Cellular Reservoirs of HIV

HIV 的细胞库

• 批准号: 10684820
• 负责人: Kathleen L. Collins
• 金额: $ 60.17万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10684820
• 关键词: Anti-Retroviral Agents; Biological Assay; Biopsy; Bone Marrow Aspiration; Cells; Clonal Expansion; Data; Disparate; Epigenetic Process; Evolution; Frequencies; Gene Expression; Generations; Genetic Transcription; Genome; HIV; HIV Infections; HIV-1; Hematopoietic stem cells; In Vitro; Individual; Infection; Length; Modeling; Outcome; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Plasma; Population; Predisposition; Proviruses; Public Health; Publishing; Rectum; Research; Residual state; Site; Source; Specimen; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; United States; Viral; Viral Genes; Viral Genome; Viremia; Virus; Virus Replication; antiretroviral therapy; cell type; daughter cell; drug development; in vivo; latent infection; new therapeutic target; pandemic virus; peripheral blood; progenitor; programs; reactivation from latency; recruit; rectal; self-renewal

Antiretroviral medications suppress viral replication but do not eradicate cellular sources of integrated proviral genomes that are a major barrier to a cure. CD4+ hematopoietic stem and progenitor cells (HSPCs) have the capacity for life-long survival, self-renewal and the generation of daughter cells. They are also susceptible to HIV infection in vitro and in vivo. Combination antiretroviral therapy effectively suppresses viremia in HIV- infected people. However, residual plasma virus (RPV) can be detected with very sensitive assays. Recently published studies demonstrate that clusters of identical proviruses from HSPCs and their likely progeny often match RPV and are sometimes infectious. A higher proportion of these sequences matched RPV than proviral genomes from peripheral blood mononuclear cells that lacked evidence of clonal expansion. Furthermore, we provide examples of proviral genomes from progenitors that were latent in peripheral blood T cells while simultaneously contributing to RPV. The cellular source of RPV in these cases is not known but is unlikely to be peripheral blood T cells, which required latency reactivation for gene expression. We have developed a model based on these data. In this model, we propose that heterogeneous differentiated progeny of infected progenitors can support either active or latent infection depending on progeny epigenetic and transcriptional programs. The overall objective of this application is to test this hypothesis by comprehensively characterizing intact HIV in peripheral blood and tissue reservoirs. A secondary objective is to determine whether infected HSPCs are required for clonal provirus and RPV and to identify any alternative proliferative sources of non- HSPC generated clonal genomes. To accomplish this, we will: 1. Analyze intact near full length viral genomes to identify sources of clonally amplified proviral genomes in peripheral blood and to determine their relationship to proliferative sources such as HSPCs; 2. use viral outgrowth assays to confirm relationships amongst sources of infectious virus; and 3. determine the active and latently infected tissue sources of infectious virus and their relationships to proliferative sources such as HSPCs. Results from these aims will comprehensively identify sources of functional virus and RPV across multiple disparate tissue sites. They will determine the extent to which multipotent and/or restricted progenitors or other proliferative sources serve as the source for clonally expanded HIV proviral genomes present in the peripheral blood and tissue sites. These studies will provide important new information that has the potential to change the way we think about the source of functionally relevant HIV reservoirs.

抗逆转录病毒药物抑制病毒复制，但不能根除综合病毒的细胞来源 是治愈的主要障碍的基因组。 CD4+造血茎和祖细胞（HSPC）具有 终身生存，自我更新和子细胞产生的能力。他们也容易受到影响 体外和体内HIV感染。抗逆转录病毒疗法有效抑制HIV- 感染人群。但是，可以通过非常敏感的测定法检测残留的血浆病毒（RPV）。最近 发表的研究表明，HSPC及其可能的后代的相同原病毒的簇经常 匹配RPV，有时具有感染力。这些序列中比病毒更高的比例匹配RPV 缺乏克隆膨胀证据的外周血单核细胞的基因组。此外，我们 提供来自外周血T细胞中潜在的祖细胞的病毒基因组的例子，而 同时为RPV做出了贡献。在这些情况下，RPV的细胞来源尚不清楚，但不可能 是外周血T细胞，需要潜伏的基因表达重新激活。我们已经开发了 基于这些数据的模型。在此模型中，我们提出异质的感染后代 祖细胞可以根据后代表观遗传和转录性支持主动感染或潜在感染 程序。该应用程序的总体目的是通过全面表征来检验该假设 外周血和组织储层中完整的HIV。次要目标是确定是否感染 HSPC是克隆病毒和RPV所必需的，并确定非 - HSPC产生克隆基因组。为此，我们将：1。分析完整的全长病毒基因组 确定外周血中克隆扩增的病毒基因组的来源，并确定它们 与诸如HSPC之类的增殖来源的关系； 2。使用病毒生长测定来确认关系 在传染病的来源中；和3。确定活性和潜在感染的组织来源 传染病及其与HSPC等增殖来源的关系。这些目标的结果将 全面识别多个不同组织部位的功能病毒和RPV的来源。他们会的 确定多能和/或受限的祖细胞或其他增殖来源的程度 外周血和组织部位中存在克隆膨胀的HIV前病毒基因组的来源。这些 研究将提供重要的新信息，从而有可能改变我们对 功能相关的HIV储藏的来源。