcttcgctc tgttttggga cgacctgcgg 2280
agcctgtgcc tgttcagcta ccacagactg cgggacttta tcctgattgt ggccagagcc 2340
gtcgaactgc tggggagaag ctctctgaga ggcctgcagc ggggctggga gattctgaag 2400
tacctgggct ccctgctgca gtactggggc ctggaactga agaagtctgc catcaatctg 2460
ctcgacacaa tcgctattgc cgtggccgaa ggcaccgata gaatcatcga gctgatccag 2520
cggatctgcc gggccatctg caacatcccc agacggatca gacagggctt cgaggccgct 2580
ctgcag 2586
<210> 26
<211> 2133
<212> DNA
<213> 人工序列
<220>
<223> 编码C4D7的核苷酸序列
<400> 26
atgagagtgc ggggcatgct gagaaactgg cagcagtggt ggatctggtc cagcctgggc 60
ttctggatgc tgatgatcta cagcgtgatg ggcaacctgt gggtcaccgt gtactacggc 120
gtgcccgtgt ggaaggacgc caagaccacc ctgttttgcg cctccgatgc caaggcctac 180
gagaaagagg tgcacaacgt ctgggccacc cacgcctgtg tgcccaccga ccccaatccc 240
caggaaatcg tcctgggcaa cgtgaccgag aacttcaaca tgtggaagaa cgacatggtc 300
gatcagatgc acgaggacat catctccctg tgggacgcct ccctggaacc ctgcgtgaag 360
ctgacccctc tgtgcgtgac cctgaactgc cggaacgtgc gcaacgtgtc cagcaacggc 420
acctacaaca tcatccacaa cgagacatac aaagagatga agaactgcag cttcaacgct 480
accaccgtgg tcgaggaccg gaagcagaag gtgcacgccc tgttctaccg gctggacatc 540
gtgcccctgg acgagaacaa cagcagcgag aagtcctccg agaacagctc cgagtactac 600
agactgatca actgcaacac cagcgccatc acccaggcct gccccaaggt gtccttcgac 660
cctatcccca tccactactg cgcccctgcc ggctacgcca tcctgaagtg caacaacaag 720
accttcaatg gcaccggccc ctgcaacaat gtgtccaccg tgcagtgcac ccacggcatc 780
aagcccgtgg tgtctaccca gctgctgctg aacggcagcc tggccgagga agagatcatt 840
atcagaagcg agaacctgac caacaacgcc aaaaccatca tcgtccacct gaacgaaacc 900
gtgaacatca cctgtacccg gcctaacaac aacacccgga agtccatccg gatcggccct 960
ggccagacct tttacgccac cggcgatatt atcggcgaca tccggcaggc ccactgcaat 1020
ctgagccggg acggctggaa caagacactg cagggcgtca agaagaagct ggccgaacac 1080
ttccctaaca agactatcaa gttcgcccct cactctggcg gcgacctgga aatcaccacc 1140
cacaccttca actgtcgggg cgagttcttc tactgcaata cctccaacct gttcaacgag 1200
agcaacatcg agcggaacga cagcatcatc acactgcctt gccggatcaa gcagattatc 1260
aatatgtggc aggaagtggg cagagccatc tacgcccctc caatcgccgg caacatcaca 1320
tgccggtcca atatcaccgg cctgctgctc accagagatg gcggctccaa caatggcgtg 1380
ccaaacgaca ccgagacatt cagacccggc ggaggcgaca tgcggaacaa ttggcggagc 1440
gagctgtaca agtacaaggt ggtggaagtg aagcccctgg gcgtggcccc taccgaggcc 1500
aagagaagag tggtcgaacg cgagaagcgg gccgtgggaa tcggagccgt gtttctggga 1560
atcctgggag ccgctggctc taccatgggc gctgcctcta tcaccctgac agtgcaggcc 1620
agacagctgc tcagcggcat cgtgcagcag cagagcaacc tgctgagagc cattgaggcc 1680
cagcagcaca tgctgcagct gaccgtgtgg ggcattaagc agctccagac acgggtgctg 1740
gccatcgaga gatacctgca ggatcagcag ctcctgggcc tgtggggctg tagcggcaag 1800
ctgatctgta ccaccgccgt gccctggaat acctcttgga gcaacaagag ccagaccgac 1860
atctgggaca acatgacctg gatgcagtgg gacaaagaaa tcggcaacta taccggcgag 1920
atctatagac tgctggaaga gtcccagaac cagcaggaaa agaacgagaa ggacctgctg 1980
gccctggatt cttggaacaa tctgtggaac tggttcagca tctccaagtg gctgtggtac 2040
atcaagatct tcatcatgat cgtgggcggc ctgatcggcc tgcggatcat ctttgccgtg 2100
ctgagcatcg tgaaccgcgt gcggcagggc tac 2133
<210> 27
<211> 2112
<212> DNA
<213> 人工序列
<220>
<223> 编码sC4的核苷酸序列
<400> 27
atgagagtgc ggggcatgct gagaaactgg cagcagtggt ggatctggtc cagcctgggc 60
ttctggatgc tgatgatcta cagcgtgatg ggcaacctgt gggtcaccgt gtactacggc 120
gtgcccgtgt ggaaggacgc caagaccacc ctgttttgcg cctccgatgc caaggcctac 180
gagaaagagg tgcacaacgt ctgggccacc cacgcctgtg tgcccaccga ccccaatccc 240
caggaaatcg tcctgggcaa cgtgaccgag aacttcaaca tgtggaagaa cgacatggtc 300
gatcagatgc acgaggacat catctccctg tgggacgcct ccctggaacc ctgcgtgaag 360
ctgacccctc tgtgcgtgac cctgaactgc cggaacgtgc gcaacgtgtc cagcaacggc 420
acctacaaca tcatccacaa cgagacatac aaagagatga agaactgcag cttcaacgct 480
accaccgtgg tcgaggaccg gaagcagaag gtgcacgccc tgttctaccg gctggacatc 540
gtgcccctgg acgagaacaa cagcagcgag aagtcctccg agaacagctc cgagtactac 600
agactgatca actgcaacac cagcgccatc acccaggcct gccccaaggt gtccttcgac 660
cctatcccca tccactactg cgcccctgcc ggctacgcca tcctgaagtg caacaacaag 720
accttcaatg gcaccggccc ctgcaacaat gtgtccaccg tgcagtgcac ccacggcatc 780
aagcccgtgg tgtctaccca gctgctgctg aacggcagcc tggccgagga agagatcatt 840
atcagaagcg agaacctgac caacaacgcc aaaaccatca tcgtccacct gaacgaaacc 900
gtgaacatca cctgtacccg gcctaacaac aacacccgga agtccatccg gatcggccct 960
ggccagacct tttacgccac cggcgatatt atcggcgaca tccggcaggc ccactgcaat 1020
ctgagccggg acggctggaa caagacactg cagggcgtca agaagaagct ggccgaacac 1080
ttccctaaca agactatcaa gttcgcccct cactctggcg gcgacctgga aatcaccacc 1140
cacaccttca actgtcgggg cgagttcttc tactgcaata cctccaacct gttcaacgag 1200
agcaacatcg agcggaacga cagcatcatc acactgcctt gccggatcaa gcagattatc 1260
aatatgtggc aggaagtggg cagagccatc tacgcccctc caatcgccgg caacatcaca 1320
tgccggtcca atatcaccgg cctgctgctc accagagatg gcggctccaa caatggcgtg 1380
ccaaacgaca ccgagacatt cagacccggc ggaggcgaca tgcggaacaa ttggcggagc 1440
gagctgtaca agtacaaggt ggtggaagtg aagcccctgg gcgtggcccc taccgaggcc 1500
aagagaagag tggtcgaacg cgaggaacgg gccgtgggaa tcggagccgt gtttctggga 1560
atcctgggag ccgctggctc taccatgggc gctgcctcta tcaccctgac agtgcaggcc 1620
agacagctgc tcagcggcat cgtgcagcag cagagcaacc tgctgagagc cattgaggcc 1680
cagcagcaca tgctgcagct gaccgtgtgg ggcattaagc agctccagac acgggtgctg 1740
gccatcgaga gatacctgca ggatcagcag ctcctgggcc tgtggggctg tagcggcaag 1800
ctgatctgta ccaccgccgt gccctggaat acctcttgga gcaacaagag ccagaccgac 1860
atctgggaca acatgacctg gatgcagtgg gacaaagaaa tcggcaacta taccggcgag 1920
atctatagac tgctggaaga gtcccagaac cagcaggaaa agatgaagca gatcgaggac 1980
aagatcgaag agattctgag caagatctac cacatcgaga acgagatcgc ccgcatcaag 2040
aaactgatcg gcgaagtggg atccggcgct cccacaaagg ccaaaagacg ggtggtgcag 2100
