CN1133597A - 能诱导对hiv免疫应答的肽及含有该肽的预防、治疗aids的药物 - Google Patents
能诱导对hiv免疫应答的肽及含有该肽的预防、治疗aids的药物 Download PDFInfo
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- CN1133597A CN1133597A CN94193851A CN94193851A CN1133597A CN 1133597 A CN1133597 A CN 1133597A CN 94193851 A CN94193851 A CN 94193851A CN 94193851 A CN94193851 A CN 94193851A CN 1133597 A CN1133597 A CN 1133597A
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Abstract
本发明涉及一种作为HIV全蛋白的片断,该片断为含有8-11个氨基酸的连续序列的肽,相当于HLA结合基序,能与HLA实际结合且能诱导以HIV感染细胞为靶细胞的杀伤细胞,这种肽作为AIDS的预防、治疗药很有效。
Description
本发明是关于一种含有人类免疫缺陷病毒(Human Immunode-ficiency Virus,以下略为HIV)蛋白的部分区域的氨基酸序列且能诱导对HIV免疫应答的肽及含有该肽的预防、治疗AIDS的药物。
众所周知,获得性免疫缺陷综合症(Acquired ImmunodeficiencyDisease Syndrome,以下略为AIDS)是因感染HIV而引起的疾病。人们正积极地研究开发治疗这种疾病的药物,叠氮脱氧胸苷(以下略为AZT)、双脱氧肌苷(以下略为DDI)等药物已在实际中应用,但存在疗效及副作用等问题,还没有发现能彻底治疗由感染HIV引起的疾病的药物,前景也难以预测。另一方面,通过增加对HIV的免疫抵抗力预防HIV感染和抑制AIDS发病的疫苗,作为可望防止这种疾病在世界范围内的迅速蔓延的最后手段,正在被广泛地研究。至今已设计出多种类型的疫苗,部分疫苗进入了临床试验,但还没有发现实际应用中被证实对人有效的预防感染或抑制发病的疫苗。
迄今为止,已知的疫苗种类有:
i)采用灭活或减毒病毒颗粒的疫苗已知有引起与HIV病原性相关的基因突变而致缺失的方法(Droc.Natl.Acad.Sci.USA,841434(1987))、应用与HIV有共同的抗原性的猴子等的类似病毒的方法(Science,232,238,(1987)),但因有潜在的危险而不容易实用。
ii)采用病毒部分抗原蛋白的亚单位疫苗:用基因重组的方法等生产只含有病毒颗粒的部分抗原蛋白作为免疫原的方法(Droc.Natl.Acad.Sci USA,84,6924,(1987)、Ann.Int.Med.,114 119,1991)、(Nature,355,728(1992))。这是最广泛尝试的方法,临床试验的例子也多。但是存在诸如中和抗体滴度不升高、抗体滴度的持续时间等应该解决的问题。还有这种方法增强产生抗体等的体液免疫的效果,很难与杀伤感染细胞的细胞免疫的激活相关联,从HIV的感染方式看单纯应用这种方法未必对预防感染有效。
iii)牛痘病毒及BCG菌等的重组活疫苗:将取自HIV的部分基因序列整合到可在人体细胞内增殖的牛痘病毒及BCG菌等的基因中使其表达理论上可望有增强细胞免疫的效果。问题在于对于免疫力低下的患者即使是通常无害的牛痘病毒也有引起严重感染的可能以及至少迄今为止研制出来的牛痘重组活疫苗都没能引起充分的免疫应答等。
iv)抗个体遗传型抗体:有报告关于不采用病毒抗原而以抗个体遣传型抗体为免疫原的方法(Proc.Natl.Acad Sci.USA,89 2546,(1992))。
v)合成肽疫苗:对化学合成中和抗体的决定区域的肽序列等进行了研究,特别是包被糖蛋白gp120的V3区域是主要的中和决定区域,正在进行以合成的V3区肽作为疫苗的尝试(Proc Natl.Acad.Sci,USA,86,6768,(1989))。关于这些疫苗的研究开发情况记载于高桥秀实,《实验医学》11卷655—8661页(1993);奥田研尔山川正,《临床上微生物》20卷55—62页;A.T.Profy,BIOmedica8卷133—139页等处。
上述至今为止的对疫苗的研究开发以通过诱导产生中和抗体来增强体液免疫的类型为主。但是与HIV作为自由的病毒颗粒相比,它更容易靠感染的细胞与未感染的细胞的融合传播。因此,依靠杀伤感染细胞的细胞毒性T细胞(cytotoxic T Cell,以下略为CTL)的细胞免疫比依靠中和抗体的体液免疫在防御感染上更重要。实际上,通过调查那些有感染HIV的机会但感染未成立的个体,常常在血液中检测不到抗体而存在CTL,因此有人报告早期诱导CTL对于预防感染很重要(J.Infec.Dis.,164,178,(1992))。
所以本发明的发明者们研究了能诱导特异地杀伤HIV感染的细胞的CTL的肽,旨在于以此治疗或预防AIDS。
为了有效地诱导针对HIV感染细胞的CTL,鉴定CTL能识别的抗原决定部位并把它应用到疫苗中是极重要的。至今为止采用的方法是首先建立特异的针对HIV的CTL克隆,然后鉴定这种CTL克隆识别的抗原决定部位(Proc.Natl.Acad.Sci.USA,85,3105,(1988))。采用这种方法通过众多的人白血球抗原(以下略为HLA)I类抗原来鉴定提呈给CTL的HIV抗原决定部位,这需要合成大量的肽,要花费大量的时间和费用,因此抗原决定部位的鉴定也没有进行。
CTL通过靶细胞表面表达的主要组织相容性抗原复合体(以下略为MHC)I类抗原识别抗原提呈的抗原决定肽,攻击靶细胞,但最近已证实,在特异的MHCI类抗原上结合的被抗原提示的抗原决定肽是一种大致9链长的肽,其氨基酸序列有一定的规律性(mo-tif)(Nature,351,290,(1991)、Eur.J.Immunol.,22,2453,(1992)、Nature,353,326,(1991)、Nature,360 434,(1992)、Immunogenet-ics,38,161,(1993))。
本发明的目的在于提供能诱导对HIV免疫应答的肽。
本发明的目的也在于提供编码上述肽的DNA。
本发明的目的还在于提供含有上述肽的预防治疗AIDS的药物。
本发明的目的还在于提供能诱导对HIV免疫应答的肽的选取方法。
下述记载会使本发明的上述及其他目的更清楚。
本发明从可能与各种HLAI类抗原结合的自身抗原肽的基序(motif)推定可能与HLAI类抗原结合的HIV肽并合成推定的HIV肽。转化细胞表层存在大量未被肽结合的表达的HLAI类抗原。选择与大量表达在其表层的HLAI类抗原实际结合的肽。
然后从选出的肽中得到与HLAI类抗原结合并能刺激患者末梢血淋巴细胞从而诱导CTL的该合成肽,将其用于预防、治疗AIDS。本发明是基于上述发现完成的。
即本发明提供的肽是HIV全部蛋白的片断、该片断含有8—11个氨基酸的连续序列、相当于与HLA结合的基序、实际与HLA结合并能诱导以HIV感染细胞为靶细胞的杀伤细胞。
本发明也提供编码上述肽的DNA。
本发明还提供含有上述肽及医药上允许的载体和/或稀释剂的预防、治疗AIDS的药物。
本发明还提供选取能诱导以感染HIV细胞为靶细胞的杀伤细胞的肽的方法。其特征是合成属于HIV全部蛋白的片断、含有8—11个连续序列的氨基酸、相当于与HLA结合的基序的肽。从合成的肽中选出与HLA实际结合的肽,然后从中选出与HLAI类抗原结合并能刺激HIV疾病患者的末梢淋巴细胞从而诱导杀伤细胞的肽。
附图说明:
图1所示为RMA—S—B*3501细胞上HLA—B*3501抗原表达水平的变化。图中△指与HLA—B*3501抗原有结合性的自身抗原肽28H(LPGPKFLQY)、○指37F(LPFDFTPGY)、□指加入无结合活性的肽MP~1(KGILGKVFTLTV)的HLA—B*3501表达水平的变化。
图2所示为使用HIV(B35)—16作为肽时的特异细胞杀伤活性。图中●指标记靶细胞为T2—B*—3501细胞、○指标记靶细胞为T2细胞,作为对照。用肽刺激培养的患者末梢淋巴细胞采用3种不同数量的细胞计数1×105,2.5×104,或者6.25×103。图中所示特异的细胞杀伤活性值是细胞数1×105个时的结果。
图3所示为使用HIV(35)—18作为肽时的特异细胞杀伤活性。图中●指标记靶细胞为T2—B*—3501细胞、○指标记靶细胞为T2细胞,作为对照。用肽刺激培养的患者末梢淋巴细胞采用3种不同数量的细胞计数1×105,2.5×104,或者6.25×103。图中所示特异的细胞杀伤活性值是细胞数1×105个时的结果。
图4所示为使用HIV(B35)—POL—2α作为肽时的特异细胞杀伤活性。图中●指标记靶细胞为T2—B*—3501细胞、○指标记细胞为T2细胞,作为对照。用肽刺激培养的患者末梢淋巴细胞采用3种不同数量的细胞计数1×105,2.5×104,或者6.25×103。图中所示特异的细胞杀伤活性值是细胞数1×105个时的结果。
