Cellular Reservoirs of HIV

HIV 的细胞库

• 批准号: 10237936
• 负责人: Kathleen L. Collins
• 金额: $ 65.66万
• 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/10237936
• 关键词: Anti-Retroviral Agents; Biological Assay; Biopsy; Bone Marrow Aspiration; CD4 Positive T Lymphocytes; Cells; Clonal Expansion; Data; Epigenetic Process; Evolution; Frequencies; Gene Expression; Generations; Genetic Transcription; Genome; HIV; HIV Infections; HIV-1; Hematopoietic stem cells; In Vitro; Individual; Infection; Length; Life; Modeling; Outcome; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Population; Proviruses; Public Health; Publishing; Research; Residual state; Seeds; Site; Source; Specimen; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; United States; Viral; Viral Genes; Viral Genome; Viremia; Virus; Virus Replication; antiretroviral therapy; base; cell type; daughter cell; drug development; in vivo; latent infection; new therapeutic target; pandemic disease; peripheral blood; progenitor; programs; reactivation from latency; recruit; rectal; self-renewal; stem cell proliferation

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，但不能根除整合前病毒的细胞来源。 基因组是治愈的主要障碍CD 4+造血干细胞和祖细胞（HSPC）具有 终身生存、自我更新和产生子细胞的能力。他们也容易受到 体外和体内HIV感染。联合抗逆转录病毒疗法有效抑制HIV-1感染者的病毒血症。 感染者。然而，残留的血浆病毒（RPV）可以用非常灵敏的检测方法检测到。最近 已发表的研究表明，来自HSPC及其可能的后代的相同前病毒簇通常 与RPV匹配，有时具有传染性。这些序列与RPV匹配的比例高于前病毒 来自外周血单核细胞的基因组缺乏克隆扩增的证据。而且我们 提供了来自外周血T细胞中潜伏的祖细胞的前病毒基因组的例子， 同时也为RPV做出了贡献。这些病例中RPV的细胞来源尚不清楚，但不太可能 是外周血T细胞，其需要基因表达的潜伏再激活。我们已经开发出一种 模型基于这些数据。在这个模型中，我们提出了感染的异质分化后代， 祖细胞可以支持主动或潜伏感染，这取决于子代表观遗传和转录 程序.本申请的总体目标是通过全面表征 外周血和组织库中的完整HIV。第二个目标是确定是否感染 克隆前病毒和RPV以及识别非病毒的任何替代增殖来源都需要HSPC HSPC产生克隆基因组。为了做到这一点，我们将：1。分析完整的近全长病毒基因组 鉴定外周血中克隆扩增的前病毒基因组的来源， 与增殖源如HSPC的关系; 2.使用病毒生长测定来确认关系 感染性病毒的来源;及3.确定活动和潜伏感染的组织来源， 感染性病毒及其与增殖源如HSPC的关系。这些目标的成果将 全面识别多个不同组织部位的功能性病毒和RPV来源。他们将 确定多能和/或限制性祖细胞或其他增殖源作为细胞的增殖源的程度。 存在于外周血和组织部位的克隆扩增的HIV前病毒基因组的来源。这些 研究将提供重要的新信息，这些信息有可能改变我们对 功能相关的艾滋病毒储存库的来源。