cgcgagaaac gc 2112
<210> 28
<211> 1350
<212> PRT
<213> 人工序列
<220>
<223> mos1GagPol 嵌合抗原序列
<400> 28
Met Gly Ala Arg Ala Ser Val Leu Ser Gly Gly Glu Leu Asp Arg Trp
1 5 10 15
Glu Lys Ile Arg Leu Arg Pro Gly Gly Lys Lys Lys Tyr Arg Leu Lys
20 25 30
His Ile Val Trp Ala Ser Arg Glu Leu Glu Arg Phe Ala Val Asn Pro
35 40 45
Gly Leu Leu Glu Thr Ser Glu Gly Cys Arg Gln Ile Leu Gly Gln Leu
50 55 60
Gln Pro Ser Leu Gln Thr Gly Ser Glu Glu Leu Arg Ser Leu Tyr Asn
65 70 75 80
Thr Val Ala Thr Leu Tyr Cys Val His Gln Arg Ile Glu Ile Lys Asp
85 90 95
Thr Lys Glu Ala Leu Glu Lys Ile Glu Glu Glu Gln Asn Lys Ser Lys
100 105 110
Lys Lys Ala Gln Gln Ala Ala Ala Asp Thr Gly Asn Ser Ser Gln Val
115 120 125
Ser Gln Asn Tyr Pro Ile Val Gln Asn Ile Gln Gly Gln Met Val His
130 135 140
Gln Ala Ile Ser Pro Arg Thr Leu Asn Ala Trp Val Lys Val Val Glu
145 150 155 160
Glu Lys Ala Phe Ser Pro Glu Val Ile Pro Met Phe Ser Ala Leu Ser
165 170 175
Glu Gly Ala Thr Pro Gln Asp Leu Asn Thr Met Leu Asn Thr Val Gly
180 185 190
Gly His Gln Ala Ala Met Gln Met Leu Lys Glu Thr Ile Asn Glu Glu
195 200 205
Ala Ala Glu Trp Asp Arg Val His Pro Val His Ala Gly Pro Ile Ala
210 215 220
Pro Gly Gln Met Arg Glu Pro Arg Gly Ser Asp Ile Ala Gly Thr Thr
225 230 235 240
Ser Thr Leu Gln Glu Gln Ile Gly Trp Met Thr Asn Asn Pro Pro Ile
245 250 255
Pro Val Gly Glu Ile Tyr Lys Arg Trp Ile Ile Leu Gly Leu Asn Lys
260 265 270
Ile Val Arg Met Tyr Ser Pro Val Ser Ile Leu Asp Ile Arg Gln Gly
275 280 285
Pro Lys Glu Pro Phe Arg Asp Tyr Val Asp Arg Phe Tyr Lys Thr Leu
290 295 300
Arg Ala Glu Gln Ala Ser Gln Asp Val Lys Asn Trp Met Thr Glu Thr
305 310 315 320
Leu Leu Val Gln Asn Ala Asn Pro Asp Cys Lys Thr Ile Leu Lys Ala
325 330 335
Leu Gly Pro Ala Ala Thr Leu Glu Glu Met Met Thr Ala Cys Gln Gly
340 345 350
Val Gly Gly Pro Gly His Lys Ala Arg Val Leu Ala Glu Ala Met Ser
355 360 365
Gln Val Thr Asn Ser Ala Thr Ile Met Met Gln Arg Gly Asn Phe Arg
370 375 380
Asn Gln Arg Lys Thr Val Lys Cys Phe Asn Cys Gly Lys Glu Gly His
385 390 395 400
Ile Ala Lys Asn Cys Arg Ala Pro Arg Lys Lys Gly Cys Trp Lys Cys
405 410 415
Gly Lys Glu Gly His Gln Met Lys Asp Cys Thr Glu Arg Gln Ala Asn
420 425 430
Phe Leu Gly Lys Ile Trp Pro Ser Asn Lys Gly Arg Pro Gly Asn Phe
435 440 445
Leu Gln Asn Arg Pro Glu Pro Thr Ala Pro Pro Glu Glu Ser Phe Arg
450 455 460
Phe Gly Glu Glu Thr Thr Thr Pro Ser Gln Lys Gln Glu Pro Ile Asp
465 470 475 480
Lys Glu Met Tyr Pro Leu Ala Ser Leu Lys Ser Leu Phe Gly Asn Asp
485 490 495
Pro Ser Ser Gln Met Ala Pro Ile Ser Pro Ile Glu Thr Val Pro Val
500 505 510
Lys Leu Lys Pro Gly Met Asp Gly Pro Arg Val Lys Gln Trp Pro Leu
515 520 525
Thr Glu Glu Lys Ile Lys Ala Leu Thr Ala Ile Cys Glu Glu Met Glu
530 535 540
Lys Glu Gly Lys Ile Thr Lys Ile Gly Pro Glu Asn Pro Tyr Asn Thr
545 550 555 560
Pro Val Phe Ala Ile Lys Lys Lys Asp Ser Thr Lys Trp Arg Lys Leu
565 570 575
Val Asp Phe Arg Glu Leu Asn Lys Arg Thr Gln Asp Phe Trp Glu Val
580 585 590
Gln Leu Gly Ile Pro His Pro Ala Gly Leu Lys Lys Lys Lys Ser Val
595 600 605
Thr Val Leu Ala Val Gly Asp Ala Tyr Phe Ser Val Pro Leu Asp Glu
610 615 620
Gly Phe Arg Lys Tyr Thr Ala Phe Thr Ile Pro Ser Thr Asn Asn Glu
625 630 635 640
Thr Pro Gly Ile Arg Tyr Gln Tyr Asn Val Leu Pro Gln Gly Trp Lys
645 650 655
Gly Ser Pro Ala Ile Phe Gln Cys Ser Met Thr Arg Ile Leu Glu Pro
660 665 670
Phe Arg Ala Lys Asn Pro Glu Ile Val Ile Tyr Gln Tyr Met Ala Ala
675 680 685
Leu Tyr Val Gly Ser Asp Leu Glu Ile Gly Gln His Arg Ala Lys Ile
690 695 700
Glu Glu Leu Arg Glu His Leu Leu Lys Trp Gly Phe Thr Thr Pro Asp
705 710 715 720
Lys Lys His Gln Lys Glu Pro Pro Phe Leu Trp Met Gly Tyr Glu Leu
725 730 735
His Pro Asp Lys Trp Thr Val Gln Pro Ile Gln Leu Pro Glu Lys Asp
740 745 750
Ser Trp Thr Val Asn Asp Ile Gln Lys Leu Val Gly Lys Leu Asn Trp
755 760 765
Ala Ser Gln Ile Tyr Pro Gly Ile Lys Val Arg Gln Leu Cys Lys Leu
770 775 780
Leu Arg Gly Ala Lys Ala Leu Thr Asp Ile Val Pro Leu Thr Glu Glu
785 790 795 800
Ala Glu Leu Glu Leu Ala Glu Asn Arg Glu Ile Leu Lys Glu Pro Val
805 810 815
His Gly Val Tyr Tyr Asp Pro Ser Lys Asp Leu Ile Ala Glu Ile Gln
820 825 830
Lys Gln Gly His Asp Gln Trp Thr Tyr Gln Ile Tyr Gln Glu Pro Phe
835 840 845
Lys Asn Leu Lys Thr Gly Lys Tyr Ala Lys Met Arg Thr Ala His Thr
850 855 860
Asn Asp Val Lys Gln Leu Thr Glu Ala Val Gln Lys Ile Ala Met Glu
865 870 875 880
Ser Ile Val Ile Trp Gly Lys Thr Pro Lys Phe Arg Leu Pro Ile Gln
885 890 895
Lys Glu Thr Trp Glu Thr Trp Trp Thr Asp Tyr Trp Gln Ala Thr Trp
900 905 910
Ile Pro Glu Trp Glu Phe Val Asn Thr Pro Pro Leu Val Lys Leu Trp
915 920 925
Tyr Gln Leu Glu Lys Asp Pro Ile Ala Gly Val Glu Thr Phe Tyr Val
930 935 940
Ala Gly Ala Ala Asn Arg Glu Thr Lys Leu Gly Lys Ala Gly Tyr Val
945 950 955 960
Thr Asp Arg Gly Arg Gln Lys Ile Val Ser Leu Thr Glu Thr Thr Asn
965 970 975
Gln Lys Thr Ala Leu Gln Ala Ile Tyr Leu Ala Leu Gln Asp Ser Gly
980 985 990
Ser Glu Val Asn Ile Val Thr Ala Ser Gln Tyr Ala Leu Gly Ile Ile
995 1000 1005
Gln Ala Gln Pro Asp Lys Ser Glu Ser Glu Leu Val Asn Gln Ile
1010 1015 1020
Ile Glu Gln Leu Ile Lys Lys Glu Arg Val Tyr Leu Ser Trp Val
1025 1030 1035
Pro Ala His Lys Gly Ile Gly Gly Asn Glu Gln Val Asp Lys Leu
1040 1045 1050
Val Ser Ser Gly Ile Arg Lys Val Leu Phe Leu Asp Gly Ile Asp
1055 1060 1065
Lys Ala Gln Glu Glu His Glu Lys Tyr His Ser Asn Trp Arg Ala
1070 1075 1080
Met Ala Ser Asp Phe Asn Leu Pro Pro Val Val Ala Lys Glu Ile
1085 1090 1095
Val Ala Ser Cys Asp Gln Cys Gln Leu Lys Gly Glu Ala Met His
1100 1105 1110
Gly Gln Val Asp Cys Ser Pro Gly Ile Trp Gln Leu Ala Cys Thr