HIV的全部蛋白记载于如Nature Vol.313,P277—283(1985)、Proc.Natl.,Acad.Sci USA Vol.83,P2209—2213(1986)等中。本发明的肽是上述HIV全部蛋白的片断。该片断是含有8—11个最好是9—11个氨基酸的连续序列的肽。本发明的肽还必须相当于HLA结合基序,与HLA实际结合。这里,HLA结合基序是8—11个氨基酸的序列,包括:第2位氨基酸是Pro、C末端是Tyr、Leu、Ile、Met、Phe及Ala中的任一种氨基酸的序列;第2位氨基酸是Pro、Ala、Gly中的任一种氨基酸,C末端是Ile、Leu、Val、Phe及Met中的任一种氨基酸的序列;第2位氨基酸是Leu、Val、Tyr及Phe中的任一种氨基酸,C末端是Arg的序列。本发明中相当于与HLA结合的基序的肽实际上与HLA结合与否,可用含有HLAI类抗原的细胞确定。这样的细胞有RMA—S—B*3501细胞、RMA—S—B*5101细胞及RMA—S—A*3101细胞等。这些细胞可以将HLA—B*3501基团、HLA—B*—5101基因及HLA—A*3101基因导入RMA—S细胞、很容易得到。有关RMA—S细胞记载于Liunggren et al.,J.Immu—nol.,142,2911,(1989)。
本发明中与HLAI类抗原结合的合成HIV肽还必须在实际应用中刺激患者的末梢血淋巴细胞从而诱导CTL,即能诱导以感染HIV的细胞为靶细胞的杀伤细胞。
例举出序列号从1至63的具备这些条件的肽。
序列号1—24中的任一种氨基酸序列的肽都能与HLA—B3501抗原结合,是利用RMA—S—B*3501细胞得到的。序列号25~46中的任一种氨基酸序列的肽都能与HLA—B51抗原结合,是利用RMA—S—B*5101细胞得到的。还有,序列号47—63中的任一种氨基酸序列的肽都能与HLA—A3101抗原结合,是利用RMA—S—A*3101细胞得到的。本发明得到肽的方法将在以后的实施例中详细说明。
序列号1—63中的任一种氨基酸序列的肽都可用本行业人员周知的方法合成或生产。近年来肽合成器的发展使由数十个氨基酸残基构成的肽能容易地生产出来。或者,将编码序列号1—63中任何一种氨基酸序列肽的DNA连接于适当的表达载体,也可以通过培养由此被转化了的大肠杆菌属细菌等的细胞来生产。这种用基因重组技术生产蛋白质、肽等的方法是本行业人员所熟知的。
编码序列号1—63中任何一种氨基酸序列的肽的DNA能从序列号1—63中任何一种氨基酸序列演译出来。各氨基酸所对应的密码是本行业人员周知的。将该DNA导入细胞使之表达时,各种细胞倾向选择的密码不同,因此应考虑这个因素。例如:使用大肠杆菌属细菌细胞内倾向选择的密码时,以编码序列号为3的氨基酸序列的肽的DNA为例,有编码序列号为64的DNA的碱基序列;以编码序列号为4的氨基酸序列的肽的DNA为例,有编码序列号为65的DNA的碱基序列;以编码序列号为5的氨基酸序列的肽的DNA为例,有编码序列号为66的DNA的碱基序列。
序列号1—63中任一种氨基酸序列的肽都是T细胞抗原决定部位,能诱导HIV特异的CTL,因此作为疫苗很有用。实际作为疫苗使用时,单纯肽的溶液、或者加上适当的辅助剂注射给药或用喷雾等方法经粘膜透皮吸收等给药方式都有好的效果。给药量每次0.1—100mg,单次或重复给药。如果同时应用多个用上述方法选出的抗原决定肽,大都会产生更好的效果。制剂上冷冻干燥,加入糖等赋形剂制成颗粒也可,并不需要任何特殊的东西。注射给药时,用注射用蒸馏水溶解后使用。本药是肽类化合物,不存在用上述给药方法成为问题的严重的急性毒性。
为提高疫苗的免疫原性而添加的佐剂可使用:BCG菌等的菌体成分、Morein等人开发的从Quilla树皮提取的ISCOM(Immunostim-ulating Complex)(Nature,308,457,(1984)Nature,344,873,(199))、皂角苷系列的QS—21—(J.Immunol.,148 1438,(1992))、脂质体(J.Immunol.,148,1585,(1992))、氢氧化铝(alum,明矾)、KLH(Keyhole Lympet Hemocymin)(J.Virol.,65,489,(1991))等。上述早先的文献及Sciencl,255,333,(1992)等也论述了用这样的方法在生物体内能诱导CTL等的免疫应答。
本发明通过采用下面两种方法使用抗原决定肽可有效适用:于试管内将该抗原决定肽给予取自患者的细胞或具有单倍型HLAI类抗原的细胞,使经抗原提示后,将细胞注入患者血管使其在患者体内有效地诱导CTL的方法以及将同一肽加入患者末梢血淋巴细胞在试管内培养,使试管内的CTL被诱导增殖后再回注给患者的方法。在序列号1—24中任一种氨基酸序列的肽的存在下培养具有HLA—B*3501抗原的末梢血淋巴细胞得到的细胞毒性T细胞可作为抗AIDS疫苗应用。实际操作是患者末梢血淋巴细胞每107—109中加入该肽0.01—1mg,培养数小时到1天后注入患者静脉中。或者是还可以用加入重组白细胞介素2(recombinant IL—2)50u/ml和该肽1μg/ml的培养液不断更换培养基连续培养数周,在试管内诱导CTL后经静脉给患者注入。培养的方法用本行业人员熟知的常规方法即可。培养后用离心分离等方法洗涤培养成分后,用生理盐水等制成混悬液给药。这种细胞注入治疗已经作为癌的治疗法应用,是本行业人员熟知的方法(New Eng.J.Med.,313,4185,(1985)、Sci-ence,233,1318,(1986))。
另外,本发明发现的CTL抗原决定部位也可活用于基因重组的牛痘病毒、BCG菌等的活疫苗即将编码序列号1—63中任一种氨基酸序列的肽的DNA整合入这些基团重组活疫苗表达的基因重组抗原蛋白基因中,该肽序列作为抗原蛋白的一部分表达后,在细胞内被加工并被HLAI类抗原提呈,能诱导识别它的CTL。BCG菌表达外来基因的方法详细记载于国际专利公开号为WO88/06626的专利中。关于BCG菌重组活疫苗详细记载于J.Exp.Med.,178,197,(1993)。给药量、给药方法可依照通常的种痘、BCG疫苗标准。急性毒性等也与通常的种痘,BCG疫苗没什么不同。只是牛痘病毒在AIDS发病、免疫力低下的患者有引起严重感染的危险,使用治疗疫苗必须慎重。BCG疫苗还没有这样的例子。用这样的方法能在生物体内诱导CTL等的免疫应答记载在Nature,332,728,(1988)、Na-ture,351,479,(1991)等处。
HIV疫苗存在的严重问题是HIV很容易发生突变从而逃脱宿主免疫。所以作为免疫原只含有一种抗原决定肽的疫苗很可能不久就失效。因此以本发明发现的众多的抗原决定肽作为免疫原的疫苗有很高的实用性。
下面通过实施例详细说明本发明。
实施例1
(1)通过与HLA—B*3501结合的自身抗原肽基序推测与HLA—B*3501结合的HIV肽。
与HLA—B*3501结合的自身抗原肽的基序在此之前已清楚(Nature,360,434,(1992)、Immunogenetics,38,161(1993),由此推定来自HIV蛋白的肽中与自身抗原肽同样由8—12个氨基酸构成、第2位是Pro,C末端是Tyr、Leu、Ile、Met、Phe中的任一种氨基酸的肽容易与HLA—B*3501结合。构成HIV全部蛋白质的氨基酸序列已经被报告过,从中选出与HLA—B*3501结合的自身抗原肽的基序相一致的肽。HIV的ARV—2株HIV的蛋白质序列中与此相合的肽如表1所示有58种。这些肽用岛津制作所生产的肽合成机合成,供测定与HLA—B*3501抗原结合实验用。
表1HIV(B35)-1 RPGGKKKY HIV(B35)—11 PPFLWMGYHIV(B35)-2 VPLRPMTY HIV(B35)-13 PPLVKLWYHIV(B35)-3 TPGPGIRY HIV(B35)-14 NPDIVIYQYHIV(B35)-4 PPIPVGEIY HIV(B35)-15 EPPFLWMGYHIV(B35)-5 GPKEPFRDY HIV(B35)-16 TPPLVKLWYHIV(335)-6 QPKTACTTCY HIV(B35)-18 EPIVGAETFYHIV(B35)-7 NPPIPVGEIY HIV(B35)-19 EPFKNLKTGKYHIV(B35)-8 EPFRDYVDRFY HIV(B35)-20 IPAETGQETAYHIV(B35)-10 TPGIRYQYHIV(B35)GAG-8 TPQDLNTML HIV(B35)GAG-21 GPGHKARVLHIV(B35)GAG-13 NPPIPVGEI HIV(B35)GAG-26 APPEESFRFHIV(B35)GAG-20 GPAATLEEMHIV(B35)POL-1 LPGRWKPKM HIV(835)POL-20 SPAIFQSSMHIV(B35)POL-7 VPVKLKPGM HIV(B35)POL-27 YPGIKVRQLHIV(B35)POL-9 GPKVKQWPLHIV(B35)ARV2-1 EPIDKELY HIV(B35)ARV2-25 EPIVGAETFHIV(B35)ARV2-2 EPVHEVYY HIV(B35)ARV2-26 QPDKSESELHIV(B35)ARV2-3 QPRTACNNCY HIV(B35)ARV2-27 LPPVVAKEIHIV(B35)ARV2-4 VPLDKDFRKY HIV(B35)ARV2-28 VPRRKAKIIHIV(B35)ARV2-5 RPWLHSLGQY HIV(B35)ARV2-29 DPGLADQLIHIV(B35)ARV2-6 RPQVPLRPMTY HIV(B35)ARV2-30 TPKKTKPPLHIV(B35)ARV2-7 RPNNNTRKSIY HIV(B35)ARV2-31 PPLPSVKKLHIV(B35)ARV2-8 FPVRPQVPL HIV(B35)ARV2-32 FPRPWLHSLHIV(B35)ARV2-9 RPQVPLRPM HIV(B35)ARV2-33 DPNPQEVVLHIV(B35)ARV2-10 RRPMTYKAAL HIV(B35)ARV2-34 KPCVKLTPLHIV(B35)ARV2-11 YPLTFGWCF HIV(B35)ARV2-35 CPKVSFEPIHIV(B35)ARV2-12 LPPLERLTL HIV(B35)ARV2-36 RPIVSTQLLHIV(B35)ARV2-18 TPSQKQEPI HIV(B35)ARV2-37 DPEIVMHSFHIV(B35)ARV2-19 YPLTSLRSL HIV(B35)ARV2-38 LPCRIKQIIHIV(B35)ARV2-20 LPGKWKPKM HIV(B35)ARV2-39 SPLSFQTRLHIV(B35)ARV2-24 IPLTEEAEL
