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

目前有超过4000万人感染了艾滋病毒-1，考虑到缺乏预防性疫苗 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。 整个世界。体液免疫很可能将成为疫苗诱导保护的必要组成部分。 抗HIV-1感染；然而，事实证明，要引起广泛和有效的中和特别困难 针对HIV-1包膜糖蛋白的抗体(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基因 可作为预防艾滋病毒-1感染的目标的瓶颈：(I)新传播的C亚型病毒 在赞比亚，Env中的糖基化程度较低，可变环区域更紧密，中和程度更高 比来自慢性感染指标病例的未传播病毒敏感，(Ii)新传播 肯尼亚的A亚型病毒具有较短的V1V2环序列和较少的N-连接糖基化 相对于循环种群的位置，以及(Iii)在恒河猴中建立感染的SIVsm病毒 猕猴(一种非自然宿主)在环境中具有致密的、糖基化程度较低的V1V2结构域 接种物中存在变种。目前的提议建立在上述最初调查结果的基础上，即 从长期感染的伴侣传播C亚型HIV-1似乎选择了一种带有 紧凑型环境，对中和敏感，可抵抗中和抗性病毒， 在指标病例的准种中，大量糖基化的环境蛋白。我们的假设是这个瓶颈 产生一种独特的但短暂的Env抗原，可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 建议新传播的env将诱导针对保守的中和表位的抗体 正常情况下不可访问的，如辅助受体和CD4结合域，因为暴露于这些 地区对传播或增长很重要。相比之下，抗中和环境因子源自 慢性感染的指示病例将无法诱导出能够中和新传播的 我们模型中的菌株。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C亚型HIV-1 env的疫苗载体 豚鼠的免疫和(Ii)配对的供体和受体env诱导能力的比较 针对一组自体和异源亚型C环境伪病毒的中和抗体。

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..