1115 1120 1125
His Leu Glu Gly Lys Ile Ile Leu Val Ala Val His Val Ala Ser
1130 1135 1140
Gly Tyr Ile Glu Ala Glu Val Ile Pro Ala Glu Thr Gly Gln Glu
1145 1150 1155
Thr Ala Tyr Phe Ile Leu Lys Leu Ala Gly Arg Trp Pro Val Lys
1160 1165 1170
Val Ile His Thr Ala Asn Gly Ser Asn Phe Thr Ser Ala Ala Val
1175 1180 1185
Lys Ala Ala Cys Trp Trp Ala Gly Ile Gln Gln Glu Phe Gly Ile
1190 1195 1200
Pro Tyr Asn Pro Gln Ser Gln Gly Val Val Ala Ser Met Asn Lys
1205 1210 1215
Glu Leu Lys Lys Ile Ile Gly Gln Val Arg Asp Gln Ala Glu His
1220 1225 1230
Leu Lys Thr Ala Val Gln Met Ala Val Phe Ile His Asn Phe Lys
1235 1240 1245
Arg Lys Gly Gly Ile Gly Gly Tyr Ser Ala Gly Glu Arg Ile Ile
1250 1255 1260
Asp Ile Ile Ala Thr Asp Ile Gln Thr Lys Glu Leu Gln Lys Gln
1265 1270 1275
Ile Ile Lys Ile Gln Asn Phe Arg Val Tyr Tyr Arg Asp Ser Arg
1280 1285 1290
Asp Pro Ile Trp Lys Gly Pro Ala Lys Leu Leu Trp Lys Gly Glu
1295 1300 1305
Gly Ala Val Val Ile Gln Asp Asn Ser Asp Ile Lys Val Val Pro
1310 1315 1320
Arg Arg Lys Val Lys Ile Ile Lys Asp Tyr Gly Lys Gln Met Ala
1325 1330 1335
Gly Ala Asp Cys Val Ala Gly Arg Gln Asp Glu Asp
1340 1345 1350
<210> 29
<211> 1341
<212> PRT
<213> 人工序列
<220>
<223> mos2GagPol 嵌合抗原序列
<400> 29
Met Gly Ala Arg Ala Ser Ile Leu Arg Gly Gly Lys Leu Asp Lys Trp
1 5 10 15
Glu Lys Ile Arg Leu Arg Pro Gly Gly Lys Lys His Tyr Met Leu Lys
20 25 30
His Leu Val Trp Ala Ser Arg Glu Leu Glu Arg Phe Ala Leu Asn Pro
35 40 45
Gly Leu Leu Glu Thr Ser Glu Gly Cys Lys Gln Ile Ile Lys Gln Leu
50 55 60
Gln Pro Ala Leu Gln Thr Gly Thr Glu Glu Leu Arg Ser Leu Phe Asn
65 70 75 80
Thr Val Ala Thr Leu Tyr Cys Val His Ala Glu Ile Glu Val Arg Asp
85 90 95
Thr Lys Glu Ala Leu Asp Lys Ile Glu Glu Glu Gln Asn Lys Ser Gln
100 105 110
Gln Lys Thr Gln Gln Ala Lys Glu Ala Asp Gly Lys Val Ser Gln Asn
115 120 125
Tyr Pro Ile Val Gln Asn Leu Gln Gly Gln Met Val His Gln Pro Ile
130 135 140
Ser Pro Arg Thr Leu Asn Ala Trp Val Lys Val Ile Glu Glu Lys Ala
145 150 155 160
Phe Ser Pro Glu Val Ile Pro Met Phe Thr Ala Leu Ser Glu Gly Ala
165 170 175
Thr Pro Gln Asp Leu Asn Thr Met Leu Asn Thr Val Gly Gly His Gln
180 185 190
Ala Ala Met Gln Met Leu Lys Asp Thr Ile Asn Glu Glu Ala Ala Glu
195 200 205
Trp Asp Arg Leu His Pro Val His Ala Gly Pro Val Ala Pro Gly Gln
210 215 220
Met Arg Glu Pro Arg Gly Ser Asp Ile Ala Gly Thr Thr Ser Asn Leu
225 230 235 240
Gln Glu Gln Ile Ala Trp Met Thr Ser Asn Pro Pro Ile Pro Val Gly
245 250 255
Asp Ile Tyr Lys Arg Trp Ile Ile Leu Gly Leu Asn Lys Ile Val Arg
260 265 270
Met Tyr Ser Pro Thr Ser Ile Leu Asp Ile Lys Gln Gly Pro Lys Glu
275 280 285
Pro Phe Arg Asp Tyr Val Asp Arg Phe Phe Lys Thr Leu Arg Ala Glu
290 295 300
Gln Ala Thr Gln Asp Val Lys Asn Trp Met Thr Asp Thr Leu Leu Val
305 310 315 320
Gln Asn Ala Asn Pro Asp Cys Lys Thr Ile Leu Arg Ala Leu Gly Pro
325 330 335
Gly Ala Thr Leu Glu Glu Met Met Thr Ala Cys Gln Gly Val Gly Gly
340 345 350
Pro Ser His Lys Ala Arg Val Leu Ala Glu Ala Met Ser Gln Thr Asn
355 360 365
Ser Thr Ile Leu Met Gln Arg Ser Asn Phe Lys Gly Ser Lys Arg Ile
370 375 380
Val Lys Cys Phe Asn Cys Gly Lys Glu Gly His Ile Ala Arg Asn Cys
385 390 395 400
Arg Ala Pro Arg Lys Lys Gly Cys Trp Lys Cys Gly Lys Glu Gly His
405 410 415
Gln Met Lys Asp Cys Thr Glu Arg Gln Ala Asn Phe Leu Gly Lys Ile
420 425 430
Trp Pro Ser His Lys Gly Arg Pro Gly Asn Phe Leu Gln Ser Arg Pro
435 440 445
Glu Pro Thr Ala Pro Pro Ala Glu Ser Phe Arg Phe Glu Glu Thr Thr
450 455 460
Pro Ala Pro Lys Gln Glu Pro Lys Asp Arg Glu Pro Leu Thr Ser Leu
465 470 475 480
Arg Ser Leu Phe Gly Ser Asp Pro Leu Ser Gln Met Ala Pro Ile Ser
485 490 495
Pro Ile Glu Thr Val Pro Val Lys Leu Lys Pro Gly Met Asp Gly Pro
500 505 510
Lys Val Lys Gln Trp Pro Leu Thr Glu Glu Lys Ile Lys Ala Leu Val
515 520 525
Glu Ile Cys Thr Glu Met Glu Lys Glu Gly Lys Ile Ser Lys Ile Gly
530 535 540
Pro Glu Asn Pro Tyr Asn Thr Pro Ile Phe Ala Ile Lys Lys Lys Asp
545 550 555 560
Ser Thr Lys Trp Arg Lys Leu Val Asp Phe Arg Glu Leu Asn Lys Arg
565 570 575
Thr Gln Asp Phe Trp Glu Val Gln Leu Gly Ile Pro His Pro Ala Gly
580 585 590
Leu Lys Lys Lys Lys Ser Val Thr Val Leu Ala Val Gly Asp Ala Tyr
595 600 605
Phe Ser Val Pro Leu Asp Glu Asp Phe Arg Lys Tyr Thr Ala Phe Thr
610 615 620
Ile Pro Ser Ile Asn Asn Glu Thr Pro Gly Ile Arg Tyr Gln Tyr Asn
625 630 635 640
Val Leu Pro Gln Gly Trp Lys Gly Ser Pro Ala Ile Phe Gln Ser Ser
645 650 655
Met Thr Lys Ile Leu Glu Pro Phe Arg Lys Gln Asn Pro Asp Ile Val
660 665 670
Ile Tyr Gln Tyr Met Ala Ala Leu Tyr Val Gly Ser Asp Leu Glu Ile
675 680 685
Gly Gln His Arg Thr Lys Ile Glu Glu Leu Arg Gln His Leu Leu Arg
690 695 700
Trp Gly Phe Thr Thr Pro Asp Lys Lys His Gln Lys Glu Pro Pro Phe
705 710 715 720
Leu Trp Met Gly Tyr Glu Leu His Pro Asp Lys Trp Thr Val Gln Pro
725 730 735
Ile Val Leu Pro Glu Lys Asp Ser Trp Thr Val Asn Asp Ile Gln Lys
740 745 750
Leu Val Gly Lys Leu Asn Trp Ala Ser Gln Ile Tyr Ala Gly Ile Lys
755 760 765
Val Lys Gln Leu Cys Lys Leu Leu Arg Gly Thr Lys Ala Leu Thr Glu
770 775 780
Val Val Pro Leu Thr Glu Glu Ala Glu Leu Glu Leu Ala Glu Asn Arg
785 790 795 800
Glu Ile Leu Lys Glu Pro Val His Gly Val Tyr Tyr Asp Pro Ser Lys
805 810 815
Asp Leu Ile Ala Glu Ile Gln Lys Gln Gly Gln Gly Gln Trp Thr Tyr
820 825 830
Gln Ile Tyr Gln Glu Pro Phe Lys Asn Leu Lys Thr Gly Lys Tyr Ala
835 840 845
Arg Met Arg Gly Ala His Thr Asn Asp Val Lys Gln Leu Thr Glu Ala
850 855 860
Val Gln Lys Ile Ala Thr Glu Ser Ile Val Ile Trp Gly Lys Thr Pro
865 870 875 880
Lys Phe Lys Leu Pro Ile Gln Lys Glu Thr Trp Glu Ala Trp Trp Thr