(2)合成HIV肽与HLA—B*3501抗原结合的测定
用表达HLA—B*3501的小鼠细胞株RMA—S株测定合成的HIV肽是否结合。
2—1,RMA—S—B*3501细胞的制备
HLA—B*3501基因可用原来报告过的方法从含有这个抗原的人末梢血淋巴细胞染色体DNA克隆化取得(Ooba et al.,Immuno-genetics,30,76(1989))。即用常规方法从含有HLA—B*3501抗原的人末梢血淋巴细胞制备染色体DNA,用限制性酶EcoRI消化后经蔗糖密度梯度离心得到6.0—8.5Kb的片断。将这些DNA片断插入噬菌体载体λZAP(购自东洋纺社)制成基因组文库。以HLA—B7CDNA(Coppin et al.,Proc.Natl.Acad.Sci.USA,82 8614,(1985)为探针筛选这个文库,得到含有HLA—B*3501基因的克隆。得到的基因用electro poration法移入RMA—S细胞(Liungguenet al.,J.Immunol.,142,2911(1989)),通过应用HLA—Bw6单克隆抗体、SFR8、B6(ATCC HB152)的fiowcytomltry来选择表达基因的细胞。RMA—S—B*3501细胞已委托通产省工业技术院生命工学工业技术研究所保藏,保藏编号为FERM BP—4727。
2—2用RMA—S—B*3501细胞测定合成的HIV肽与HLA—B*3501细胞抗原的结合。
RMA—S细胞是缺乏TAP(Transporter Associated Protein)抗原的小鼠细胞株。因此,在37℃培养时,细胞表面只表达低水平的MHCI类抗原。但已经发现在低温(26℃)培养时,未结合肽的I类抗原在细胞表面高水平表达(Liunggren et al.,Nature,346,476,(1990))。
RMA—S—B*3501细胞也同样在26℃培养时HLA—B*3501抗原在细胞表面高水平表达,但在37℃培养时表达水平低下。而且26℃培养的RMA—S—B*3501细胞置于37℃3小时,其HLA—B*3501抗原的表达则与37℃培养的情形相同,表达量减低。但是未结合肽的HLA—B*3501抗原结合了从外面加入的肽时,肽结合的HLA—B*3501抗原即使置于37℃也不消失,保持高表达量。图1表示加入与HLA—B*3501抗原有结合活性的自身抗原肽28H(LPGPKFLQY:图中用△表示)、37F(LPFDFTPGY:图中用○表示)和无结合活性的肽MP—1(KGILGKVFTLTV:图中用□表示)时,HLA—B*3501表达水平的变化。得出了HLA—B*3501抗原的表达量依赖于有结合活性的肽的加入量的结论。关于有与HLA—B*3501抗原结合活性的自身抗原肽28H、37F和无结合活性的肽MP—1,记载在Nature,360,434(1992)、Immunogenetics,38,161(1993)。因此,这个实验体系以HLA—B*3501抗原的细胞表层表达量为指标首次能容易地测定外加肽与HLA—B*3501结合的活性。实际测定被测肽的结合操作是于26℃培养的RMA—S—B*3501细胞中加入该肽,在26℃下放置1小时,然后37℃放置3小时后使用抗HLA—Bw6单克隆抗体、SFR8·B6和flowcytometry测定HLA—B*3501抗原的表达水平。▲:未添加肽的对照、●:未添加肽且只在26℃培养的对照,■:未加肽且只在37℃培养的对照。
测定了58种HIV肽与HLA—B*3501抗原的结合,如表2所示26种肽发生了结合。
表2结合的亲和性 肽 序列 位置高亲和性 HIV(B35)-3 TPGPGIRY nef 133-139
HIV(B35)-14 NPDIVIYQY pol 330-338
HIV(B35)ARV2-8 FPVRPQVPL nef 72-80中亲和性 HIV(B35)-16 TPPLVKLWY pol 574-582
HIV(B35)-18 EPIVGAETFY pol 587-596
HIV(B35)-20 IPAETGQETAY pol 804-814
HIV(B35)POL-20 SPAIFQSSM pol 311-319
HIV(B35)ARV2-11 YPLTFGWCF nef 139-147
HIV(B35)ARV2-19 YPLTSLRSL gag 486-494
HIV(B35)ARV2-25 EPIVGAETF pol 587-595低亲和性 HIV(B35)-7 NPPIPVGEIY gag 255-264
HIV(B35)-8 EPFRDYVDRFY gag 293-303
HIV(B35)-15 EPPFLWMGY pol 379-387
HIV(B35)-19 EPFKNLKTGKY pol 587-596
HIV(B35)GAG-20 GPAATLEEM gag 340-348
HIV(B35)GAG-26 APPEESFRF gag 459-467
HIV(B35)ARV2-1 EPIDKELY gag 479-486
HIV(B35)ARV2-2 EPVHEVYY pol 467-474
HIV(B35)ARV2-4 VPLDKDFRKY pol 273-282
HIV(B35)ARV2-6 RPQVPLRPMTY nef 75-85
HIV(B35)ARV2-9 RPQVPLRPM nef 75-83
HIV(B35)ARV2-12 LPPLERLTL rev 75-83
HIV(B35)ARV2-24 IPLTEEAEL pol 448-456
HIV(B35)ARV2-33 DPNPQEVVL env 77-85
HIV(B35)ARV2-36 RPIVSTQLL env 255-263
HIV(B35)ARV2-38 LPCRIKQII env 413-421
(3)与HLA—B*3501结合的肽诱导感染HIV患者的CTL的作用。
具有HLA—B*3501的感染HIV患者3人:患者A(HLA—A24/31,B35/61,Cw3/—)、患者B(HLA—A24/26,B35/61,Cw3/—)及患者C(HLA—A24/26,B35/51,Cw3/—)。分离他们的淋巴细胞。淋巴细胞的分离采用常用的Ficoll—Cnray比重离心法(矢田纯一、藤原道夫编著,《新淋巴球机能检索法》,中外医学社(1987)、《新生化学实验讲座12·分子免疫学I》,东京化学同人(1989)。即用加肝素的注射器采血后用生理盐水稀释加到Ficoll—Paqul分离液(Pharmacia公司)上分层后室温下以400×g离心30分钟。用移液管回收、洗涤中间层的淋巴细胞组分。于24孔培养板的各孔内加入2×106个淋巴细胞,再用加入了终浓度分别为50μ/ml及1μM的人重组白细胞介素2(recombinant IL2)及合成肽的RP-MI1640(含10%FCS)培养液培养。隔2—3天,用加入了浓度为50μ/ml的IL2的RPMI1640培养液进行半量换液。1周后,用PHA刺激后分别加入经放射线照射的自身淋巴细胞(1×106)和1μM的合成肽再次刺激特异CTL细胞使增殖后,再培养1周,测定CTL的活性。
(4)使用HLA—B*3501结合肽而诱导产生的CTL的细胞杀伤活性的测定。
4—1,T2—B*—3501细胞的制备
将HLA—B*3501基因用electropration法移至TAP抗原基因缺失的人淋巴细胞株T2细胞内(salter et al.,EMBO J.,5,943,(1986)),用SFR·B6单克隆抗体经flowcytometry选择表达的细胞,命名这种细胞为T2—B*3501。T2—B*3501细胞已委托通产省工业技术院生命工学工业技术研究所保藏,保藏编号为FERM BP—4726。
HLA—B35的患者感染HIV发病时,感染HIV的淋巴细胞表面表达HLA—B*3501抗原和提呈HIV肽。T2—B*3501细胞与(2)中RMA—S—B*3501细胞同样在26℃表达时,大量表达未结合肽的HLA—B*3501抗原。所以在这样的条件下使肽与之结合,所谓人为制造感染了HIV的淋巴细胞作为测定CTL的细胞性活性的靶细胞使用。
4—2,测定CTL的细胞毒性活性
