HIV-1 reservoir dynamics in the female genital tract

描述（由申请人提供）：有效的抗逆转录病毒联合疗法（ART）改变了资源丰富国家的艾滋病毒流行情况。潜伏感染的细胞，被称为HIV储存库，是罕见的，但在接受治疗的患者中持续存在，是病毒根除的主要障碍。该病毒库由血浆中的残留病毒和潜伏感染的外周血单核细胞（PBMC）亚群组成，这些亚群分布在组织隔间中。血液和组织中HIV储存库之间的确切关系目前尚不清楚。人们已经做了很多工作来描述肠道和最近的淋巴结组织中的HIV储存库，而对生殖道中的储存库知之甚少。提高对组织中HIV储存库动力学的理解对HIV根除和治愈工作至关重要。这项提议的目标是帮助回答一个基本问题：相对于在血浆和PBMC中进行的类似分析，对女性生殖道中HIV持久性的测量是否为可测试的病毒根除策略提供了新的见解？女性生殖道作为HIV病毒储存库有几个独特的特征，值得进一步的详细研究。首先，尽管在抑制性抗逆转录病毒治疗期间，血液或胃肠道组织中是否存在持续的病毒复制仍存在争议，但当血浆HIV-1 RNA水平无法检测到时，女性生殖道中是否存在病毒复制的证据已得到充分证明。其次，相对于血浆或PBMC中的水平，非核苷类逆转录酶抑制剂（NNRTIs）和一些蛋白酶抑制剂（pi）进入女性生殖道的抗逆转录病毒药物组织渗透可以大大减少，并且可能在外周抑制性抗逆转录病毒治疗期间为局部维持和/或补充HIV库创造有利条件。我们提出一项跨学科研究，以表征女性生殖道中的HIV储存库，鉴定HIV持续存在的细胞和组织来源，研究非t细胞储存库，确定组织药物水平对病毒进化的影响，并建立血液和女性生殖道储存库之间的关系。我们假设，在抗逆转录病毒治疗期间，女性生殖道HIV-1储存库的衰减和持久性与外周血中的相比是不同的。我们将研究抗逆转录病毒药物组织渗透对抑制抗逆转录病毒治疗期间病毒进化和潜伏期的贡献，并探索病毒再激活策略在组织源性细胞中的作用。该建议的具体目的是：1)定义外周血与女性生殖道HIV-1储存库之间的关系，使用两组妇女：开始抗逆转录病毒治疗的未接受治疗的参与者和病毒学抑制的稳定抗逆转录病毒治疗的受试者；

DESCRIPTION (provided by applicant): Effective combination antiretroviral therapy (ART) has transformed the HIV epidemic in resource-rich countries. Latently infected cells, referred to as the HIV reservoir, are rare but persist in treated patients and represent a major barrier to virus eradication. This reservoir is comprised of residual virus in plasma and latently infected peripheral blood mononuclear cell (PBMC) subpopulations that distribute into tissue compartments. The exact relationship between blood and tissue HIV reservoirs is not currently known. Much work is being done to characterize HIV reservoirs in gut and more recently lymph node tissues, whereas less is known about reservoirs in the genital tract. An improved understanding of HIV reservoir dynamics in tissue is critical to HIV eradication and cure efforts. The goal of this proposal is to help answer a fundamental question: Do measures of HIV persistence in the female genital tract provide novel insights into testable virus eradication strategies, relative to similar analyses performed in plasma and PBMC? The female genital tract has several unique features as an HIV reservoir that warrant further detailed study. First, while the presence of ongoing virus replication in blood or gastrointestinal tissues during suppressive ART remains controversial, the evidence for virus production in the female genital tract when plasma HIV-1 RNA levels are undetectable is well documented. Second, the antiretroviral drug tissue penetration of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and some protease inhibitors (PIs) into female genital tract can be substantially reduced, relative to levels in plasma or PBMC, and may create conditions favorable for local maintenance and/or replenishment of the HIV reservoir during peripherally suppressive ART. We propose an interdisciplinary study to characterize the HIV reservoir in female genital tract, identify cellula and tissue sources of HIV persistence, investigate non-T cell reservoirs, define the impact of tissue drug levels on virus evolution, and establish the relationship between blood and female genital tract reservoirs. We hypothesize that the female genital tract HIV-1 reservoir is distinct n its decay and persistence during ART, compared to that in peripheral blood. We will investigate the contribution of antiretroviral drug tissue penetration to ongoing virus evolution and latency during suppressive ART, and explore the effects of virus reactivation strategies in tissue-derived cells. Specific aims of this proposal are: 1) Define the relationship between the peripheral blood and female genital tract HIV-1 reservoirs using two groups of women: treatment- naive participants initiating antiretroviral therapy and virologically suppressed subjects on stable ART, 2) Investigate female genital tract HIV-1 evolution during suppressive ART and correlate with tissue drug concentrations, and 3) Determine the sensitivity of female genital tract tissue reservoirs to virus re-activation strategies.