885 890 895
Glu Tyr Trp Gln Ala Thr Trp Ile Pro Glu Trp Glu Phe Val Asn Thr
900 905 910
Pro Pro Leu Val Lys Leu Trp Tyr Gln Leu Glu Lys Glu Pro Ile Val
915 920 925
Gly Ala Glu Thr Phe Tyr Val Ala Gly Ala Ala Asn Arg Glu Thr Lys
930 935 940
Leu Gly Lys Ala Gly Tyr Val Thr Asp Arg Gly Arg Gln Lys Val Val
945 950 955 960
Ser Leu Thr Asp Thr Thr Asn Gln Lys Thr Ala Leu Gln Ala Ile His
965 970 975
Leu Ala Leu Gln Asp Ser Gly Leu Glu Val Asn Ile Val Thr Ala Ser
980 985 990
Gln Tyr Ala Leu Gly Ile Ile Gln Ala Gln Pro Asp Lys Ser Glu Ser
995 1000 1005
Glu Leu Val Ser Gln Ile Ile Glu Gln Leu Ile Lys Lys Glu Lys
1010 1015 1020
Val Tyr Leu Ala Trp Val Pro Ala His Lys Gly Ile Gly Gly Asn
1025 1030 1035
Glu Gln Val Asp Lys Leu Val Ser Arg Gly Ile Arg Lys Val Leu
1040 1045 1050
Phe Leu Asp Gly Ile Asp Lys Ala Gln Glu Glu His Glu Lys Tyr
1055 1060 1065
His Ser Asn Trp Arg Ala Met Ala Ser Glu Phe Asn Leu Pro Pro
1070 1075 1080
Ile Val Ala Lys Glu Ile Val Ala Ser Cys Asp Lys Cys Gln Leu
1085 1090 1095
Lys Gly Glu Ala Ile His Gly Gln Val Asp Cys Ser Pro Gly Ile
1100 1105 1110
Trp Gln Leu Ala Cys Thr His Leu Glu Gly Lys Val Ile Leu Val
1115 1120 1125
Ala Val His Val Ala Ser Gly Tyr Ile Glu Ala Glu Val Ile Pro
1130 1135 1140
Ala Glu Thr Gly Gln Glu Thr Ala Tyr Phe Leu Leu Lys Leu Ala
1145 1150 1155
Gly Arg Trp Pro Val Lys Thr Ile His Thr Ala Asn Gly Ser Asn
1160 1165 1170
Phe Thr Ser Ala Thr Val Lys Ala Ala Cys Trp Trp Ala Gly Ile
1175 1180 1185
Lys Gln Glu Phe Gly Ile Pro Tyr Asn Pro Gln Ser Gln Gly Val
1190 1195 1200
Val Ala Ser Ile Asn Lys Glu Leu Lys Lys Ile Ile Gly Gln Val
1205 1210 1215
Arg Asp Gln Ala Glu His Leu Lys Thr Ala Val Gln Met Ala Val
1220 1225 1230
Phe Ile His Asn Phe Lys Arg Lys Gly Gly Ile Gly Glu Tyr Ser
1235 1240 1245
Ala Gly Glu Arg Ile Val Asp Ile Ile Ala Ser Asp Ile Gln Thr
1250 1255 1260
Lys Glu Leu Gln Lys Gln Ile Thr Lys Ile Gln Asn Phe Arg Val
1265 1270 1275
Tyr Tyr Arg Asp Ser Arg Asp Pro Leu Trp Lys Gly Pro Ala Lys
1280 1285 1290
Leu Leu Trp Lys Gly Glu Gly Ala Val Val Ile Gln Asp Asn Ser
1295 1300 1305
Asp Ile Lys Val Val Pro Arg Arg Lys Ala Lys Ile Ile Arg Asp
1310 1315 1320
Tyr Gly Lys Gln Met Ala Gly Asp Asp Cys Val Ala Ser Arg Gln
1325 1330 1335
Asp Glu Asp
1340
<210> 30
<211> 709
<212> PRT
<213> 人工序列
<220>
<223> sC1 序列
<400> 30
Met Arg Val Arg Gly Ile Gln Arg Asn Trp Pro Gln Trp Trp Ile Trp
1 5 10 15
Gly Ile Leu Gly Phe Trp Met Ile Ile Ile Cys Arg Val Met Gly Asn
20 25 30
Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys Glu Ala Lys
35 40 45
Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Glu Lys 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 Met Val Leu Glu Asn Val Thr Glu Asn Phe Asn Met Trp Lys
85 90 95
Asn Asp Met Val Asp Gln Met His Glu Asp Ile Ile Arg Leu Trp Asp
100 105 110
Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
115 120 125
Glu Cys Arg Asn Val Arg Asn Val Ser Ser Asn Gly Thr Tyr Asn Ile
130 135 140
Ile His Asn Glu Thr Tyr Lys Glu Met Lys Asn Cys Ser Phe Asn Ala
145 150 155 160
Thr Thr Val Val Glu Asp Arg Lys Gln Lys Val His Ala Leu Phe Tyr
165 170 175
Arg Leu Asp Ile Val Pro Leu Asp Glu Asn Asn Ser Ser Glu Lys Ser
180 185 190
Ser Glu Asn Ser Ser Glu Tyr Tyr Arg Leu Ile Asn Cys Asn Thr Ser
195 200 205
Ala Ile Thr Gln Ala Cys Pro Lys Val Ser Phe Asp Pro Ile Pro Ile
210 215 220
His Tyr Cys Ala Pro Ala Gly Tyr Ala Ile Leu Lys Cys Asn Asn Lys
225 230 235 240
Thr Phe Asn Gly Thr Gly Pro Cys Asn Asn Val Ser Thr Val Gln Cys
245 250 255
Thr His Gly Ile Lys Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly
260 265 270
Ser Leu Ala Glu Glu Glu Ile Ile Ile Arg Ser Glu Asn Leu Thr Asn
275 280 285
Asn Ala Lys Thr Ile Ile Val His Leu Asn Glu Thr Val Asn Ile Thr
290 295 300
Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys Ser Ile Arg Ile Gly Pro
305 310 315 320
Gly Gln Thr Phe Tyr Ala Thr Gly Asp Ile Ile Gly Asp Ile Arg Gln
325 330 335
Ala His Cys Asn Leu Ser Arg Asp Gly Trp Asn Lys Thr Leu Gln Gly
340 345 350
Val Lys Lys Lys Leu Ala Glu His Phe Pro Asn Lys Thr Ile Asn Phe
355 360 365
Thr Ser Ser Ser Gly Gly Asp Leu Glu Ile Thr Thr His Ser Phe Asn
370 375 380
Cys Arg Gly Glu Phe Phe Tyr Cys Asn Thr Ser Gly Leu Phe Asn Gly
385 390 395 400
Thr Tyr Met Pro Asn Gly Thr Asn Ser Asn Ser Ser Ser Asn Ile Thr
405 410 415
Leu Pro Cys Arg Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly
420 425 430
Arg Ala Met Tyr Ala Pro Pro Ile Ala Gly Asn Ile Thr Cys Arg Ser
435 440 445
Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly Ser Asn Asn Gly
450 455 460
Val Pro Asn Asp Thr Glu Thr Phe Arg Pro Gly Gly Gly Asp Met Arg
465 470 475 480
Asn Asn Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Glu Val Lys
485 490 495
Pro Leu Gly Val Ala Pro Thr Glu Ala Lys Arg Arg Val Val Glu Arg
500 505 510
Glu Glu Arg Ala Val Gly Ile Gly Ala Val Phe Leu Gly Ile Leu Gly
515 520 525
Ala Ala Gly Ser Thr Met Gly Ala Ala Ser Ile Thr Leu Thr Val Gln
530 535 540
Ala Arg Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Ser Asn Leu Leu
545 550 555 560
Arg Ala Ile Glu Ala Gln Gln His Met Leu Gln Leu Thr Val Trp Gly
565 570 575
Ile Lys Gln Leu Gln Thr Arg Val Leu Ala Ile Glu Arg Tyr Leu Gln
580 585 590
Asp Gln Gln Leu Leu Gly Leu Trp Gly Cys Ser Gly Lys Leu Ile Cys
595 600 605
Thr Thr Ala Val Pro Trp Asn Thr Ser Trp Ser Asn Lys Ser Gln Thr
610 615 620
Asp Ile Trp Asp Asn Met Thr Trp Met Gln Trp Asp Lys Glu Ile Gly
625 630 635 640
Asn Tyr Thr Gly Glu Ile Tyr Arg Leu Leu Glu Glu Ser Gln Asn Gln
645 650 655
Gln Glu Lys Met Lys Gln Ile Glu Asp Lys Ile Glu Glu Ile Leu Ser
660 665 670