将1×106个T2—B*3501细胞或T 2细胞与100μCi的Na2 51CrO4于26℃的条件下混合90分钟,然后用含10%FCS的RPMI-1640培养液洗涤3次后作为标记靶细胞。于96孔培养板的各孔内加入悬浮于50μl培养液的5×103个标记靶细胞(T2或T2—B*3501细胞),再加入稀释至4μM~4×10-4μM的合成肽溶液5μl,放入CO2温箱中30分钟后,加入前项肽刺激下培养的患者末梢淋巴细胞1×105、2.5×104或6.25×103(悬浮于100μl的培养液中),放入37℃的CO2温箱中4小时。然后取各孔半量的培养液(100μl),用7计数仪测定因培养的患者末梢淋巴细胞的细胞毒性活性而从靶细胞游离的51Cr。特异的细胞毒性活性可按下面公式计算。
但,最小释放值是只放入靶细胞的孔的测定值,是51Cr从靶细胞的自然游离值。最大释放值是靶细胞中加入表面活性剂Triton100破坏细胞时的标记游离值。
结果见图2、3、4。图2为HIV(B35)—16(序列号3)、图3为HIV(B35)—18(序列号4)、图4为HIV(B35)POL—20(序列号6)的结果。证实了这些合成肽能有效地诱导杀伤结合了肽的T2—B*3501细胞的CTL细胞。
用同样的方法测定了表2中记载的肽能否诱导对HIV的免疫应答,其中能诱导对HIV免疫应答的肽总结在表3中。
表3结合的亲和性 肽 序列 位置高亲和性 HIV(B35)-14 NPDIIYQY pol 330-338
HIV(B35)ARV2-8 FPVRPQVPL nef 72-80中亲和性 HIV(B35)-16 TPPLVKLWY pol 574-582
HIV(B35)-18 EPIVGAETFY pol 587-596
HIV(B35)POL-20 SPAIFQSSM pol 311-319
HIV(B35)ARV2-11 YPLTFGWCF nef 139-147
HIV(B35)ARV2-25 EPIVGAETF pol 587-595低亲和性 HIV(B35)ARV2-4 VPLDKDFRKY pol 273-282
HIV(B35)ARV2-6 RPQVPLRPMTY nef 75-85
HIV(B35)ARV2-24 IPLTEEAEL pol 448-456
HIV(B35)ARV2-33 DPNPQEVVL env 77-85
HIV(B35)ARV2-36 RPIVSTQLL env 255-263
HIV(B35)ARV2-38 LPCRIKQII env 413-421
同样对MN株、NDK株、HXB2株HIV序列进行测试,选出了表4中所列的肽。
表4结合的亲和性 肽 序列 位置高亲和性 HIV(B35)GAG-24 FPQSRTEPT gag 450-458(MN)
HIV(B35)POL-5 FPISPIETV pol 155-163中亲和性 HIV(B35)-17 VPLDEDFRKY pol 182-191(HXB2)
HIV(B35)-29 EPIIGAETFY pol 586-595(NDK)
HIV(B35)GAG-9 HPVHAGPIT gag 219-227(MN)
HIV(B35)GAG-29 YPLASLKSL gag 490-498(MN)低亲和性 HIV(B35)-9 KPQVPLRPMTY nef 73-83(MN)
HIV(B35)-12 EPVHGVYY pol 466-473(NDK)
HIV(B35)-25 NPEIVIYQY pol 329-327(NDK)
HIV(B35)GAG-4 VPIVQNIEG gag 135-143(MN)
HIV(B35)POL-26 LPEKDSWTV pol 401-409
实施例2
作为与HLA结合基序,采用HLA—B51结合抗原肽的基序,是由8~11个氨基酸组成、第2位是Pro、Ala、及Gly中的任一种氨基酸、C末端是Ile、Leu、Val、Phe及Met中任一种氨基酸的氨基酸序列,且采用SF—2株HIV的蛋白质序列及RMA—S—B*5101细胞,余皆同实施例1,得到能诱导对HIV免疫应答的肽。这些肽总结于表5。RMA—S—B*5101细胞已委托通产省工业技术院生命工学工业技术研究所保藏,保藏编号为FERM BP—4834。
表5
肽 序列 位置HIV-B35-GAG-13(A55) NPPIPVGEI GAG255-264HIV-B35-GAG-29(A69) YPLASLKSL GAG490-498HIV-B35-POL-5(A74) FPISPIETV POL155-163HIV-B35-POL-7(A76) VPVKLKPGM POL163-171HIV-B35-POL-26(A95) LPEKDSWTV POL401-409HIV-B35-SF2-8(C-1) FPVRPQVPL NEF71-80HIV-B35-SF2-21(C-7) YPLTSLRSL GAG486-494HIV-B35-SF2-27(C-12) LPPVVAKEI POL743-751HIV-B35-SF2-32(C-17) FPRPWLHSL VPR34-42HIV-B35-SF2-35(C-20) CPKVSFEPI ENV208-216HIV-B35-SF2-38(C-23) LPCRIKQII ENV413-421HIV-B35-33(C-31) YPCTVNFTI ENV618-626HIV-B35-34(C-32) LPALSTGLI ENV682-690HIV-B35-36(C-34) CPSGHAVGI ENV1171-1179HIV-B35-39(C-37) IPTSGDVVI ENV1426-1434HIV-B35-50(C-48) LPPTIGPPI ENV2316-2324HIV-B35-55(C-53) APTLWARMI ENV2835-2843HIV-B35-56(C-54) EPLDLPQII ENV2874-2882HIV-B51-3(H-3) NANPDCKTI GAG327-335HIV-B51-7(H-7) TAVQMAVFI POL989-997HIV-B51-9(H-9) RAFHTTGRI ENV316-324HIV-B51-10(H-10) YAPPIGGQI ENV432-440HIV-B51-11(H-11) QARQLLSGI ENV539-547HIV-B51-12(H-12) VAQRAYRAI ENV831-839HIV-B51-13(H-13) RAYRAILHI ENV834-842HIV-B51-29(H-18) VGPTPVNII POL133-141HIV-B51-32(H-21) QGWKGSPAI POL306-314HIV-B51-43(H-32) VGGLVGLRI ENV688-696HIV-B51-53(H-42) DARAYDTEV ENV56-64HIV-B51-54(H-43) NALFRNLDV ENV171-179HIV-B51-70(H-50) IPLGDAKLV VIF57-65HIV-B51-71(H-51) GPCTNVSTV ENV240-248HIV-B51-83(H-63) CGHKAIGTV POL123-131
实施例3
作为与HLA结合基序,采用HLA—A*3101结合抗原肽的基序,是由8~11个氨基酸组成、第2位氨基酸是Leu、Val、Tyr及Phe中的任一种氨基酸、C末端是Arg的氨基酸序列,且采用MN株HIV的蛋白质序列或SF—2株HIV的蛋白质序列及RMA—S—A*3101细胞,余皆同实施例1,得到能诱导对HIV免疫应答的肽。这些肽总结于表6。RMA—S—A*3101细胞已委托通产省工业技术院生命工学工业技术研究所保藏,保藏编号为FERM BP—4823。
表6肽 序列 位置 Kd值C-119 IVMHSFNCR ENV373-381 3.0×10-5C-121 VLAVERYLR ENV579-587 9.0×10-5C-117 NYRLIHCNR ENV193-201 1.1×10-4C-104 MVHQAISPR GAG144-152 1.4×10-4C-114 SVKKLTEDR VIF165-173 1.4×10-4C-124 SLCLFSYRR ENV761-769 2.2×10-4C-125 CLFSYRRLR ENV763-771 2.2×10-4C-111 AVFIHNFKR POL893-901 2.9×10-4C-100 KLAFHHMAR NEF192-200 3.7×10-4C-118 TVQCTHGIR ENV247-255 7.4×10-4C-113 ILGYRVSPR VIF124-132 8.9×10-4C-112 IVWQVDRMR VIF9-17 >10-4C-98 PVRPQVPLR NEF73-81 >10-4C-126 ILHIHRRIR ENV838-846 >10-4C-106 ELYPLTSLR GAG424-432 >10-4C-123 VLSIVNRVR ENV700-708 >10-4C-122 IVGGLVGLR ENV687-695 >10-4
本发明的肽,因能诱导对HIV的免疫应答,可以有效地应用在AIDS的预防、治疗上。具体地,可制成含有上述肽的AIDS疫苗,也可将具有含有编码上述肽的DNA的重组DNA的牛痘疫苗及BCG疫苗制成AIDS疫苗。而且在上述肽存在的条件下培养末梢血淋巴细胞得到的细胞毒性T细胞可作为治疗AIDS的药物应用。
