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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目前有4000多万人感染了艾滋病毒-1，在世界许多不发达地区，这一数字预计将呈指数级增长。体液免疫很可能将是疫苗诱导的针对HIV-1感染的保护的必要组成部分；然而，事实证明，针对HIV-1包膜(Env)糖蛋白的广泛和有效的中和抗体(NAB)尤其困难。最近的几项研究乐观地指出，在某些环境中传播并建立感染的病毒通过了一个可以针对HIV-1感染的遗传瓶颈：(I)在赞比亚新传播的C亚型病毒在环境中的糖基化程度较低，在环境中的可变环区域更紧凑，并且比来自慢性感染指标病例的未传播病毒更敏感；(Ii)在肯尼亚新传播的A亚型病毒的环境病毒具有较短的V1V2环序列和较少的N-连接糖基化位点，(Iii)在恒河猴(非自然宿主)中建立感染的SIVsm病毒具有紧凑、与接种物中存在的变体相比，Env中的V1V2糖基化结构域较少。 目前的项目建立在上述最初发现的基础上，即从慢性感染的伴侣传播C亚型HIV-1似乎选择了具有紧凑环境的病毒，该病毒对中和敏感，而在指标病例的准种中，针对具有大的、大量糖基化的环境的中和耐药病毒。 我们的假设是，这一瓶颈产生了一种独特的但短暂的Env抗原，该抗原将在豚鼠免疫后诱导抗体，能够中和自体病毒并交叉中和其他新传播的毒株。新传播的env应能激发针对保守的中和表位的抗体，而这些表位通常是无法获得的，例如辅助受体和CD4结合域，因为这些区域的暴露对传播或生长是重要的。相反，在我们的模型中，来自慢性感染指征病例的中和抗性环境病毒将无法诱导出能够中和新传播毒株的抗体。

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.