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）已经改变了资源丰富国家的艾滋病毒流行。潜伏感染的细胞，被称为艾滋病毒水库，是罕见的，但在治疗的患者中持续存在，并代表了病毒根除的主要障碍。该储库由血浆中的残留病毒和分布到组织隔室中的潜伏感染的外周血单核细胞（PBMC）亚群组成。血液和组织HIV储库之间的确切关系目前尚不清楚。许多工作正在做的特点，艾滋病毒水库在肠道和最近的淋巴结组织，而很少有人知道水库在生殖道。更好地了解组织中的HIV储库动态对于HIV根除和治疗工作至关重要。该提案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，女性生殖道中HIV持续性的测量是否为可测试的病毒根除策略提供了新的见解？ 女性生殖道作为艾滋病毒储存库有几个独特的特征，值得进一步详细研究。首先，虽然在抑制性ART期间血液或胃肠道组织中持续病毒复制的存在仍然存在争议，但当血浆HIV-1 RNA水平无法检测时，女性生殖道中病毒产生的证据已得到充分证明。第二，相对于血浆或PBMC中的水平，非核苷逆转录酶抑制剂（NNRTI）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显著降低，并且可以创造有利于本地维护和/或维护的条件。我们提出了一个跨学科的研究，以表征艾滋病毒水库在女性生殖道，确定HIV持久性的细胞和组织来源，调查非T细胞储库，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库之间的关系。我们假设，女性生殖道HIV-1水库是不同的，其衰变和持久性在ART期间，相比，在外周血。我们将研究抗逆转录病毒药物的组织渗透的贡献，正在进行的病毒进化和潜伏期在抑制性ART，并探讨病毒的再激活策略在组织来源的细胞的影响。1）使用两组女性定义外周血和女性生殖道HIV-1储库之间的关系：开始抗逆转录病毒治疗的未接受过治疗的参与者和接受稳定ART的病毒学抑制受试者， 2)研究女性生殖道HIV-1在抑制性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.