序列表序列号:1序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Asn Pro Asp Ile Val Ile Tyr Gin Tyr序列号:2序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Phe Pro Val Arg Pro Gin Val Pro Leu序列号:3序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Thr Pro Pro Leu Val Lys Leu Trp Tyr序列号:4序列长:10序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Glu Pro Ile Val Gly Ala Glu Thr Phe Tyr序列号:5序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Ser Pro Ala Ile Phe Gln Ser Ser Met序列号:6序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Tyr Pro Leu Thr Phe Gly Trp Cys Phe序列号:7序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Glu Pro Ile Val Gly Ala Glu Thr Phe序列号:8序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Val Pro Leu Asp Lys Asp Phe Arg Lys Tyr序列号:9序列长:11序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Arg Pro Gln Val Pro Leu Arg Pro Met Thr Tyr序列号:10序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Ile Pro Leu Thr Glu Glu Ala Glu Leu序列号:11序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Asp Pro Asn Pro Gln Glu Val Val Leu序列号:12序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Arg Pro Ile Val Ser Thr Gln Leu Leu序列号:13序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Leu Pro Cys Arg Ile Lys Gln Ile Ile序列号:14序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Phe Pro Gln Ser Arg Thr Glu Pro Thr序列号:15序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Phe Pro Ile Ser Pro Ile Giu Thr Val序列号:16序列长:10序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Val Pro Leu Asp Glu Asp Phe Arg Lys Tyr序列号:17序列长:10序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Glu Pro Ile Ile Gly Ala Glu Thr Phe Tyr序列号:18序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列His Pro Val His Ala Gly Pro Ile Thr序列号:19序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Tyr Pro Leu Ala Ser Leu Lys Ser Leu序列号:20序列长:11序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Lys Pro Gln Val Pro Leu Arg Pro Met Thr Tyr序列号:21序列长:8序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Glu Pro Val His Gly Val Tyr Tyr序列号:22序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Asn Pro Glu Ile Val Ile Tyr Gln Tyr序列号:23序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Val Pro Ile Val Gln Asn Ile Glu Gly序列号:24序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Leu Pro Glu Lys Asp Ser Trp Thr Val序列号:25序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Asn Pro Pro Ile Pro Val Gly Glu Ile序列号:26序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Tyr Pro Leu Ala Ser Leu Lys Ser Leu序列号:27序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Val Pro Val Lys Leu Lys Pro Gly Met序列号:28序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Tyr Pro Leu Thr Ser Leu Arg Ser Leu序列号:29序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Leu Pro Pro Val Val Ala Lys Glu Ile序列号:30序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Phe Pro Arg Pro Trp Leu His Ser Leu序列号:31序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Cys Pro Lys Val Ser Phe Glu Pro Ile序列号:32序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Asn Ala Asn Pro Asp Cys Lys Thr Ile序列号:33序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Thr Ala Val Gln Met Ala Val Phe Ile序列号:34序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Arg Ala Phe His Thr Thr Gly Arg Ile序列号:35序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Tyr Ala Pro Pro Ile Gly Gly Gln Ile序列号:36序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Gln Ala Arg Gln Leu Leu Ser Gly Ile序列号:37序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Val Ala Gln Arg Ala Tyr Arg Ala Ile序列号:38序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Arg Ala Tyr Arg Ala Ile Leu His Ile序列号:39序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Val Gly Pro Thr Pro Val Asn Ile Ile序列号:40序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Gln Gly Trp Lys Gly Ser Pro Ala Ile序列号:41序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Val Gly Gly Leu Val Gly Leu Arg Ile序列号:42序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Asp Ala Arg Ala Tyr Asp Thr Glu Val序列号:43序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Asn Ala Leu Phe Arg asn Leu Asp Val序列号:44序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Ile Pro Leu Gly Asp Ala Lys