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攻击深层组织，包括胃肠道（GI）和泌尿生殖器（GU）。 传输给一个新人。然后，它迅速且不可逆转地改变了局部免疫环境， 在居民细胞中建立一个储层。我们目前对允许艾滋病毒的不同机制的理解 GI，GU和脂肪组织的持久性以及局部免疫环境如何影响HIV储量 但是，持久性和动态仍然是肤浅的。该项目的理由是了解这些 流程对于艾滋病毒治疗工作将很重要，直到最近，这些努力仍在很大程度上忽略了非血液储层， 并随着年龄的增长来改善艾滋病毒（PWH）患者的健康。 为了回应RFA DK-20-023，我们建立了由DRS领导的团队。史密斯和里维拉·纽维斯（互补的共同提示 病毒学，胃肠病学和粘膜免疫学专业知识，目的是精确定义 NIDDK跨越HIV储层更新和持久性的各种病毒和宿主机制的贡献 靶向组织和血液，使用新颖的最后礼物快速尸检队列。 我们的总体假设是，艾滋病毒储量持续存在于NIDDK靶向组织中，并通过 各种细胞和病毒机制。 为了解决这些开放的问题，我们的研究将在整个过程中收集和分析NIDDK的目标组织 人类的gi和gu段以及腹腔内和皮下脂肪组织的无私PWH 最后的礼物队列，一项持续的快速尸检研究。死亡之前从这些人收集的免疫细胞将 同样可以并行分析，以促进与先前的工作进行比较。一些参与者（n = 15）将 保持病毒抑制直到死亡时间，而其他人（n = 5）会选择阻止其抗逆转录病毒（ARV） 死亡前的治疗。 拟议的研究具有创新性，因为我们建议在具有不同的组织中绘制HIV负担和活动 免疫和ARV环境（AIM 1），确定克隆扩张作为HIV持久性的驱动力的作用 在治疗和治疗中断后的病毒反弹期间（AIM 2）并发展综合/创新性 植物地理学贝叶斯方法共同分析病毒学和免疫数据以揭示病毒 相对于当地环境，分散和播种。通过分析这些连接，我们 期望揭示可能影响与HIV相关的炎症的途径和相互作用。 我们认为我们拟议的研究很重要，因为这是一个提供新见解的独特机会 艾滋病毒持久性的机制。这样的发现对于制定针对的战略很重要 阻止局部HIV相关的炎症，这与肠道中的HIV发病机理有关 和脂肪组织。