Role of chemokines in establishing and maintaining HIV latency

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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.