Leu Val序列号:45序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Gly Pro Cys Thr Asn Val Ser Thr Val序列号:46序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Cys Gly His Lys Ala Ile Gly Thr Val序列号:47序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Ile Val Met His Ser Phe Asn Cys Arg序列号:48序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Val Leu Ala Val Glu Arg Tyr Leu Arg序列号:49序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Asn Tyr Arg Leu Ile His Cys Asn Arg序列号:50序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Met Val His Gln ALa Ile Ser Pro Arg序列号:51序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Ser Val Lys Lys Leu Thr Glu Asp Arg序列号:52序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Ser Leu Cys Leu Phe Ser Tyr Arg Arg序列号:53序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Cys Leu Phe Ser Tyr Arg Arg Leu Arg序列号:54序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Ala Val Phe Ile His Asn Phe Lys Arg序列号:55序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Lys Leu Ala Phe His His Met Ala Arg序列号:56序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Thr Val Gln Cys Thr His Gly Ile Arg序列号:57序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Ile Leu Gly Tyr Arg Val Ser Por Arg序列号:58序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Ile Val Trp Gln Val Asp Arg Met Arg序列号:59序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Pro Val Arg Pro Gln Val Pro Leu Arg序列号:60序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Ile Leu His Ile His Arg Arg ILe Arg序列号:61序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Glu Leu Tyr Pro Leu Thr Ser Leu Arg序列号:62序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Val Leu Ser Ile Val Asn Arg Val Arg序列号:63序列长:9序列类型:氨基酸拓扑结构:直链序列种类:肽来源生物名:人类免疫缺陷病毒序列Ile Val Gly Gly Leu Val Gly Leu Arg序列号:64序列长:27序列类型:核酸拓扑结构:直链链数:双链来源生物名:人类免疫缺陷病毒序列ACTCCGCCGC TGGTTAAACT GTGGTAC序列号:65序列长:30序列类型:核酸拓扑结构:直链 链数:双链序列种类:肽来源生物名:人类免疫缺陷病毒序列GAACCGATCG TTGGTGCTGA AACTTTCTAC序列号:66序列长:27序列类型:核酸拓扑结构:直链链数:双链序列种类:肽来源生物名:人类免疫缺陷病毒序列TCTCCGGCTA TCTTCCAGTC TTCTATG
Claims (17)
1.一种作为HIV全蛋白片断的肽,该片断为含有8-11个氨基酸的连续序列的肽,相当于与HLA结合的基序,能与HLA实际结合且能诱导以HIV感染细胞为靶细胞的杀伤细胞。
2.权利要求1中记载的肽,该肽具有9—11个氨基酸的连续序列。
3.权利要求1中记载的肽,该肽具有序列号为1—63中任一种氨基酸序列。
4.权利要求1中记载的肽,其中与HLA结合的基序是8—11个氨基酸的序列,是从第2位是Pro、C末端是Tyr、Leu、Ile、Met、Phe及Ala的氨基酸组成的组中选择的氨基酸。
5.权利要求4中记载的肽,该肽具有序列号1—24中任一种氨基酸序列。
6.权利要求4中记载的肽,该肽具有序列号1—13中任一种氨基酸序列。
7.权利要求1中记载的肽,其中与HLA结合的基序是8—11个氨基酸的序列,是从第2位是Pro、Ala及Gly、C末端是Ile、Leu、Val、Phe及Met的氨基酸组成的组中选择的氨基酸。
8.权利要求7中记载的肽,该肽具有序列号25—46中的任一种氨基酸序列。
9.权利要求1中记载的肽,其中与HLA结合的基序是8—11个氨基酸的序列,是从第2位是Leu、Val、Tyr及Phe、C末端是Arg的氨基酸组成的组中选择的氨基酸。
10.权利要求9中记载的肽,该肽具有序列号47—63中的任一种氨基酸序列。
11.编码权利要求1中记载的肽的DNA。
12.含有权利要求1中记载的肽及医药上允许使用的载体和/或稀释剂的预防、治疗AIDS的药物。
13.含有权利要求3中记载的肽及医药上允许使用的载体和/或稀释剂的预防、治疗AIDS的药物。
14.含有权利要求4中记载的肽及医药上允许使用的载体和/或稀释剂的预防、治疗AIDS的药物。
15.含有权利要求6中记载的肽及医药上允许使用的载体和/或稀释剂的预防、治疗AIDS的药物。
16.通过向AIDS患者给以权利要求1中记载的肽来治疗AIDS的方法。
17.选取能诱导以HIV感染细胞为靶细胞的杀伤细胞的肽的方法,其特征在于,合成作为HIV全蛋白片断的含有8—11个氨基酸的连续序列的相当于HLA结合基序的肽,从合成的肽中选择能与HLA实际结合的肽,然后从选择的合成肽中选取与HLAI类抗原结合并能通过刺激HIV疾病患者末梢淋巴细胞从而诱导杀伤细胞的肽。
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US (1) | US5756666A (zh) |
EP (1) | EP0728764A4 (zh) |
JP (1) | JP3814828B2 (zh) |
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CN (1) | CN1055701C (zh) |
AU (1) | AU685521B2 (zh) |
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Families Citing this family (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7252829B1 (en) | 1998-06-17 | 2007-08-07 | Idm Pharma, Inc. | HLA binding peptides and their uses |
US20020168374A1 (en) * | 1992-08-07 | 2002-11-14 | Ralph T. Kubo | Hla binding peptides and their uses |
US6555114B1 (en) * | 1993-11-04 | 2003-04-29 | Innogenetics N.V. | Immunodominant human T-cell epitopes of hepatitis C virus |
UA68327C2 (en) * | 1995-07-04 | 2004-08-16 | Gsf Forschungszentrum Fur Unwe | A recombinant mva virus, an isolated eukaryotic cell, infected with recombinant mva virus, a method for production in vitro of polypeptides with use of said cell, a method for production in vitro of virus parts (variants), vaccine containing the recombinant mva virus, a method for immunization of animals |
