Determinants of Natural Host Resistance to SIV agm

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。这项提议的一个主要焦点是开发一个发病机制的差异模型。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。我们的研究表明，自然感染的猕猴的血浆和脑脊液中都存在较高水平的病毒血症，但感染细胞的数量一般低于SIV感染的猕猴。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患者PBMC中的CD4CCR5T细胞池至少比PTM低5倍，这表明易感T细胞池大小的根本差异可能导致细胞杀伤以及进而细胞介导的杀伤的深刻差异。在这一应用中，我们建议：L：确定在病毒复制的解剖相关部位宿主特异性受体/辅助受体表达的差异是否是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。我们还将比较嗜神经性SIVagm(R5)菌株在细胞嗜性、中枢神经系统的进化方面的作用，并确定致病结果。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。我们将对自然和非自然宿主的细胞免疫进行纵向研究。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。

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.