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

描述（由申请人提供）：目前有4 000多万人感染艾滋病毒-1，考虑到在可预见的将来缺乏预防性疫苗，这一数字预计将在世界许多不发达地区呈指数级增长。体液免疫很可能是疫苗诱导的预防HIV-1感染的必要组成部分；然而，事实证明，激发针对HIV-1包膜（Env）糖蛋白的广泛而有效的中和抗体（Nab）尤其困难。最近的几项研究提供了乐观的看法，即在某些环境中传播和建立感染的病毒通过了一个遗传瓶颈，可以针对这个瓶颈来防止艾滋病毒-1感染：(i)在赞比亚新传播的C亚型病毒在Env中具有较少的糖基化，更紧凑的可变环区，并且比来自慢性感染指示病例的未传播病毒更具中和敏感性；（ii）在肯尼亚新传播的A亚型病毒的Env具有较短的V1V2环序列和较少的n链糖基化位点。（iii）在恒河猴（非自然宿主）中建立感染的SIVsm病毒在Env中具有紧凑的、糖基化程度较低的V1V2结构域，与接种物中的变体相比。目前的建议建立在上面描述的原始发现的基础上，即从慢性感染的伴侣传播的C亚型HIV-1似乎选择了具有中和敏感的紧凑Env的病毒，而在指数病例的准物种中，具有大量糖基化Env的抗中和病毒。我们的假设是，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，能够中和自身病毒和交叉中和其他新传播的毒株。我们提出，新传播的Envs会引发对通常不可接近的保守中和表位的抗体，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很重要。相比之下，来自慢性感染指示病例的中和抗性Envs将无法诱导抗体来中和我们模型中新传播的菌株。具体目的是：(i)产生亲性修饰的异源腺病毒5型（Ad5）疫苗载体，表达匹配的新传播和慢性C亚型HIV-1 Envs用于豚鼠免疫；（ii）比较匹配的供体和受体Envs诱导针对一组自体和异源C亚型Env假病毒的中和抗体的能力。

DESCRIPTION (provided by applicant): 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..