ATE511849T1 (de) * | 1996-03-11 | 2011-06-15 | Epimmune Inc | Peptide mit erhöhter bindungsaffinität für mindestens drei hla-a3-ähnliche moleküle |
US6734287B1 (en) | 1998-04-09 | 2004-05-11 | Idexx Laboratories, Inc. | Specific binding proteins for treating canine allergy |
EP0955311A3 (en) * | 1998-04-09 | 2000-08-16 | Idexx Laboratories, Inc. | Peptide vaccine for canine allergy |
US6667037B1 (en) * | 1998-10-09 | 2003-12-23 | Ludwig Institute For Cancer Research | Isolated peptides which bind to HLA-B35 molecules, larger peptides which contain these, nucleic acid molecules encoding peptides, and uses thereof |
WO2000023053A2 (en) | 1998-10-20 | 2000-04-27 | Salvatore Albani | Artificial antigen-specific cells and related methods |
US7807377B2 (en) | 1998-10-20 | 2010-10-05 | Salvatore Albani | Method of isolating antigen-specific T cells employing artificial antigen presenting cells |
US6787154B2 (en) * | 1998-10-20 | 2004-09-07 | Salvatore Albani | Artificial antigen presenting cells |
NO311807B1 (no) | 1999-03-04 | 2002-01-28 | Bionor Immuno As | HIV-peptider, antigener, vaksinepreparater, immunoassay- testsett og en metode for påvisning av antistoffer fremkalt av HIV |
JP2002539818A (ja) * | 1999-03-30 | 2002-11-26 | アイデックス ラボラトリーズ インコーポレイテッド | イヌのアレルギーを治療するための特異的結合蛋白 |
EP1082340A1 (en) * | 1999-03-30 | 2001-03-14 | Idexx Laboratories, Inc. | Peptide vaccine for canine allergy |
WO2000073465A1 (fr) * | 1999-05-28 | 2000-12-07 | Ajinomoto Co.,Inc. | Peptides capables d'induire des cellules tueuses specifiques du vih et agents prophylactiques/medicaments contre le vih contenant ces peptides |
FR2794370B1 (fr) | 1999-06-03 | 2003-10-17 | Biovector Therapeutics | Fragments proteiques polyepitopiques, leur obtention et leurs utilisations notamment en vaccination |
AU1075001A (en) * | 1999-10-05 | 2001-05-10 | Epimmune, Inc. | Inducing cellular immune responses to human immunodeficiency virus-1 using peptide and nucleic acid compositions |
WO2002020053A1 (en) * | 2000-09-01 | 2002-03-14 | Epimmune Inc. | Hla binding peptides and their uses |
WO2004031345A2 (en) * | 2002-05-20 | 2004-04-15 | The General Hospital Corporation | Cytotoxic t-cell epitopes of hiv-1 virus |
WO2004024129A1 (en) * | 2002-09-10 | 2004-03-25 | Samir Chachoua | Induced remission therapy |
US7442375B2 (en) * | 2002-12-13 | 2008-10-28 | Case Western Reserve University | Compositions of beta-defensin inducing agents |
AU2003301012A1 (en) * | 2002-12-13 | 2004-07-09 | Case Western Reserve University | Use of beta-defensins for treating hiv infections |
US20060147997A1 (en) * | 2004-11-30 | 2006-07-06 | Virosys Pharmaceuticals, Inc. | PenetraBodies: receptor-mediated targeted delivery of functionally-active human antibody fragments into cytosol for the treatment of chronic infections and diseases |
ES2573105T3 (es) | 2006-03-10 | 2016-06-06 | Peptcell Limited | Secuencias de péptidos y composiciones |
US20090175838A1 (en) * | 2007-01-26 | 2009-07-09 | Newell Rogers M Karen | Methods of modulating immune function |
EP2215108A4 (en) * | 2007-10-23 | 2012-07-04 | Univ Colorado | COMPETITIVE INHIBITORS OF THE EXPRESSION OF THE CONSTANT CHAIN AND / OR THE ECTOPIC CLIP BINDING |
WO2010008554A2 (en) | 2008-07-14 | 2010-01-21 | The Regents Of The University Of Colorado | Methods and products for treating proliferative diseases |
CA2737144A1 (en) * | 2008-07-25 | 2010-01-28 | The Regents Of The University Of Colorado | Methods for treating viral disorders |
US20100166789A1 (en) * | 2008-07-25 | 2010-07-01 | The Regents Of The University Of Colorado | Proteins for use in diagnosing and treating infection and disease |
US20100166782A1 (en) * | 2008-07-25 | 2010-07-01 | Martha Karen Newell | Clip inhibitors and methods of modulating immune function |
US8986712B2 (en) | 2009-11-29 | 2015-03-24 | Yeda Research And Development Co., Ltd. | Peptides derived from HIV-1 gp41 transmembrane domain for t-immunomodulation |
CA2793959C (en) | 2010-03-25 | 2019-06-04 | Oregon Health & Science University | Cmv glycoproteins and recombinant vectors |
