Cellular Reservoirs of HIV

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。CD4+造血干/祖细胞(HSPC)具有 终生生存、自我更新和产生子代细胞的能力。他们也容易患上 HIV在体外和体内的感染。联合抗逆转录病毒疗法有效抑制HIV病毒血症 被感染的人。然而，残留血浆病毒(RPV)可以用非常敏感的方法检测出来。最近 已发表的研究表明，来自HSPC及其可能的后代的一群相同的前病毒通常 与RPV相匹配，有时具有传染性。这些序列中与RPV匹配的比例高于前病毒 缺乏克隆扩增证据的外周血单核细胞的基因组。此外，我们 提供在外周血T细胞中潜伏的祖细胞的前病毒基因组的例子 同时对RPV做出贡献。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，需要潜伏期重新激活基因表达。我们已经开发出一种 基于这些数据的模型。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感染或潜伏感染，这取决于后代的表观遗传和转录 程序。这个应用程序的总体目标是通过全面描述 在外周血液和组织储存库中存在完整的艾滋病毒。次要目标是确定是否感染了 克隆前病毒和RPV需要HSPC，并确定任何替代的非增殖性来源 HSPC产生了克隆基因组。要做到这一点，我们将：1.分析接近全长的完整病毒基因组 鉴定外周血中克隆扩增的前病毒基因组的来源，并确定其 与HSPC等增殖源的关系；2.使用病毒生长分析来确认关系 感染性病毒的来源；以及3.确定活跃和潜伏感染的组织来源 传染性病毒及其与HSPC等增殖源的关系。这些目标的结果将 全面识别跨多个不同组织部位的功能性病毒和RPV来源。他们会 确定多能和/或受限制的祖细胞或其他增殖源的作用程度 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，有可能改变我们对 在功能上相关的艾滋病毒储存库的来源。

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.