HIV-1 VACCINE CANDIDATES USING NEWLY TRANSMITTED CLADE C ENVS AS IMMUNOGENS

使用新传播的 C 型 ENVS 作为免疫原的 HIV-1 候选疫苗

• 批准号: 7715838
• 负责人: Jerry L Blackwell
• 金额: $ 6.8万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715838
• 关键词: Antibodies; Antigens; Autologous; Binding; Cavia; Computer Retrieval of Information on Scientific Projects Database; Epitopes; Funding; Genetic; Glycoproteins; Grant; HIV-1; Humoral Immunities; Immunization; Infection; Institution; Kenya; Link; Macaca mulatta; Modeling; Numbers; Population; Relative (related person); Research; Research Personnel; Resistance; Resources; Site; Source; United States National Institutes of Health; Vaccines; Variant; Virus; Zambia; glycosylation; indexing; neutralizing antibody; optimism; transmission process

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Over 40 million people are currently infected with HIV-1 and this number is expected to rise exponentially in many underdeveloped regions of the world. It is likely that humoral immunity will be a necessary component of vaccine-induced protection against HIV-1 infection; however, it has proven especially difficult to elicit broad and potent neutralizing antibodies (Nab) against the HIV-1 envelope (Env) glycoproteins. Several recent studies provide optimism that the viruses that are transmitted and establish infection in some settings pass through a genetic bottleneck that could be targeted to protect against HIV-1 infection: (i) newly transmitted subtype C viruses in Zambia have less glycosylated, more compact variable loop regions in Env and are more neutralization sensitive than the non-transmitted viruses from the chronically infected index case, (ii) newly transmitted subtype A viruses in Kenya have Envs with shorter V1V2 loop sequences and fewer N-linked glycosylation sites relative to the circulating population, and (iii) SIVsm viruses that establish infection in rhesus macaques (a non-natural host) have compact, less glycosylated V1V2 domains in Env compared to the variants present in the inoculum. The current project builds on the original finding described above that transmission of subtype C HIV-1 from a chronically infected partner appears to select FOR a virus with a compact Env that is neutralization sensitive, and AGAINST neutralization resistant viruses with large, heavily glycosylated Envs in the quasispecies of the index case. Our hypothesis is that this bottleneck produces a unique yet transient Env antigen that will induce antibodies upon immunization of guinea pigs that are able to neutralize the autologous virus and cross-neutralize other newly transmitted strains. Newly transmitted Envs should elicit antibodies to conserved neutralization epitopes that are not normally accessible, such as the coreceptor and CD4 binding domain, because exposure of these regions is important for transmission or outgrowth. By contrast, neutralization resistant Envs derived from the chronically infected index case will fail to induce antibodies that can neutralize the newly transmitted strains in our model.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 目前，超过4000万人感染了HIV-1，这一数字预计在世界许多欠发达地区将呈指数增长。 体液免疫可能是疫苗诱导的防止HIV-1感染的必要组成部分。然而，事实证明，引起对HIV-1包膜（ENV）糖蛋白的广泛而有效的中和抗体（NAB）的广泛和有效的中和抗体的困难。最近的几项研究表明，在某些情况下传播并建立感染的病毒经过遗传瓶颈，该病毒可以针对防止HIV-1感染来防止HIV-1感染：（i）赞比亚在赞比亚的新传播的亚型C病毒具有糖基较少的糖基化，在Env和II中具有更高的中性病毒性（在ENV上更加敏感）（更加中性）（均具有更高的状态），该病毒率（CORN）比（Chrons consex anderaintial carration consex anderizatization carry consex and carry）（chrol）（chrol）（con）（chrol）consemantial（chrop）consemantial（chrop）的质量比（chard）更敏感。 newly transmitted subtype A viruses in Kenya have Envs with shorter V1V2 loop sequences and fewer N-linked glycosylation sites relative to the circulating population, and (iii) SIVsm viruses that establish infection in rhesus macaques (a non-natural host) have compact, less glycosylated V1V2 domains in Env compared to the variants present in the inoculum. 当前的项目建立在上面描述的原始发现的基础上，从慢性感染的伴侣中传播亚型C HIV-1似乎可以选择具有中和敏感的紧凑型ENV的病毒，并在索引情况的准典型中具有大型，大糖基化的耐中和抗中和抗性病毒。 我们的假设是，这种瓶颈会产生一种独特而瞬态的ENV抗原，该抗原将在能够中和自体病毒并交叉中和其他新传播菌株的豚鼠免疫后诱导抗体。新传输的Envs应引起对通常无法获得的保守中和表位的抗体，例如coleceptor和CD4结合结构域，因为这些区域的暴露对于传播或出现很重要。相比之下，从慢性感染的指数病例中得出的中和抗性Envs将无法诱导可以中和我们模型中新传播菌株的抗体。