Impact of the gastrointestinal microbiome on HIV reservoirs

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Antiretroviral therapy (ART) can reduce viremia to undetectable levels in people living with HIV (PLWH) . However, replication-competent virus persists in peripheral blood and tissues that is capable of reestablishing the infection upon antiretroviral therapy interruption (ATI). One of our long-term goals is to aid the development of effective HIV cure strategies by gaining a better understanding of the host physiological and metabolic processes by which cellular reservoirs are established and maintained, and those of viral reactivation. Regardless of how HIV infection is acquired, the gastrointestinal (GI) tract is a major site of HIV replication. Although the majority of immune cells in the body, including CD4+ T cells, reside in the GI tract, little is known about the HIV reservoir that is established in this tissue. Analyses of ART-treated patients have demonstrated higher HIV-DNA levels in GI tract cells compared to blood cells, suggestive of a larger HIV reservoir. Examination of HIV transcripts in cells from the blood and rectum of ART-treated PLWH also indicates that the GI tract may be enriched in latently-infected cells and suggests that HIV latency is maintained by different mechanisms in the GI tract and/or that a deeper s tate of latency may be maintained. Based on these observations, our overarching hypothesis is that HIV establishes a latent infection in the GI tract that contributes to virus rebound during ATI. T o our knowledge there is virtually no information addressing the role of the microbiome in establishing or maintaining the latent reservoir in the GI tract. Currently, a large amount of indirect evidence suggests that the GI microbiome is involved in HIV persistence. The GI microbiome in PLWH promotes inflammation and immune activation in the GI tract, which may influence HIV reservoir size. Furthermore, in vitro studies show that microbiota and microbial metabolites can influence HIV transcription. Therefore, we further hypothesize that the intestinal microbiome contributes to the establishment and persistence of the HIV reservoir and thereby impacts the contribution of the GI tract to virus rebound. A role for the microbiome in HIV remission would be fundamentally important to HIV cure development. Previously, we and others demonstrated that HIV establishes a latent infection in ART-suppressed humanized mice that upon discontinuation of ART results in robust virus rebound. Importantly, we recently demonstrated reproducible induction of HIV in resting CD4+ T cells in multiple tissues of ART-suppressed humanized mice using two different latency reversal approaches. Our objective is to analyze the HIV reservoir in the GI tract using BLT humanized mice, a well- characterized model of HIV latency, persistence and reactivation. We will 1) analyze HIV reservoir formation in the GI tract, 2) evaluate the contribution of the GI tract to viral rebound, and 3) assess HIV induction in the Gl tract by latency reversing agents. We will also use an innovative germ-free BLT mouse model to determine how the presence of the GI microbiome contributes to HIV persistence and rebound.