DETERMINANTS OF NATURAL HOST RESISTANCE TO SIV AGM

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。 尽管在确定HIV-1致病的重要机制方面取得了重大进展，但宿主和病毒因素在疾病进展中的作用仍然知之甚少。越来越多的证据支持这一假设，即HIV/SIV共同受体的不同使用以及宿主对早期感染的反应是HIV-1传播和艾滋病发病的关键决定因素。SIV的自然宿主物种表现出一个不同寻常的特征：缺乏SIV诱导的艾滋病。这一提议的一个主要焦点是开发一种不同的发病机制模型。SIVagm感染非洲绿猴(AGM)不会导致临床疾病，但感染辫尾猕猴(PTM)会导致经典T细胞耗尽和艾滋病。像HIV-1一样，大多数SIVagm和SIVsm毒株利用CD4和CCR5进行病毒进入，从而针对这些细胞进行感染和杀伤。在这一应用中，我们建议：1.确定病毒复制的解剖相关部位受体/辅助受体表达的宿主特异性差异是否是SIVagm不同发病机制的一个因素。2.确定具有更广泛细胞嗜性的SIVagm菌株(R5X4)是否会改变AGM和PTM的发病机制。3.确定病毒复制解剖部位的细胞免疫反应的宿主特异性差异是否是SIVagm发病的一个因素。综上所述，本研究试图了解辅助受体表达、病毒复制和细胞免疫在SIV发病机制中的作用。

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. Despite significant progress in identifying important mechanisms underlying HIV-1 pathogenesis, the role of host and viral factors contributing to progression to disease are still poorly understood. There is growing evidence supporting the hypothesis that differences in HIV/SIV co receptor usage, and the host response to early infection are critical determinants of HIV-1 transmission and AIDS pathogenesis. The natural host species for SIV displays an unusual feature; lack of SIV-induced AIDS. A major focus on this proposal is to develop a differential model for pathogenesis. SIVagm infection in African green monkeys (Agms) does not result in clinical disease however, infection of pigtailed macaques (Ptm) results in classical T cell depletion and AIDS. Like HIV-1, most SIVagm and SIVsm strains utilize CD4 and CCR5 for viral entry, thus targeting these cells for infection and killing. In this application, we propose to: 1. Determine if host-specific differences in receptor/coreceptor expression at anatomically relevant sites of viral replication are a factor in the differential pathogenesis of SIVagm. 2. Determine if SIVagm strains with broader cell tropism (R5X4) will alter pathogenesis in Agm and Ptm. 3. Determine if host-specific differences in cellular immune responses at anatomic sites for viral replication are a factor in SIVagm pathogenesis. In summary, this proposal seeks to understand the role of coreceptor expression, viral replication and cellular immunity in the pathogenesis of SIV.