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

项目 2：感染 SIV 的恒河猴的储库动力学分析

• 批准号: 10459662
• 负责人: Dan H. Barouch
• 金额: $ 40.12万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10459662
• 关键词: Address; Aftercare; Apoptosis; Biological Assay; Blood; Blood Circulation; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; DNA; Epitopes; Frequencies; Gene Expression; Genomics; HIV-1; Human; Immune; Individual; Infection; Lymphoid Tissue; Macaca; Macaca mulatta; Measurement; Mediating; Modeling; Mutation; Nature; Pathogenesis; Peripheral; Phase; Plasma; Population; Population Analysis; Prevention; Process; Property; Research Personnel; Resistance; Rest; SIV; Shapes; Spleen; Testing; Time; Vaccine Therapy; Viral; Viral Genes; Viral reservoir; Viremia; Virus; antibody-dependent cell cytotoxicity; cell type; design; experimental study; insight; lymph nodes; neutralizing antibody; nonhuman primate; novel; simian human immunodeficiency virus; viral rebound

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.

摘要-项目2 非人灵长类动物（NHP）模型为HIV-1的发病机制、预防和治疗提供了有价值的见解。 治疗特别重要的是涉及用SIV或SHIV感染恒河猴的模型。与 关于病毒储存库，我们先前已经表明，广泛的SIV传播和储存库播种 发生在感染的最初几天。Barouch实验室还探索了恒河猴的治疗策略 猕猴，重点是免疫刺激剂，治疗性疫苗接种，广泛中和抗体， 这些方法的组合。这些研究提供了一些有希望的早期证据， 病毒反弹和治疗后控制。Siliciano实验室提供了早期证据， 血液、淋巴结和脾脏中的CD 4 + T细胞是SIV感染猕猴的重要宿主。可用 对SIV感染猕猴的储库动力学的研究表明， PLWH。在本文的研究中，我们将利用NHP模型的优势， 建立，组成和动态的潜在水库。这些研究旨在扩展研究 在项目1中提出的PLWH，并解决油藏动态中的关键问题， 在人类中解决。该项目的具体目标是： 具体目标1。确定负责病毒血症衰减第一和第二阶段的细胞类型 我们假设（1）大多数血浆病毒是由一种快速衰变的 淋巴结和其他淋巴组织中存在的活化的CD 4 + T细胞群，（2）第二个 衰减阶段反映了处于较低活化状态的不同CD 4 + T细胞群的消除， 产生病毒的时间更长，（3）第二阶段代表选择过程， 稳定潜在储层的组成和动态。 具体目标2。为了确定感染细胞在第一次和第二次感染中被清除的机制， 腐烂的第二阶段。使用CD 8耗竭实验，我们将检验以下假设： 第二期细胞由病毒特异性CTL介导。