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

> **NIH NIH R21** · TULANE UNIVERSITY OF LOUISIANA · 2024 · $212,215

## Abstract

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.

## Key facts

- **NIH application ID:** 10904659
- **Project number:** 5R21AI174901-02
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Joseph Christopher Mudd
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $212,215
- **Award type:** 5
- **Project period:** 2023-08-10 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904659

## Citation

> US National Institutes of Health, RePORTER application 10904659, The intersection of diet, cell metabolic state, and SIV reservoir transcription (5R21AI174901-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10904659. Licensed CC0.

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