Mechanisms of Formation and Persistence of Active HIV Reservoirs

活性 HIV 病毒库的形成和持续机制

• 批准号: 8705776
• 负责人: JAMES Ivan MULLINS
• 金额: $ 80.58万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8705776
• 关键词: Acute; Address; Adult; Anti-Retroviral Agents; Antigen Targeting; Antigenic Specificity; Antigens; Apoptosis; Back; Biopsy; Blood; Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; Cell Cycle; Cell Proliferation; Cells; Chromosomes; Chronic; Cytomegalovirus; DNA; Data; Early treatment; Enrollment; Event; Genes; Goals; Gut associated lymphoid tissue; HIV; HIV Infections; HIV vaccine; HIV-1; Human Herpesvirus 4; Immunity; Individual; Infant; Infection; Interruption; Irrigation; Kinetics; Knowledge; Lead; Life; Link; Liquid substance; Methods; Myelogenous; Patient Care; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Population; Production; Proliferating; Proteins; Provirus Integration; Proviruses; Public Health; RNA; Relative (related person); Reporting; Research; Rest; Simplexvirus; Site; Sorting - Cell Movement; Specimen; Staging; Study Subject; T memory cell; Targeted Toxins; Tetanus; Time; Tissues; Viral; Virion; Virus; antiretroviral therapy; cohort; experience; follow-up; improved; infected B cell; pandemic disease; prevent; public health relevance; sample collection; site-specific integration; viral DNA; viral RNA

ABSTRACT We propose to address several important questions relevant to achieving a functional cure of HIV infection in individuals on suppressive antiretroviral therapy (ART). Specifically, we will examine the timing and mechanisms that establish the "active" or infectious reservoirs in primary human immunodeficiency virus type 1 (HIV-1) infection; identify the mechanisms by which active HIV reservoirs persist for many years under ART, identify the cells that harbor active reservoirs, and; discern whether reservoirs in individuals initiating ART during primary infection persist in antigen-specific cells and are thus amenable to activation with their target antigens for destruction strategies. Our subject population derives from a unique and long standing cohort of individuals enrolled while in the first few days to months of HIV infection, who went onto suppressive ART prior to 4 months from the date of infection and have had intensive specimen collection during follow-up for up to ~14 years. One hundred and one subjects who initiated ART in Fiebig stages I-V, and remained on ART and virologically suppressed for at least 2 years, form the primary set of subjects for study. Specimens from 4 additional subjects who started ART in chronic HIV infection and experienced a viral rebound when ART was interrupted will be also be used to address one of our questions. We will quantify virus in plasma RNA, as total viral DNA and as 2LTR circular unintegrated viral DNA in peripheral blood mononuclear cells (PBMC), and examine the infectious capacity of proviral DNA in resting CD4+T cells. We will also determine the contribution of proliferating HIV-infected cells, and the relationship between disruption of cellular genes regulating the cell cycle by HIV integration into the chromosome, to the persistence of active reservoirs in blood and in specific subpopulations in PBMC, bronchioalveolar lavage fluids and biopsies of gut-associated lymphoid tissues. Additionally, we will determine whether the putative reservoirs we identify allow HIV to remain active by virtue of inadequate intracellular levels of antiretroviral drugs. Our specific aims are to determine: 1) The mechanisms and kinetics of establishment of active HIV reservoirs; 2) the relative contributions of (A) proliferating HIV- infected cells, and (B) low-level viral replication to the persistence of active reservoirs during ART, and; 3) the proportion of HIV reservoir cells composed of virus-specific CD4+T cells.

抽象的 我们建议解决与实现HIV感染功能治疗有关的几个重要问题 接受抑制性抗逆转录病毒疗法（ART）的人。具体而言，我们将检查时间和 在原发性人类免疫缺陷病毒1型中建立“活跃”或传染库的机制 （HIV-1）感染；确定活跃的艾滋病毒水库在艺术下持续多年的机制， 识别带有活跃储层的细胞，并且；辨别个人是否在个人发起艺术的水库 在原发性感染期间，抗原特异性细胞持续存在，因此可以激活其靶标 破坏策略的抗原。我们的受试者人口源于独特而长期的队列 在艾滋病毒感染的最初几天到几个月中，人们参加了入学 从感染之日起到4个月，并且在随访期间收集了大量标本 〜14年。在菲比格（Fiebig）阶段发起艺术的一百一名主题，并继续进行艺术和 在病毒学上至少抑制了2年，构成了研究的主要受试者。来自4的标本 在慢性艾滋病毒感染中开始艺术并在艺术时经历了病毒反弹的其他科目 中断也将用于解决我们的问题之一。我们将在血浆RNA中定量病毒，作为总体 病毒DNA和AS AS 2LTR圆形未集成的病毒DNA在外周血单核细胞（PBMC）中，并且 检查前病毒DNA在静止的CD4+T细胞中的感染能力。我们还将确定贡献 增殖的HIV感染细胞，以及调节细胞的细胞基因破坏之间的关系 通过HIV整合到染色体中，循环到血液中活性储层的持续性 PBMC，支气管肺泡灌洗液和肠道相关淋巴组织的活检中的亚群。 此外，我们将确定我们确定的假定储层是否允许艾滋病毒保持活跃 细胞内抗逆转录病毒药物的水平不足。我们的具体目的是确定：1​​）机制 建立活跃的艾滋病毒水库的动力学； 2）（a）增殖的HIV-的相对贡献 感染的细胞，以及（b）在艺术期间活跃储层的持久性的低水平病毒复制， 3） 由病毒特异性CD4+T细胞组成的HIV储层细胞的比例。