Determinants of Natural Host Resistance to SIV agm

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共受体的使用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。本建议的一个主要焦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。我们的研究表明，在自然感染猴的血浆和脑脊液中都存在高水平的病毒血症，但感染细胞的数量普遍低于SIV感染猴。此外，在自然宿主中的研究未能将细胞免疫反应与自然宿主中的病毒复制联系起来。我们还发现，Agm的PBMC中的CD4+CCR5+ T细胞库至少比Ptm低5倍，这表明易感T细胞库大小的根本差异可能导致细胞杀伤和细胞介导杀伤的深刻差异。在这项应用中，我们提出：1 .确定在病毒复制的解剖学相关位点上受体/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。我们还将比较嗜神经SIVagm （R5）菌株在中枢神经系统的细胞趋向性、进化和确定致病结果方面的差异。3. 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。我们将纵向研究自然宿主和非自然宿主的细胞介导免疫。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。

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 coreceptor 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 of 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. Our studies have shown that there is a high level of viremia both in the plasma and cerebrospinal fluids of naturally infected monkeys however, the number o infected cells was generally lower than SIV infected macaques. Moreover, studies in the natural host have failed to correlate cellular immune responses with viral replication in the natural host. We have also shown that the CD4+CCR5+ T cell pool in PBMC of Agm is at least 5 fold lower than in Ptm suggesting fundamental differences in the size of the susceptible T cell pool may lead to profound differences in cell killing and by extension, cell-mediated killing. In this application, we propose to: l. 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. We will also compare neurotropic SIVagm (R5) strains in terms of cell tropism, evolution in the central nervous system and define pathogenic outcomes. 3. Determine if host-specific differences in cellular immune responses at anatomic sites for viral replication are a factor in SIVagm pathogenesis. We will examine longitudinally, cell- mediated immunity in the natural and unnatural host. In summary, this proposal seeks to understand the role of coreceptor expression, viral replication and cellular immunity in the pathogenesis of SIV.