HIV-1 reservoir dynamics in the female genital tract

描述(由申请人提供)：有效的联合抗逆转录病毒疗法(ART)改变了资源丰富国家的艾滋病毒流行。潜伏感染的细胞被称为艾滋病毒储存库，这种细胞很罕见，但在接受治疗的患者中持续存在，是根除病毒的主要障碍。这个储存库由血浆中残留的病毒和潜伏感染的外周血单个核细胞(PBMC)亚群组成，这些亚群分布在组织间。目前尚不清楚血液和组织中艾滋病毒储存库之间的确切关系。人们正在做大量的工作来确定肠道和最近的淋巴组织中的艾滋病毒储存库的特征，而对生殖道的储存库知之甚少。更好地了解组织中艾滋病毒储存库的动态对于根除和治愈艾滋病毒至关重要。这项建议的目的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，衡量艾滋病毒在女性生殖道中的持久性是否为可检测的病毒根除战略提供了新的见解？女性生殖道作为艾滋病毒储存库有几个独特的特点，值得进一步详细研究。首先，虽然在抑制抗逆转录病毒治疗期间血液或胃肠道组织中存在持续的病毒复制仍然存在争议，但当血浆HIV-1RNA水平无法检测到时，在女性生殖道产生病毒的证据已经得到很好的记录。其次，相对于血浆或PBMC中的水平，非核苷类逆转录酶抑制剂(NNRTI)和一些蛋白酶抑制剂(PI)对女性生殖道的抗逆转录病毒药物组织渗透率可以显著降低，并可能在外周抑制ART期间为艾滋病毒储存库的局部维持和/或补充创造有利条件。我们提出了一项跨学科的研究，以确定女性生殖道中HIV储存库的特征，确定HIV持续存在的细胞和组织来源，调查非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，女性生殖道HIV-1储存库在抗逆转录病毒治疗期间的腐烂和持久性方面与外周血中的储存库相比是不同的。我们将研究抗逆转录病毒药物的组织渗透对正在进行的病毒进化和抑制ART期间的潜伏期的贡献，并探索组织来源细胞中病毒重新激活策略的影响。这项建议的具体目的是：1)使用两组妇女确定外周血和女性生殖道HIV-1宿主之间的关系：接受治疗的未接受治疗的参与者开始抗逆转录病毒治疗，以及接受稳定抗逆转录病毒治疗的病毒学受试者， 2)研究女性生殖道HIV-1在抑制ART期间的演变，并与组织药物浓度相关；3)确定女性生殖道组织储存库对病毒再激活策略的敏感性。

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.