Lys Ile Tyr His Ile Glu Asn Glu Ile Ala Arg Ile Lys Lys Leu Ile
675 680 685
Gly Glu Val Gly Ser Gly Ala Pro Thr Lys Ala Lys Arg Arg Val Val
690 695 700
Gln Arg Glu Lys Arg
705
<210> 31
<211> 867
<212> PRT
<213> 人工序列
<220>
<223> C1 序列
<400> 31
Met Arg Val Arg Gly Ile Gln Arg Asn Trp Pro Gln Trp Trp Ile Trp
1 5 10 15
Gly Ile Leu Gly Phe Trp Met Ile Ile Ile Cys Arg Val Met Gly Asn
20 25 30
Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys Glu Ala Lys
35 40 45
Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Glu Lys 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 Met Val Leu Glu Asn Val Thr Glu Asn Phe Asn Met Trp Lys
85 90 95
Asn Asp Met Val Asp Gln Met His Glu Asp Ile Ile Arg Leu Trp Asp
100 105 110
Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
115 120 125
Glu Cys Arg Asn Val Arg Asn Val Ser Ser Asn Gly Thr Tyr Asn Ile
130 135 140
Ile His Asn Glu Thr Tyr Lys Glu Met Lys Asn Cys Ser Phe Asn Ala
145 150 155 160
Thr Thr Val Val Glu Asp Arg Lys Gln Lys Val His Ala Leu Phe Tyr
165 170 175
Arg Leu Asp Ile Val Pro Leu Asp Glu Asn Asn Ser Ser Glu Lys Ser
180 185 190
Ser Glu Asn Ser Ser Glu Tyr Tyr Arg Leu Ile Asn Cys Asn Thr Ser
195 200 205
Ala Ile Thr Gln Ala Cys Pro Lys Val Ser Phe Asp Pro Ile Pro Ile
210 215 220
His Tyr Cys Ala Pro Ala Gly Tyr Ala Ile Leu Lys Cys Asn Asn Lys
225 230 235 240
Thr Phe Asn Gly Thr Gly Pro Cys Asn Asn Val Ser Thr Val Gln Cys
245 250 255
Thr His Gly Ile Lys Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly
260 265 270
Ser Leu Ala Glu Glu Glu Ile Ile Ile Arg Ser Glu Asn Leu Thr Asn
275 280 285
Asn Ala Lys Thr Ile Ile Val His Leu Asn Glu Thr Val Asn Ile Thr
290 295 300
Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys Ser Ile Arg Ile Gly Pro
305 310 315 320
Gly Gln Thr Phe Tyr Ala Thr Gly Asp Ile Ile Gly Asp Ile Arg Gln
325 330 335
Ala His Cys Asn Leu Ser Arg Asp Gly Trp Asn Lys Thr Leu Gln Gly
340 345 350
Val Lys Lys Lys Leu Ala Glu His Phe Pro Asn Lys Thr Ile Asn Phe
355 360 365
Thr Ser Ser Ser Gly Gly Asp Leu Glu Ile Thr Thr His Ser Phe Asn
370 375 380
Cys Arg Gly Glu Phe Phe Tyr Cys Asn Thr Ser Gly Leu Phe Asn Gly
385 390 395 400
Thr Tyr Met Pro Asn Gly Thr Asn Ser Asn Ser Ser Ser Asn Ile Thr
405 410 415
Leu Pro Cys Arg Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly
420 425 430
Arg Ala Met Tyr Ala Pro Pro Ile Ala Gly Asn Ile Thr Cys Arg Ser
435 440 445
Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly Ser Asn Asn Gly
450 455 460
Val Pro Asn Asp Thr Glu Thr Phe Arg Pro Gly Gly Gly Asp Met Arg
465 470 475 480
Asn Asn Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Glu Val Lys
485 490 495
Pro Leu Gly Val Ala Pro Thr Glu Ala Lys Arg Arg Val Val Glu Arg
500 505 510
Glu Lys Arg Ala Val Gly Ile Gly Ala Val Phe Leu Gly Ile Leu Gly
515 520 525
Ala Ala Gly Ser Thr Met Gly Ala Ala Ser Ile Thr Leu Thr Val Gln
530 535 540
Ala Arg Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Ser Asn Leu Leu
545 550 555 560
Arg Ala Ile Glu Ala Gln Gln His Met Leu Gln Leu Thr Val Trp Gly
565 570 575
Ile Lys Gln Leu Gln Thr Arg Val Leu Ala Ile Glu Arg Tyr Leu Gln
580 585 590
Asp Gln Gln Leu Leu Gly Leu Trp Gly Cys Ser Gly Lys Leu Ile Cys
595 600 605
Thr Thr Ala Val Pro Trp Asn Thr Ser Trp Ser Asn Lys Ser Gln Thr
610 615 620
Asp Ile Trp Asp Asn Met Thr Trp Met Gln Trp Asp Lys Glu Ile Gly
625 630 635 640
Asn Tyr Thr Gly Glu Ile Tyr Arg Leu Leu Glu Glu Ser Gln Asn Gln
645 650 655
Gln Glu Lys Asn Glu Lys Asp Leu Leu Ala Leu Asp Ser Trp Lys Asn
660 665 670
Leu Trp Asn Trp Phe Asp Ile Thr Asn Trp Leu Trp Tyr Ile Lys Ile
675 680 685
Phe Ile Met Ile Val Gly Gly Leu Ile Gly Leu Arg Ile Ile Phe Ala
690 695 700
Val Leu Ser Ile Val Asn Arg Val Arg Gln Gly Tyr Ser Pro Leu Ser
705 710 715 720
Leu Gln Thr Leu Thr Gln Asn Pro Gly Gly Leu Asp Arg Leu Gly Arg
725 730 735
Ile Glu Glu Glu Gly Gly Glu Gln Asp Lys Asp Arg Ser Ile Arg Leu
740 745 750
Val Asn Gly Phe Phe Ala Leu Phe Trp Asp Asp Leu Arg Ser Leu Cys
755 760 765
Leu Phe Ser Tyr His Arg Leu Arg Asp Phe Ile Leu Ile Val Ala Arg
770 775 780
Ala Val Glu Leu Leu Gly Arg Ser Ser Leu Arg Gly Leu Gln Arg Gly
785 790 795 800
Trp Glu Ile Leu Lys Tyr Leu Gly Ser Leu Leu Gln Tyr Trp Gly Leu
805 810 815
Glu Leu Lys Lys Ser Ala Ile Asn Leu Leu Asp Thr Ile Ala Ile Ala
820 825 830
Val Ala Glu Gly Thr Asp Arg Ile Ile Glu Leu Ile Gln Arg Ile Cys
835 840 845
Arg Ala Ile Cys Asn Ile Pro Arg Arg Ile Arg Gln Gly Phe Glu Ala
850 855 860
Ala Leu Gln
865
<210> 32
<211> 716
<212> PRT
<213> 人工序列
<220>
<223> C1D7 序列
<400> 32
Met Arg Val Arg Gly Ile Gln Arg Asn Trp Pro Gln Trp Trp Ile Trp
1 5 10 15
Gly Ile Leu Gly Phe Trp Met Ile Ile Ile Cys Arg Val Met Gly Asn
20 25 30
Leu Trp Val Thr Val Tyr Tyr Gly Val Pro Val Trp Lys Glu Ala Lys
35 40 45
Thr Thr Leu Phe Cys Ala Ser Asp Ala Lys Ala Tyr Glu Lys 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 Met Val Leu Glu Asn Val Thr Glu Asn Phe Asn Met Trp Lys
85 90 95
Asn Asp Met Val Asp Gln Met His Glu Asp Ile Ile Arg Leu Trp Asp
100 105 110
Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
115 120 125
Glu Cys Arg Asn Val Arg Asn Val Ser Ser Asn Gly Thr Tyr Asn Ile
130 135 140
Ile His Asn Glu Thr Tyr Lys Glu Met Lys Asn Cys Ser Phe Asn Ala
145 150 155 160
Thr Thr Val Val Glu Asp Arg Lys Gln Lys Val His Ala Leu Phe Tyr
165 170 175
Arg Leu Asp Ile Val Pro Leu Asp Glu Asn Asn Ser Ser Glu Lys Ser
180 185 190
Ser Glu Asn Ser Ser Glu Tyr Tyr Arg Leu Ile Asn Cys Asn Thr Ser
195 200 205
Ala Ile Thr Gln Ala Cys Pro Lys Val Ser Phe Asp Pro Ile Pro Ile
210 215 220
His Tyr Cys Ala Pro Ala Gly Tyr Ala Ile Leu Lys Cys Asn Asn Lys
