Novel HIV-1 vaccine candidates using newly transmitted clade C Envs as immunogens

目前有4 000多万人感染了艾滋病毒1型， 在可预见的未来，这一数字预计将在许多欠发达地区呈指数级增长， 世界很可能体液免疫将是疫苗诱导保护的必要组成部分 针对HIV-1感染;然而，已经证明特别难以引起广泛和有效的中和， 针对HIV-1包膜（Env）糖蛋白的抗体（Nab）。最近的几项研究提供了乐观的看法 在某些环境中传播并建立感染的病毒通过遗传途径传播， 可针对防止HIV-1感染的瓶颈：（i）新传播的C亚型病毒 在赞比亚，在Env中具有较少糖基化、更紧凑可变环区， 敏感性高于慢性感染指示病例的非传播病毒，（ii）新传播的 肯尼亚的A亚型病毒的Env具有较短的V1 V2环序列和较少的N连接糖基化 相对于循环人群的位点，以及（iii）在恒河猴中建立感染的SIVsm病毒 猕猴（非天然宿主）与正常猕猴相比，在Env中具有紧凑的、糖基化较少的V1 V2结构域。 接种物中存在的变体。目前的建议是建立在上述最初调查结果的基础上的， 从慢性感染的伴侣传播C亚型HIV-1似乎选择了一种具有 紧凑的Env是中和敏感的， 高度糖基化的Envs在准种的索引情况下。我们假设这个瓶颈 产生一种独特但短暂的Env抗原，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病毒株。我们 新传播的Envs将引发针对保守中和表位的抗体， 通常不可接近的，例如辅助受体和CD 4结合结构域，因为这些的暴露 区域对于传播或生长是重要的。相比之下，来源于 慢性感染的指示病例将不能诱导出能够中和新传播的 在我们的模型中。具体目的是（i）产生嗜性修饰的异源腺病毒5型 (Ad5)表达匹配的新传播和慢性亚型C HIV-1 Env的疫苗载体， 免疫豚鼠和（ii）比较匹配的供体和受体Env的能力， 针对一组自体和异源C亚型Env假病毒的中和抗体。

Over 40 million people are currently infected with HIV-1 and, considering the lack of a prophylactic vaccine in the foreseeable future, 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 proposal 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. We propose that the newly transmitted Envs will 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. The Specific Aims are to (i) generate tropism-modified heterologous adenovirus type 5 (Ad5) vaccine vectors that express matched newly transmitted and chronic subtype C HIV-1 Envs for immunization of guinea pigs and (ii)compare the abilities of matched donor and recipient Envs to elicit neutralizing antibodies against a panel of autologous and heterologous subtype C Env pseudoviruses..