Project 2: Analysis of Reservoir Dynamics in SIV-Infected Rhesus Macaques

摘要 – 项目 2 非人类灵长类动物 (NHP) 模型为 HIV-1 发病机制、预防和治疗提供了宝贵的见解。 治疗。特别重要的是涉及恒河猴感染 SIV 或 SHIV 的模型。与 关于病毒储存库，我们之前已经表明，广泛的 SIV 传播和储存库播种 发生在感染的最初几天。巴鲁克实验室还探索了恒河猴的治疗策略 猕猴，专注于免疫刺激剂、治疗性疫苗接种、广泛中和抗体，以及 这些方法的组合。这些研究提供了一些有希望的早期证据，证明了对 病毒反弹和治疗后控制。西利西亚诺实验室提供了早期证据，表明静息状态下潜伏感染 血液、淋巴结和脾脏中的 CD4 T 细胞是感染 SIV 的猕猴的重要储存库。可用 对感染 SIV 的猕猴的水库动态的研究表明，与感染 SIV 的猕猴的水库动态总体相似。 感染者。在这里提出的研究中，我们将利用 NHP 模型的优势来探索 潜在储层的建立、组成和动态。这些研究旨在扩展研究 项目 1 中提出的 PLWH，并解决水库动态中不易解决的关键问题 在人类中得到解决。该项目的具体目标是： 具体目标 1. 确定导致病毒血症第一和第二阶段衰退的细胞类型 开始 ART 后。我们假设（1）大部分血浆病毒是由快速腐烂的 淋巴结和其他淋巴组织中存在的活化 CD4 T 细胞群，(2) 第二个 衰变阶段反映了处于较低激活状态的不同 CD4 T 细胞群的消除 产生病毒的时间较长，并且（3）第二阶段代表形成病毒的选择过程 稳定潜伏储层的组成和动态。 具体目标 2. 确定受感染细胞在第一和第二阶段被消除的机制 腐烂的第二阶段。使用 CD8 耗尽实验，我们将检验以下假设： 第二期细胞由病毒特异性 CTL 介导。

Summary – Project 2 Non-human primate (NHP) models have provided valuable insights into HIV-1 pathogenesis, prevention, and treatment. Of particular importance are models involving infection of rhesus macaques with SIV or SHIV. With respect to viral reservoirs, we have previously shown that widespread SIV dissemination and reservoir seeding take place in the first few days of infection. The Barouch lab have also explored cure strategies in rhesus macaques, focusing on immune stimulating agents, therapeutic vaccination, broadly neutralizing antibodies, and combinations of these approaches. These studies have provided some promising early evidence of effects on viral rebound and post-treatment control. The Siliciano lab provided early evidence that latently infected resting CD4+ T cells in blood, lymph nodes, and spleen are an important reservoir in SIV-infected macaques. Available studies on reservoir dynamics in SIV-infected macaques suggest an overall similarity to reservoir dynamics in PLWH. In the studies proposed here, we will capitalize on the advantages of NHP models to explore the establishment, composition, and dynamics of the latent reservoir. The studies are designed to extend the studies in PLWH proposed in Project 1 and address critical questions in reservoir dynamics that cannot be easily addressed in humans. The Specific Aims of this project are: Specific Aim 1. To define the cell types responsible for the first and second phases of decay of viremia following initiation of ART. We hypothesize (1) that most of the plasma virus is produced by a rapidly decaying population of activated CD4+ T cells present in the lymph nodes and other lymphoid tissues, (2) that the 2nd phase of decay reflects the elimination of a distinct population of CD4+ T cells in a lower state of activation that produce virus for a longer period of time, and (3) that the 2nd phase represents selection process that shapes the composition and dynamics of the stable latent reservoir. Specific Aim 2. To determine the mechanism by which infected cells are eliminated during the first and second phases of decay. Using CD8 depletion experiments, we will test the hypothesis that the elimination of 2nd phase cells is mediated by virus-specific CTL.