225 230 235 240
Thr Phe Asn Gly Thr Gly Pro Cys Asn Asn Val Ser Thr Val Gln Cys
245 250 255
Thr His Gly Ile Lys Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly
260 265 270
Ser Leu Ala Glu Glu Glu Ile Ile Ile Arg Ser Glu Asn Leu Thr Asn
275 280 285
Asn Ala Lys Thr Ile Ile Val His Leu Asn Glu Thr Val Asn Ile Thr
290 295 300
Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys Ser Ile Arg Ile Gly Pro
305 310 315 320
Gly Gln Thr Phe Tyr Ala Thr Gly Asp Ile Ile Gly Asp Ile Arg Gln
325 330 335
Ala His Cys Asn Leu Ser Arg Asp Gly Trp Asn Lys Thr Leu Gln Gly
340 345 350
Val Lys Lys Lys Leu Ala Glu His Phe Pro Asn Lys Thr Ile Asn Phe
355 360 365
Thr Ser Ser Ser Gly Gly Asp Leu Glu Ile Thr Thr His Ser Phe Asn
370 375 380
Cys Arg Gly Glu Phe Phe Tyr Cys Asn Thr Ser Gly Leu Phe Asn Gly
385 390 395 400
Thr Tyr Met Pro Asn Gly Thr Asn Ser Asn Ser Ser Ser Asn Ile Thr
405 410 415
Leu Pro Cys Arg Ile Lys Gln Ile Ile Asn Met Trp Gln Glu Val Gly
420 425 430
Arg Ala Met Tyr Ala Pro Pro Ile Ala Gly Asn Ile Thr Cys Arg Ser
435 440 445
Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly Ser Asn Asn Gly
450 455 460
Val Pro Asn Asp Thr Glu Thr Phe Arg Pro Gly Gly Gly Asp Met Arg
465 470 475 480
Asn Asn Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Glu Val Lys
485 490 495
Pro Leu Gly Val Ala Pro Thr Glu Ala Lys Arg Arg Val Val Glu Arg
500 505 510
Glu Lys Arg Ala Val Gly Ile Gly Ala Val Phe Leu Gly Ile Leu Gly
515 520 525
Ala Ala Gly Ser Thr Met Gly Ala Ala Ser Ile Thr Leu Thr Val Gln
530 535 540
Ala Arg Gln Leu Leu Ser Gly Ile Val Gln Gln Gln Ser Asn Leu Leu
545 550 555 560
Arg Ala Ile Glu Ala Gln Gln His Met Leu Gln Leu Thr Val Trp Gly
565 570 575
Ile Lys Gln Leu Gln Thr Arg Val Leu Ala Ile Glu Arg Tyr Leu Gln
580 585 590
Asp Gln Gln Leu Leu Gly Leu Trp Gly Cys Ser Gly Lys Leu Ile Cys
595 600 605
Thr Thr Ala Val Pro Trp Asn Thr Ser Trp Ser Asn Lys Ser Gln Thr
610 615 620
Asp Ile Trp Asp Asn Met Thr Trp Met Gln Trp Asp Lys Glu Ile Gly
625 630 635 640
Asn Tyr Thr Gly Glu Ile Tyr Arg Leu Leu Glu Glu Ser Gln Asn Gln
645 650 655
Gln Glu Lys Asn Glu Lys Asp Leu Leu Ala Leu Asp Ser Trp Lys Asn
660 665 670
Leu Trp Asn Trp Phe Asp Ile Thr Asn Trp Leu Trp Tyr Ile Lys Ile
675 680 685
Phe Ile Met Ile Val Gly Gly Leu Ile Gly Leu Arg Ile Ile Phe Ala
690 695 700
Val Leu Ser Ile Val Asn Arg Val Arg Gln Gly Tyr
705 710 715
<210> 33
<211> 2127
<212> DNA
<213> 人工序列
<220>
<223> 编码 sC1的核苷酸序列
<400> 33
atgagagtgc ggggcattca gagaaactgg ccccagtggt ggatctgggg catcctgggc 60
ttttggatga tcattatctg ccgcgtgatg ggcaacctgt gggtcaccgt gtactacggc 120
gtgcccgtgt ggaaagaggc caagaccacc ctgttctgcg ccagcgacgc caaggcctac 180
gagaaagagg tgcacaacgt ctgggccacc cacgcctgtg tgcccaccga ccccaatccc 240
caggaaatgg tcctggaaaa cgtgaccgag aacttcaaca tgtggaagaa cgacatggtg 300
gaccagatgc acgaggacat catccggctg tgggaccaga gcctgaagcc ctgcgtgaag 360
ctgacccctc tgtgcgtgac cctggaatgc cggaacgtgc gcaacgtgtc cagcaacggc 420
acctacaata tcatccacaa cgagacatac aaagagatga agaactgcag cttcaacgct 480
accaccgtgg tcgaggaccg gaagcagaag gtgcacgccc tgttttaccg gctggacatc 540
gtgcccctgg acgagaacaa cagcagcgag aagtcctccg agaacagctc cgagtactac 600
agactgatca actgcaacac cagcgccatc acccaggcct gccccaaggt gtccttcgac 660
cctatcccca tccactactg cgcccctgcc ggctacgcca tcctgaagtg caacaacaag 720
accttcaatg gcaccggccc ctgcaacaat gtgtccaccg tgcagtgcac ccacggcatc 780
aagcccgtgg tgtctaccca gctgctgctg aacggcagcc tggccgagga agagatcatc 840
atcagaagcg agaacctgac caacaacgcc aagacaatca tcgtccacct gaacgaaacc 900
gtgaacatca cctgtacccg gcctaacaac aacacccgga agtccatccg gatcggccct 960
ggccagacct tttacgccac cggcgatatt atcggcgaca tccggcaggc ccactgcaat 1020
ctgagccggg acggctggaa caagacactg cagggcgtca agaagaagct ggccgaacac 1080
ttccccaaca aaaccatcaa cttcaccagc tcctctggcg gcgacctgga aatcaccacc 1140
cacagcttta actgcagagg cgagttcttc tactgcaata cctccggcct gttcaatgga 1200
acctacatgc ccaacgggac caacagcaac tccagcagca atatcaccct gccttgccgg 1260
atcaagcaga ttatcaatat gtggcaggaa gtgggcagag ctatgtacgc ccctccaatc 1320
gccggcaaca tcacatgcag aagcaacatt accggcctgc tgctcaccag ggacggcggc 1380
tctaacaatg gcgtgccaaa cgacaccgag acattcagac ccggcggagg cgacatgcgg 1440
aacaattggc ggagcgagct gtacaagtac aaggtggtgg aagtgaagcc cctgggcgtg 1500
gcccctaccg aagccaagag aagagtggtc gaacgcgagg aacgggccgt gggcattgga 1560
gccgtgtttc tgggaatcct gggagccgct ggcagcacca tgggcgctgc ctctatcaca 1620
ctgacagtgc aggccagaca gctcctgagc ggcatcgtgc agcagcagag caacctgctg 1680
agagccatcg aggcacagca gcacatgctg cagctgaccg tgtggggcat taagcagctc 1740
cagacacggg tgctggccat tgagagatac ctgcaggatc agcagctgct cggcctgtgg 1800
ggctgtagcg gcaagctgat ctgtaccacc gccgtgcctt ggaacacctc ctggtccaac 1860
aagagccaga ccgacatctg ggacaacatg acctggatgc agtgggacaa agaaatcggc 1920
aactataccg gcgagatcta ccgactgctg gaagagtccc agaaccagca ggaaaagatg 1980
aagcagatcg aggacaagat cgaagagatt ctgagcaaaa tctaccacat cgagaacgag 2040
atcgcccgca tcaagaaact gatcggcgaa gtgggatccg gcgctcccac aaaggccaaa 2100
agacgggtgg tgcagcgcga gaaacgc 2127
<210> 34
<211> 2601
<212> DNA
<213> 人工序列
<220>
<223> 编码 C1的核苷酸序列
<400> 34
atgagagtgc ggggcattca gagaaactgg ccccagtggt ggatctgggg catcctgggc 60
ttttggatga tcattatctg ccgcgtgatg ggcaacctgt gggtcaccgt gtactacggc 120
gtgcccgtgt ggaaagaggc caagaccacc ctgttctgcg ccagcgacgc caaggcctac 180
gagaaagagg tgcacaacgt ctgggccacc cacgcctgtg tgcccaccga ccccaatccc 240
caggaaatgg tcctggaaaa cgtgaccgag aacttcaaca tgtggaagaa cgacatggtg 300
gaccagatgc acgaggacat catccggctg tgggaccaga gcctgaagcc ctgcgtgaag 360
ctgacccctc tgtgcgtgac cctggaatgc cggaacgtgc gcaacgtgtc cagcaacggc 420