CA2832109C (en) | 2011-06-10 | 2021-07-06 | Oregon Health & Science University | Cmv glycoproteins and recombinant vectors |
AU2012216792A1 (en) | 2011-09-12 | 2013-03-28 | International Aids Vaccine Initiative | Immunoselection of recombinant vesicular stomatitis virus expressing HIV-1 proteins by broadly neutralizing antibodies |
EP2586461A1 (en) | 2011-10-27 | 2013-05-01 | Christopher L. Parks | Viral particles derived from an enveloped virus |
EP2679596B1 (en) | 2012-06-27 | 2017-04-12 | International Aids Vaccine Initiative | HIV-1 env glycoprotein variant |
WO2014026033A1 (en) * | 2012-08-08 | 2014-02-13 | University Of Florida Research Foundation, Inc. | Cross-reactive t cell epitopes of hiv, siv, and fiv for vaccines in humans and cats |
US20150065381A1 (en) | 2013-09-05 | 2015-03-05 | International Aids Vaccine Initiative | Methods of identifying novel hiv-1 immunogens |
EP2873423B1 (en) | 2013-10-07 | 2017-05-31 | International Aids Vaccine Initiative | Soluble hiv-1 envelope glycoprotein trimers |
US10174292B2 (en) | 2015-03-20 | 2019-01-08 | International Aids Vaccine Initiative | Soluble HIV-1 envelope glycoprotein trimers |
US9931394B2 (en) | 2015-03-23 | 2018-04-03 | International Aids Vaccine Initiative | Soluble HIV-1 envelope glycoprotein trimers |
JP2018528974A (ja) | 2015-09-25 | 2018-10-04 | フロリダ大学 リサーチファウンデーション インコーポレイティッド | ヒトおよびネコにおけるワクチンのためのhiv、sivおよびfivの交差反応性t細胞エピトープ |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CS256960B1 (en) * | 1985-11-16 | 1988-04-15 | Viktor Krchnak | Peptides with properties of antigenic determinants and method of their production |
EP0347425B1 (en) * | 1987-03-02 | 1995-12-27 | Whitehead Institute For Biomedical Research | Recombinant mycobacterial vaccine |
US5128319A (en) * | 1987-08-28 | 1992-07-07 | Board Of Regents, The University Of Texas System | Prophylaxis and therapy of acquired immunodeficiency syndrome |
EP0330359A3 (en) * | 1988-02-25 | 1991-06-05 | Bio-Rad Laboratories, Inc. | Composition useful in the diagnosis and treating of hiv-1 infection |
US4943628A (en) * | 1988-06-13 | 1990-07-24 | Ortho Pharmaceutical Corporation | HIV peptide-inducted T cell stimulation |
GB8918200D0 (en) * | 1989-08-09 | 1989-09-20 | Medical Res Council | The peptide fragments of hiv |
US5480967A (en) * | 1990-01-05 | 1996-01-02 | United Biomedical, Inc. | HIV-1 core protein fragments |
ES2145768T3 (es) * | 1991-12-02 | 2000-07-16 | Univ Texas | Composiciones para provocar respuestas de linfocitos t citotoxicos contra virus. |
DE69435292D1 (de) * | 1993-03-05 | 2010-06-17 | Epimmune Inc | Verfahren zur herstellung von immunogenen hla-a2.1-bindenden peptiden |
DE69430315T2 (de) * | 1993-08-06 | 2002-11-21 | Epimmune Inc | Methoden zur (ex vivo) therapie mittels peptid - bestueckten antigen - praesentierenden zellen zur aktivierung von ctl |
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1994
- 1994-10-19 WO PCT/JP1994/001756 patent/WO1995011255A1/ja not_active Application Discontinuation
- 1994-10-19 US US08/615,181 patent/US5756666A/en not_active Expired - Lifetime
- 1994-10-19 CA CA002173138A patent/CA2173138A1/en not_active Abandoned
- 1994-10-19 KR KR1019960701994A patent/KR100235849B1/ko not_active IP Right Cessation
- 1994-10-19 EP EP94930335A patent/EP0728764A4/en not_active Withdrawn
- 1994-10-19 CN CN94193851A patent/CN1055701C/zh not_active Expired - Fee Related
- 1994-10-19 JP JP51160595A patent/JP3814828B2/ja not_active Expired - Fee Related
- 1994-10-19 AU AU79487/94A patent/AU685521B2/en not_active Ceased
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EP0728764A4 (en) | 1999-01-20 |
JP3814828B2 (ja) | 2006-08-30 |
CA2173138A1 (en) | 1995-04-27 |
US5756666A (en) | 1998-05-26 |
EP0728764A1 (en) | 1996-08-28 |
AU7948794A (en) | 1995-05-08 |
CN1055701C (zh) | 2000-08-23 |
KR960704923A (ko) | 1996-10-09 |
KR100235849B1 (ko) | 1999-12-15 |
AU685521B2 (en) | 1998-01-22 |
WO1995011255A1 (fr) | 1995-04-27 |
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