Role of chemokines in establishing and maintaining HIV latency

尽管联合抗逆转录病毒疗法(ART)可以无限期地抑制艾滋病毒的复制，但它不能 彻底根除具有复制能力的艾滋病毒。根除的主要障碍似乎是存在 长期潜伏感染的静息记忆T细胞，尽管在组织中有低水平的隐蔽复制 避难所也可能是一个促成因素。确定HIV持续存在的部位和机制 这是我们合作实验室的一个主要主题。在接受最佳治疗的艾滋病毒感染者中 人类和感染SIV的猕猴，在胃肠道和淋巴组织中被感染的T细胞的频率是 几乎是在外周血液中发现的十倍。感染细胞在体内的这种浓缩机制 这些组织尚不清楚。我们的总体假设是，趋化因子在两者的建立中起着关键作用 并维持潜伏期，潜伏期在很大程度上是在组织中高表达 与趋化因子受体(CCR7、CXCR3、CCR6和CCR5)结合的特定趋化因子 静息的CD4+T细胞。在目标1中，我们将确定是否在静息的CD4+T细胞中建立了潜伏库 有特定的趋化因子受体表达，专注于静止记忆的CD4+T细胞亚群 表达CXCR3、CCR6或CCR5，并驻留在组织中。在目标2中，我们将使用一种体外培养的新技术 主要T细胞潜伏期的模型，以筛选将逆转潜伏期的代理。我们将检验这一假设 体外使用趋化因子对静息T细胞的初次感染准确地反映了体外潜伏感染的细胞， 这个模型可以用来筛选逆转潜伏期的化合物。我们将使用此模型来 协助合作实验室中的其他人测试新的干预措施。在目标3中，我们将探讨CCR5的影响 拮抗剂马拉韦罗，对循环和肠道组织来源的潜伏感染的CD4+T细胞。这项工作将 补充项目7中正在进行的临床试验。

Although combination antiretroviral therapy (ART) can suppress HIV replication indefinitely, it fails to completely eradicate replication-competent HIV. The major barrier to eradication appears to be the existence of long-lived latently infected resting memory T-cells, although low-level cryptic replication in tissue sanctuaries may also be a contributing factor. Identifying the sites of HIV persistence and the mechanisms that account for this persistence is a major theme of our Collaboratory. In optimally-treated HIV-infected humans and SIV-infected macaques, the frequency of infected T-cells in the Gl tract and lymphoid tissue is almost ten times that found in peripheral blood. The mechanism for such enrichment of infected cells in these tissues is not known. Our overall hypothesis is that chemokines play a critical role in both establishing and maintaining latency and that latency is largely established in tissue where there is high expression of specific chemokines that bind to the chemokine receptors (CCR7, CXCR3, CCR6 and CCR5) found in resting CD4+ T-cells. In Aim 1, we will identify whether the latent reservoir is established in resting CD4+ T-cells with specific chemokine receptor expression, focusing on subsets of resting memory CD4+ T-cells that express either CXCR3, CCR6, or CCR5 and that reside in tissues. In Aim 2, we will use a novel in vitro model of primary T-cell latency to screen for agents that will reverse latency. We will test the hypothesis that primary infection of resting T-cells using chemokines in vitro accurately reflects latently-infected cells ex vivo, and that this model can be used to screen for compounds that reverse latency. We will use this model to assist others in the Collaboratory to test novel interventions. In Aim 3, we will explore the impact of the CCR5 antagonist, maraviroc, on circulating and gut tissue-derived, latently-infected CD4+ T-cells. This work will complement the clinical trial ongoing in Project 7.