acctacaata tcatccacaa cgagacatac aaagagatga agaactgcag cttcaacgct 480
accaccgtgg tcgaggaccg gaagcagaag gtgcacgccc tgttttaccg gctggacatc 540
gtgcccctgg acgagaacaa cagcagcgag aagtcctccg agaacagctc cgagtactac 600
agactgatca actgcaacac cagcgccatc acccaggcct gccccaaggt gtccttcgac 660
cctatcccca tccactactg cgcccctgcc ggctacgcca tcctgaagtg caacaacaag 720
accttcaatg gcaccggccc ctgcaacaat gtgtccaccg tgcagtgcac ccacggcatc 780
aagcccgtgg tgtctaccca gctgctgctg aacggcagcc tggccgagga agagatcatc 840
atcagaagcg agaacctgac caacaacgcc aagacaatca tcgtccacct gaacgaaacc 900
gtgaacatca cctgtacccg gcctaacaac aacacccgga agtccatccg gatcggccct 960
ggccagacct tttacgccac cggcgatatt atcggcgaca tccggcaggc ccactgcaat 1020
ctgagccggg acggctggaa caagacactg cagggcgtca agaagaagct ggccgaacac 1080
ttccccaaca aaaccatcaa cttcaccagc tcctctggcg gcgacctgga aatcaccacc 1140
cacagcttta actgcagagg cgagttcttc tactgcaata cctccggcct gttcaatgga 1200
acctacatgc ccaacgggac caacagcaac tccagcagca atatcaccct gccttgccgg 1260
atcaagcaga ttatcaatat gtggcaggaa gtgggcagag ctatgtacgc ccctccaatc 1320
gccggcaaca tcacatgcag aagcaacatt accggcctgc tgctcaccag ggacggcggc 1380
tctaacaatg gcgtgccaaa cgacaccgag acattcagac ccggcggagg cgacatgcgg 1440
aacaattggc ggagcgagct gtacaagtac aaggtggtgg aagtgaagcc cctgggcgtg 1500
gcccctaccg aagccaagag aagagtggtc gaacgcgaga agcgggccgt gggcattgga 1560
gccgtgtttc tgggaatcct gggagccgct ggcagcacca tgggcgctgc ctctatcaca 1620
ctgacagtgc aggccagaca gctcctgagc ggcatcgtgc agcagcagag caacctgctg 1680
agagccatcg aggcacagca gcacatgctg cagctgaccg tgtggggcat taagcagctc 1740
cagacacggg tgctggccat tgagagatac ctgcaggatc agcagctgct cggcctgtgg 1800
ggctgtagcg gcaagctgat ctgtaccacc gccgtgcctt ggaacacctc ctggtccaac 1860
aagagccaga ccgacatctg ggacaacatg acctggatgc agtgggacaa agaaatcggc 1920
aactataccg gcgagatcta ccgactgctg gaagagtccc agaaccagca ggaaaagaac 1980
gagaaggacc tgctggccct ggacagctgg aaaaatctgt ggaattggtt cgacatcacc 2040
aactggctgt ggtacatcaa gatcttcatc atgatcgtgg gcggcctgat cggcctgcgg 2100
atcatctttg ccgtgctgag catcgtgaac cgcgtgcggc agggatacag ccctctgagc 2160
ctgcagaccc tgacccagaa tccaggcgga ctggatcggc tgggccggat tgaggaagaa 2220
ggcggcgagc aggacaagga ccgcagcatc agactcgtga acggcttctt cgctctgttt 2280
tgggacgacc tgcggagcct gtgcctgttc tcctaccaca gactgcggga ctttatcctg 2340
attgtggcca gagccgtcga gctgctgggc agatcttctc tgagaggcct gcagcggggc 2400
tgggagattc tgaagtacct gggctccctg ctgcagtatt ggggcctgga actgaagaag 2460
tccgccatca atctgctcga cacaatcgct attgccgtgg ccgaaggcac cgacagaatc 2520
atcgagctga tccagcggat ctgccgggcc atctgcaaca tccccagacg gatcagacag 2580
ggctttgaag ccgccctcca g 2601
<210> 35
<211> 2148
<212> DNA
<213> 人工序列
<220>
<223> 编码C1D7的核苷酸序列
<400> 35
atgagagtgc ggggcattca gagaaactgg ccccagtggt ggatctgggg catcctgggc 60
ttttggatga tcattatctg ccgcgtgatg ggcaacctgt gggtcaccgt gtactacggc 120
gtgcccgtgt ggaaagaggc caagaccacc ctgttctgcg ccagcgacgc caaggcctac 180
gagaaagagg tgcacaacgt ctgggccacc cacgcctgtg tgcccaccga ccccaatccc 240
caggaaatgg tcctggaaaa cgtgaccgag aacttcaaca tgtggaagaa cgacatggtg 300
gaccagatgc acgaggacat catccggctg tgggaccaga gcctgaagcc ctgcgtgaag 360
ctgacccctc tgtgcgtgac cctggaatgc cggaacgtgc gcaacgtgtc cagcaacggc 420
acctacaata tcatccacaa cgagacatac aaagagatga agaactgcag cttcaacgct 480
accaccgtgg tcgaggaccg gaagcagaag gtgcacgccc tgttttaccg gctggacatc 540
gtgcccctgg acgagaacaa cagcagcgag aagtcctccg agaacagctc cgagtactac 600
agactgatca actgcaacac cagcgccatc acccaggcct gccccaaggt gtccttcgac 660
cctatcccca tccactactg cgcccctgcc ggctacgcca tcctgaagtg caacaacaag 720
accttcaatg gcaccggccc ctgcaacaat gtgtccaccg tgcagtgcac ccacggcatc 780
aagcccgtgg tgtctaccca gctgctgctg aacggcagcc tggccgagga agagatcatc 840
atcagaagcg agaacctgac caacaacgcc aagacaatca tcgtccacct gaacgaaacc 900
gtgaacatca cctgtacccg gcctaacaac aacacccgga agtccatccg gatcggccct 960
ggccagacct tttacgccac cggcgatatt atcggcgaca tccggcaggc ccactgcaat 1020
ctgagccggg acggctggaa caagacactg cagggcgtca agaagaagct ggccgaacac 1080
ttccccaaca aaaccatcaa cttcaccagc tcctctggcg gcgacctgga aatcaccacc 1140
cacagcttta actgcagagg cgagttcttc tactgcaata cctccggcct gttcaatgga 1200
acctacatgc ccaacgggac caacagcaac tccagcagca atatcaccct gccttgccgg 1260
atcaagcaga ttatcaatat gtggcaggaa gtgggcagag ctatgtacgc ccctccaatc 1320
gccggcaaca tcacatgcag aagcaacatt accggcctgc tgctcaccag ggacggcggc 1380
tctaacaatg gcgtgccaaa cgacaccgag acattcagac ccggcggagg cgacatgcgg 1440
aacaattggc ggagcgagct gtacaagtac aaggtggtgg aagtgaagcc cctgggcgtg 1500
gcccctaccg aagccaagag aagagtggtc gaacgcgaga agcgggccgt gggcattgga 1560
gccgtgtttc tgggaatcct gggagccgct ggcagcacca tgggcgctgc ctctatcaca 1620
ctgacagtgc aggccagaca gctcctgagc ggcatcgtgc agcagcagag caacctgctg 1680
agagccatcg aggcacagca gcacatgctg cagctgaccg tgtggggcat taagcagctc 1740
cagacacggg tgctggccat tgagagatac ctgcaggatc agcagctgct cggcctgtgg 1800
ggctgtagcg gcaagctgat ctgtaccacc gccgtgcctt ggaacacctc ctggtccaac 1860
aagagccaga ccgacatctg ggacaacatg acctggatgc agtgggacaa agaaatcggc 1920
aactataccg gcgagatcta ccgactgctg gaagagtccc agaaccagca ggaaaagaac 1980
gagaaggacc tgctggccct ggacagctgg aaaaatctgt ggaattggtt cgacatcacc 2040
aactggctgt ggtacatcaa gatcttcatc atgatcgtgg gcggcctgat cggcctgcgg 2100
atcatctttg ccgtgctgag catcgtgaac cgcgtgcggc agggctac 2148
<210> 36
<211> 724
<212> PRT
<213> 人工序列
<220>
<223> 嵌合Env 三聚体序列
<400> 36
Met Arg Val Arg Gly Ile Gln Arg Asn Cys Gln His Leu Trp Arg Trp
1 5 10 15
Gly Thr Leu Ile Leu Gly Met Leu Met Ile Cys Ser Ala Ala Gly Lys
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 Glu Asn Val Thr Glu Asn Phe Asn Met Trp Lys
85 90 95
