HIV Persistence and Renewal in the Gastrointestinal, Genitourinary and Adipose Tissues

HIV 在胃肠道、泌尿生殖系统和脂肪组织中的持续存在和更新

• 批准号: 10675778
• 负责人: Jesus Rivera-Nieves
• 金额: $ 78.21万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675778
• 关键词: Address; Adipose tissue; Aftercare; Age; Aging; Altruism; Anti-Retroviral Agents; Automobile Driving; Autopsy; Bayesian Method; Binding; Blood; Blood specimen; CD4 Positive T Lymphocytes; Cell Proliferation; Cell division; Cells; Cessation of life; Clonal Expansion; Clonality; Collecting Cell; Cytometry; DNA; DNA Sequence; Data; Data Set; Development; Enrollment; Environment; Event; Gastroenterology; Gastrointestinal tract structure; Genetic Transcription; Genitourinary system; Gifts; HIV; HIV Genome; Health; Human; Immune; Immunologic Markers; Immunologics; Immunology; Individual; Inflammation; Interruption; Intra-abdominal; Length; Linear Models; Macrophage; Maps; Mass Spectrum Analysis; Measures; Modernization; Mucous Membrane; National Institute of Diabetes and Digestive and Kidney Diseases; Participant; Pathogenesis; Pathway interactions; Penetration; Persons; Pharmaceutical Preparations; Phenotype; Plasma; Predisposition; Process; Prostate; Proviruses; RNA; Research; Role; Site; Source; Time; Tissue Sample; Tissues; Viral; Viremia; Virus; Work; antiretroviral therapy; assault; biomarker panel; body system; cell motility; cohort; defined contribution; density; digital; gastrointestinal; genome sequencing; ileum; improved; innovation; insight; integration site; interest; migration; novel; peripheral blood; reproductive tract; response; subcutaneous; trafficking; trait; transmission process; urogenital tract; viral rebound; virology

SUMMARY HIV assaults deep tissues including the gastrointestinal (GI) and genitourinary (GU) tract within days after transmission to a new person. It then quickly and irreversibly changes the local immune environment and establishes a reservoir in resident cells. Our current understanding of the different mechanisms that allow HIV persistence in GI, GU, and adipose tissues and of how the local immune environment impacts HIV reservoir persistence and dynamics remains superficial, however. The rationale for this project is that understanding these processes will be important for HIV cure efforts, which have until recently largely ignored non-blood reservoirs, and to improve the health of persons with HIV (PWH) as they age. In response to RFA DK-20-023, we built a team led by Drs. Smith and Rivera-Nieves (Co-PIs with complementary expertise in virology, gastroenterology and mucosal immunology) with the objective to precisely define the contributions of various viral and host mechanisms of HIV reservoir renewal and persistence across NIDDK targeted tissues and blood, using the novel Last Gift rapid autopsy cohort. Our overall hypothesis is that HIV reservoirs persist in NIDDK targeted tissues and are differentially renewed by various cellular and viral mechanisms. To address these open questions, our study will collect and analyze NIDDK targeted tissues throughout the human GI and GU tracts and intra-abdominal and subcutaneous adipose tissue of altruistic PWH enrolled in the Last Gift cohort, an ongoing rapid autopsy study. Immune cells collected from these individuals before death will also be analyzed, in parallel, in order to facilitate comparison with prior work. Some participants (n=15) will remain virally suppressed until the time of death, while others (n=5) will choose to stop their antiretroviral (ARV) treatment before death. The proposed research is innovative because we propose to map HIV burden and activity in tissues with different immune and ARV environments (Aim 1), to determine the role of clonal expansion as a driver of HIV persistence during treatment and viral rebound after treatment interruption (Aim 2) and to develop an integrative/innovative phylogeographic Bayesian approach to jointly analyze virological and immunological data to unravel viral dispersal and reseeding across the body in relation to local environments. By analyzing these connections, we expect to reveal pathways and interactions that may differentially impact HIV associated inflammation. We believe our proposed study to be significant because this is a unique opportunity to provide new insights into the mechanisms of HIV persistence. Such findings would be important for the development of strategies aimed to thwart local HIV-associated inflammation, which is associated with HIV pathogenesis in the gut, genital tract and adipose tissues.

概括 HIV 在感染后数天内攻击深层组织，包括胃肠道 (GI) 和泌尿生殖道 (GU)。 传递给一个新的人。然后它会迅速且不可逆地改变局部免疫环境， 在常驻细胞中建立一个水库。我们目前对艾滋病毒感染的不同机制的理解 胃肠道、泌尿道和脂肪组织中的持久性以及局部免疫环境如何影响艾滋病毒储存库 然而，持久性和动力仍然是肤浅的。该项目的基本原理是了解这些 过程对于艾滋病毒治疗工作非常重要，直到最近，这些工作在很大程度上忽视了非血库， 改善艾滋病毒感染者 (PWH) 随着年龄增长的健康状况。 为了响应 RFA DK-20-023，我们建立了一个由 Drs. 领导的团队。 Smith 和 Rivera-Nieves（联合 PI，具有互补性 病毒学、胃肠病学和粘膜免疫学方面的专业知识），目的是精确定义 NIDDK 中各种病毒和宿主机制对 HIV 储存库更新和持久性的贡献 使用新颖的“最后的礼物”快速尸检队列瞄准组织和血液。 我们的总体假设是，HIV 储存库持续存在于 NIDDK 目标组织中，并通过以下方式进行差异更新： 各种细胞和病毒机制。 为了解决这些悬而未决的问题，我们的研究将在整个过程中收集和分析 NIDDK 靶向组织。 人类胃肠道和胃肠道以及利他性 PWH 的腹内和皮下脂肪组织 最后的礼物队列，一项正在进行的快速尸检研究。在这些个体死前收集的免疫细胞将 也可以并行分析，以便于与以前的工作进行比较。一些参与者（n=15）将 保持病毒抑制直至死亡，而其他人 (n=5) 将选择停止抗逆转录病毒 (ARV) 死亡前的治疗。 拟议的研究具有创新性，因为我们建议绘制不同组织中艾滋病毒负担和活动的图谱。 免疫和 ARV 环境（目标 1），以确定克隆扩增作为 HIV 持续性驱动因素的作用 治疗期间和治疗中断后病毒反弹（目标 2），并制定综合/创新方案 系统地理学贝叶斯方法联合分析病毒学和免疫学数据以揭示病毒 与当地环境相关的在体内的传播和重新播种。通过分析这些联系，我们 期望揭示可能对 HIV 相关炎症产生不同影响的途径和相互作用。 我们相信我们提出的研究意义重大，因为这是一个提供新见解的独特机会 HIV持续存在的机制。这些发现对于制定旨在实现目标的战略非常重要 阻止局部与艾滋病毒相关的炎症，这与肠道、生殖道的艾滋病毒发病机制有关 和脂肪组织。