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SIV或SIV感染恒河猴的模型。使用 关于病毒库，我们以前已经表明，广泛的SIV传播和水库播种 发生在感染的头几天。巴鲁奇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、广谱中和抗体，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 病毒反弹和治疗后控制。西里西亚诺实验室提供了潜伏感染休息的早期证据 血液、淋巴结和脾中的CD4+T细胞是SIV感染猕猴的重要储存库。可用 对感染SIV的猕猴的水库动力学的研究表明，总体上与 PLWH。在这里提出的研究中，我们将利用NHP模式的优势来探索 潜伏油气藏的建立、组成和动态。这些研究旨在扩大研究范围。 在项目1中提出的PLWH中，并解决油藏动力学中不易解决的关键问题 在人类身上写的。该项目的具体目标是： 具体目标1.确定导致病毒血症衰变的第一和第二阶段的细胞类型 随着艺术的兴起。我们假设(1)大多数血浆病毒是由迅速腐烂的 存在于淋巴结和其他淋巴组织中的活化的CD4+T细胞群，(2)第二 衰变阶段反映了处于较低激活状态的一组不同的CD4+T细胞的消除 产生病毒的时间更长，以及(3)第二阶段代表形成 稳定潜伏油藏的组成和动态。 具体目标2.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。利用CD8耗尽实验，我们将检验这一假设 第二相细胞由病毒特异性CTL介导。