Determinants of Natural Host Resistance to SIV agm

自然宿主对 SIV agm 抗性的决定因素

• 批准号: 6703116
• 负责人: Jonathan S Allan
• 金额: $ 68.76万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-15 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6703116
• 关键词: Cercopithecidae; Macaca nemestrina; cellular immunity; cytokine receptors; cytotoxic T lymphocyte; helper T lymphocyte; host organism interaction; microorganism immunology; pathologic process; receptor expression; simian AIDSs; simian immunodeficiency virus; species difference; virus receptors; virus replication

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.

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这一假设：HIV/SIV 辅助受体使用的差异以及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。 SIV 的自然宿主物种表现出一个不寻常的特征：缺乏SIV诱发的艾滋病。 该提案的一个主要重点是开发发病机制的差异模型。 非洲绿猴 (Agms) 的 SIVagm 感染不会导致临床疾病，但猪尾猕猴 (Ptm) 的感染会导致典型的 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，自然感染猴子的血浆和脑脊液中病毒血症水平很高，但感染细胞的数量普遍低于感染SIV的猕猴。此外，对自然宿主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。 我们还表明，Agm 的 PBMC 中的 CD4+CCR5+ T 细胞库比 Ptm 中至少低 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以及细胞介导杀伤的显着差异。在此应用中，我们建议： l．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 差异发病机制的一个因素。 2. 确定具有更广泛细胞向性 (R5X4) 的 SIVagm 菌株是否会改变 Agm 和 Ptm 的发病机制。 我们还将在细胞趋向性、中枢神经系统进化方面比较神经性 SIVagm (R5) 菌株并定义致病结果。 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和非自然宿主中细胞介导的免疫。总之，该提案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。