DETERMINANTS OF NATURAL HOST RESISTANCE TO SIV AGM

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。尽管在确定HIV-1发病机制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HIV/SIV共受体使用的差异和宿主对早期感染的反应是HIV-1传播和艾滋病发病机制的关键决定因素这一假设。SIV的自然宿主物种表现出一种不寻常的特征；缺乏siv诱发的艾滋病。本建议的主要重点是建立发病机制的差异模型。非洲绿猴（Agms）感染SIVagm不会导致临床疾病，但尾猴（Ptm）感染会导致典型的T细胞耗竭和艾滋病。与HIV-1一样，大多数SIVagm和SIVsm毒株利用CD4和CCR5进入病毒，从而靶向这些细胞进行感染和杀伤。在本申请中，我们建议：1。确定病毒复制解剖相关位点受体/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趋向性（R5X4）的SIVagm菌株是否会改变Agm和Ptm的发病机制。确定病毒复制解剖部位细胞免疫反应的宿主特异性差异是否是SIVagm发病机制的一个因素。总之，本研究旨在了解辅助受体表达、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.