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.

总结 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，它迅速和不可逆地改变局部免疫环境， 在常驻细胞中建立储库。我们目前对艾滋病病毒的不同机制的理解 在胃肠道、胃肠道和脂肪组织中的持久性，以及局部免疫环境如何影响HIV储库 然而，持久性和动态仍然是表面现象。这个项目的基本原理是， 这一过程对于艾滋病毒治疗工作将是重要的，直到最近，艾滋病毒治疗工作在很大程度上忽视了非血液储存库， 以及改善爱滋病病毒感染者的健康。 为了响应RFA DK-20-023，我们建立了一个由Smith博士和Rivera-Nieves博士领导的团队（具有互补性的共同PI） 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 各种病毒和宿主机制对NIDDK中HIV储库更新和持续性的贡献 目标组织和血液，使用新的最后的礼物快速尸检队列。 我们的总体假设是，HIV储库持续存在于NIDDK靶向组织中，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，我们的研究将收集和分析整个NIDDK靶组织， 人胃肠道和胃肠道以及腹腔内和皮下脂肪组织的利他性PWH参加了 最后一个礼物队列，正在进行的快速尸检研究。从这些人死亡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 保持病毒抑制直到死亡，而其他人（n=5）将选择停止抗逆转录病毒（ARV） 死亡前的治疗 这项研究是创新的，因为我们建议绘制不同组织中的HIV负担和活性， 免疫和ARV环境（目标1），以确定克隆扩张作为HIV持续存在驱动因素的作用 治疗期间和治疗中断后病毒反弹（目标2），并制定一个综合/创新的 联合分析病毒学和免疫学数据的地理贝叶斯方法 与局部环境相关的在身体上的传播和重新播种。通过分析这些联系，我们 期望揭示可能不同地影响HIV相关炎症的途径和相互作用。 我们相信我们提出的研究是重要的，因为这是一个独特的机会，提供新的见解， 艾滋病毒持续存在的机制。这些调查结果对于制定旨在 以阻止局部HIV相关炎症，这与肠道、生殖道和生殖道中的HIV发病机制有关， 和脂肪组织。