The intersection of diet, cell metabolic state, and SIV reservoir transcription

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Project Summary/Abstract The main obstacle to curing HIV-1 infection is a reservoir that consists of resting memory CD4 T cells whose genomes contain inducible and replication-competent HIV-1 proviruses. Decay of the reservoir is slow and this has reinforced a notion that proviral HIV-1 DNA is largely transcriptionally silent. A wide body of recent evidence has pointed to the contrary. At any point in time, a non-negligible fraction of the HIV-1 reservoir remains transcriptionally active despite complete suppression with antiretroviral therapy (ART). Moreover, latent HIV-1 transcription can be induced above these apparent baseline levels with HIV-1 stimulatory compounds, deemed latency reversal agents (LRAs). Some LRAs have been able to modestly reduce reservoir size in small clinical or pre-clinical trials of HIV-1+ humans or SIV+ rhesus macaques (RMs). However, a current limitation of LRA use is that to date, these agents have been tested only in very narrow patient/animal cohorts, not representative of heterogeneity that exists in the HIV-1+ population, and not accounting for age, gender, or the prevalence of additional co-morbidities associated with HIV-1. Type 2 diabetes in particular is a co- morbidity that is prevalent in PLWH, and is the result of an imbalance of the dietary hormone insulin. In preliminary studies, we find that CD4 T cells (which serve as the principle reservoir for HIV-1) express the insulin receptor and respond to insulin by activating the PI3K signaling pathway. PI3K signaling is known to be upstream of (1) metabolic regulators of latent HIV-1 transcription (mTORC signaling) and (2) transcription factors involved in binding to the HIV-1 promoter (Sp1 and FOXO1). In these proposed studies, we will take advantage of an existing well-powered cohort of fully ART-suppressed SIV+ RMs to probe the role of insulin signaling as a regulator of the HIV-1/SIV lifecycle. We will employ cutting-edge phospho-proteomic methods to examine how the dietary hormone insulin influences transcription of latent SIV in (Aim 1) the context of LRA-based biologics that share common signaling cascades with insulin and (Aim 2) the context of natural blood glucose/insulin fluctuations that occur with dietary intake. The application will seek to define on a basic level (1) the insulin “signalome” in CD4 T cells (2) as-yet explored dietary factors that may influence transcriptional activity of latent HIV-1 and importantly (3) provide a conceptual framework for future studies on LRA use in settings in which insulin signaling is impaired.