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 非人类灵长类动物（NHP）模型为HIV-1发病机理，预防和 治疗。尤其重要的是涉及感染具有SIV或SHIV的恒河猴的模型。和 对病毒储层的尊重，我们以前已经表明宽度SIV传播和储层播种 发生在感染的头几天。 Barouch Lab还探索了恒河猴的治疗策略 猕猴，专注于免疫刺激剂，热疫苗接种，广泛中和抗体和 这些方法的组合。这些研究提供了一些有望的早期证据证明对 病毒反弹和治疗后控制。硅体实验室提供了早期的证据，表明潜在感染了休息 血液，淋巴结和脾脏中的CD4+ T细胞是SIV感染猕猴的重要储备。可用的 SIV感染猕猴中的储层动力学的研究表明，与储层动力学的总体相似性 plwh。在此处提出的研究中，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。研究旨在扩展研究 在项目1中提出的PLWH中，解决了储层动态中的关键问题 在人类中解决。该项目的具体目的是： 特定目的1。定义负责病毒血症第一和第二阶段的细胞类型 遵循艺术计划。我们假设（1）大多数等离子体病毒是通过快速衰减产生的 淋巴结和其他淋巴组织中存在活化的CD4+ T细胞的群体，（2） 衰减的阶段反映了在较低的激活状态下消除不同群体的CD4+ T细胞种群 产生较长时间的病毒，（3）第二阶段代表塑造的选择过程 稳定潜在储层的组成和动力学。 具体目的2。确定第一次消除感染细胞的机制，并 衰变的第二阶段。使用CD8耗竭实验，我们将检验以下假设。 第二相细胞由病毒特异性CTL介导。