Asn Asn Met Val Glu Gln Met His Glu Asp Ile Ile Ser Leu Trp Asp
100 105 110
Gln Ser Leu Lys Pro Cys Val Lys Leu Thr Pro Leu Cys Val Thr Leu
115 120 125
Asn Cys Thr Asp Asp Val Arg Asn Val Thr Asn Asn Ala Thr Asn Thr
130 135 140
Asn Ser Ser Trp Gly Glu Pro Met Glu Lys Gly Glu Ile Lys Asn Cys
145 150 155 160
Ser Phe Asn Ile Thr Thr Ser Ile Arg Asn Lys Val Gln Lys Gln Tyr
165 170 175
Ala Leu Phe Tyr Lys Leu Asp Val Val Pro Ile Asp Asn Asp Ser Asn
180 185 190
Asn Thr Asn Tyr Arg Leu Ile Ser Cys Asn Thr Ser Val Ile Thr Gln
195 200 205
Ala Cys Pro Lys Val Ser Phe Glu Pro Ile Pro Ile His Tyr Cys Ala
210 215 220
Pro Ala Gly Phe Ala Ile Leu Lys Cys Asn Asp Lys Lys Phe Asn Gly
225 230 235 240
Thr Gly Pro Cys Thr Asn Val Ser Thr Val Gln Cys Thr His Gly Ile
245 250 255
Arg Pro Val Val Ser Thr Gln Leu Leu Leu Asn Gly Ser Leu Ala Glu
260 265 270
Glu Glu Val Val Ile Arg Ser Glu Asn Phe Thr Asn Asn Ala Lys Thr
275 280 285
Ile Met Val Gln Leu Asn Val Ser Val Glu Ile Asn Cys Thr Arg Pro
290 295 300
Asn Asn Asn Thr Arg Lys Ser Ile His Ile Gly Pro Gly Arg Ala Phe
305 310 315 320
Tyr Thr Ala Gly Asp Ile Ile Gly Asp Ile Arg Gln Ala His Cys Asn
325 330 335
Ile Ser Arg Ala Asn Trp Asn Asn Thr Leu Arg Gln Ile Val Glu Lys
340 345 350
Leu Gly Lys Gln Phe Gly Asn Asn Lys Thr Ile Val Phe Asn His Ser
355 360 365
Ser Gly Gly Asp Pro Glu Ile Val Met His Ser Phe Asn Cys Gly Gly
370 375 380
Glu Phe Phe Tyr Cys Asn Ser Thr Lys Leu Phe Asn Ser Thr Trp Thr
385 390 395 400
Trp Asn Asn Ser Thr Trp Asn Asn Thr Lys Arg Ser Asn Asp Thr Glu
405 410 415
Glu His Ile Thr Leu Pro Cys Arg Ile Lys Gln Ile Ile Asn Met Trp
420 425 430
Gln Glu Val Gly Lys Ala Met Tyr Ala Pro Pro Ile Arg Gly Gln Ile
435 440 445
Arg Cys Ser Ser Asn Ile Thr Gly Leu Leu Leu Thr Arg Asp Gly Gly
450 455 460
Asn Asp Thr Ser Gly Thr Glu Ile Phe Arg Pro Gly Gly Gly Asp Met
465 470 475 480
Arg Asp Asn Trp Arg Ser Glu Leu Tyr Lys Tyr Lys Val Val Lys Ile
485 490 495
Glu Pro Leu Gly Val Ala Pro Thr Lys Ala Lys Glu Arg Val Val Gln
500 505 510
Arg Glu Glu Arg Ala Val Gly Ile Gly Ala Val Phe Leu Gly Phe Leu
515 520 525
Gly Ala Ala Gly Ser Thr Met Gly Ala Ala Ser Met Thr Leu Thr Val
530 535 540
Gln Ala Arg Leu Leu Leu Ser Gly Ile Val Gln Gln Gln Asn Asn Leu
545 550 555 560
Leu Arg Ala Ile Glu Ala Gln Gln His Leu Leu Gln Leu Thr Val Trp
565 570 575
Gly Ile Lys Gln Leu Gln Ala Arg Val Leu Ala Val Glu Arg Tyr Leu
580 585 590
Lys Asp Gln Gln Leu Leu Gly Ile Trp Gly Cys Ser Gly Lys Leu Ile
595 600 605
Cys Thr Thr Thr Val Pro Trp Asn Ala Ser Trp Ser Asn Lys Ser Leu
610 615 620
Asp Lys Ile Trp Asn Asn Met Thr Trp Met Glu Trp Glu Arg Glu Ile
625 630 635 640
Asn Asn Tyr Thr Ser Leu Ile Tyr Thr Leu Ile Glu Glu Ser Gln Asn
645 650 655
Gln Gln Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala
660 665 670
Ser Leu Trp Asn Trp Phe Asp Ile Ser Asn Trp Leu Trp Tyr Ile Lys
675 680 685
Ser Arg Ile Glu Gly Arg Gly Ser Gly Gly Tyr Ile Pro Glu Ala Pro
690 695 700
Arg Asp Gly Gln Ala Tyr Val Arg Lys Asp Gly Glu Trp Val Leu Leu
705 710 715 720
Ser Thr Phe Leu
<210> 37
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> SEQ ID NO:18的残基655-682
<400> 37
Asn Glu Lys Asp Leu Leu Ala Leu Asp Ser Trp Asn Asn Leu Trp Asn
1 5 10 15
Trp Phe Ser Ile Ser Lys Trp Leu Trp Tyr Ile Lys
20 25
Claims (22)
1.一种载体,其包含编码合成的HIV包膜蛋白的核酸,其中所述合成的HIV包膜蛋白包含SEQ ID NO:18的氨基酸序列或由SEQ ID NO:18的氨基酸序列组成。
2.权利要求1的载体,其中所述载体是病毒载体。
3.权利要求1或2的载体,其中所述载体是腺病毒载体。
4.权利要求3的载体,其中所述腺病毒载体是人类腺病毒载体或猿猴腺病毒载体。
5.权利要求3的载体,其中所述腺病毒载体是人类腺病毒血清型26(Ad26)载体。
6.权利要求1或2的载体,其中所述载体是腺相关病毒载体、痘病毒载体、MVA载体、肠系病毒载体、委内瑞拉马脑炎病毒载体、塞姆利基森林病毒载体、烟草花叶病毒载体或慢病毒载体。
7.权利要求1或2的载体,其中所述载体是MVA载体。
8.权利要求1或2的载体,其中所述载体是质粒、细菌人工染色体、酵母人工染色体或噬菌体载体。
9.一种组合物,其包含免疫学有效量的权利要求6或7任一项的载体和运载体,其中编码所述合成的HIV包膜蛋白的核酸与启动子序列可操作连接。
10.一种疫苗组合产品,其包含:
(i)第一组合物,所述第一组合物包含免疫原性有效量的编码具有SEQ ID NO:18的氨基酸序列的合成的HIV包膜蛋白的Ad26载体;和
(ii)第二组合物,所述第二组合物包含免疫原性有效量的编码包含SEQ ID NO:5的氨基酸序列的HIV抗原性多肽的第二Ad26载体;
其中所述第一组合物和第二组合物存在于同一组合物或不同组合物中。
11.权利要求10的疫苗组合产品,其进一步包含至少一种另外的组合物,所述至少一种另外的组合物包含免疫原性有效量的载体,所述载体编码具有选自SEQ ID NO:1-4、28和29的氨基酸序列的至少一种抗原性多肽,
其中所述第一组合物、第二组合物和另外的组合物存在于同一组合物或一种或多种不同组合物中。
12.权利要求10或11的疫苗组合产品,其进一步包含至少一种进一步的组合物,所述至少一种进一步的组合物包含免疫原性有效量的一种或多种分离的HIV抗原性多肽,
其中所述第一组合物、第二组合物、另外的组合物和进一步的组合物存在于同一组合物或一种或多种不同组合物中。
13.权利要求12的疫苗组合产品,其中所述一种或多种分离的HIV抗原性多肽包括选自稳定化的HIV分枝C三聚gp140蛋白和镶嵌HIV Env三聚体蛋白中的一种或多种HIV抗原性多肽,所述稳定化的HIV分枝C三聚gp140蛋白包含SEQ ID NO:7的氨基酸序列的残基30-708,,所述镶嵌Env三聚体蛋白包含SEQ ID NO:36的残基30-724。
14.一种试剂盒,其包含权利要求10-13任一项的疫苗组合产品。
15.权利要求9的组合物,或权利要求10-13任一项的疫苗组合产品,其用于在受试者中诱导针对HIV的免疫应答。
16.一种组合物,其包含:
(i)第一腺病毒26(Ad26)载体,所述第一Ad26载体编码包含SEQ ID NO:18的氨基酸序列的合成的HIV包膜蛋白;
(ii)第二Ad26载体,所述第二Ad26载体编码包含SEQ ID NO:5的氨基酸序列的HIV抗原性多肽;
(iii)第三Ad26载体,所述第三Ad26载体编码包含SEQ ID NO:28的氨基酸序列的HIV抗原性多肽;和
(iv)第四Ad26载体,所述第四Ad26载体编码包含SEQ ID NO:29的氨基酸序列的HIV抗原性多肽。
17.权利要求16的组合物,其中所述第一、第二、第三和第四Ad26载体以病毒颗粒比1:1:1:1存在。
18.一种疫苗组合,其包含权利要求16的组合物和一种或多种分离的HIV抗原性多肽。
19.权利要求18的疫苗组合,其中所述一种或多种分离的HIV抗原性多肽包含HIV包膜蛋白,例如稳定化的HIV分枝C三聚gp140蛋白和/或镶嵌包膜三聚体蛋白。
20.权利要求19的疫苗组合,其中所述分枝C三聚gp140蛋白包含SEQ ID NO:7的氨基酸序列的残基30-708,和/或其中所述镶嵌包膜三聚体蛋白包含SEQ ID NO:36的氨基酸序列的残基30-724。
21.一种Ad26载体,其包含编码包含SEQ ID NO:18的氨基酸序列的合成的HIV包膜蛋白的核酸,其用于在受试者中诱导针对HIV的免疫应答。
22.一种腺病毒载体疫苗,其包含:(i)第一腺病毒26(Ad26)载体,所述第一Ad26载体编码包含SEQ ID NO:18的氨基酸序列的合成的HIV包膜蛋白;(ii)第二Ad26载体,所述第二Ad26载体编码包含SEQ ID NO:5的氨基酸序列的HIV抗原性多肽;(iii)第三Ad26载体,所述第三Ad26载体编码包含SEQ ID NO:28的氨基酸序列的HIV抗原性多肽;和(iv)第四Ad26载体,所述第四Ad26载体编码包含SEQ ID NO:29的氨基酸序列的HIV抗原性多肽,
其用于引发施用,
和
分离的HIV Env gp140蛋白,例如(a)包含SEQ ID NO:7的残基30-708的分枝C gp140蛋白或(b)包含SEQ ID NO:36的残基30-724的镶嵌gp140蛋白或(c)分枝C gp140蛋白和镶嵌gp140蛋白的组合,
其与所述腺病毒载体疫苗一起用于加强施用,
其中所述引发施用和加强施用用于在受试者中产生针对HIV的免疫应答。
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