# Immunometabolic regulation of CD8+ T cell mediated intestinal epithelial cell death in people with HIV (PWH)

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $708,025

## Abstract

A hallmark of human immunodeficiency virus (HIV) infection is intestinal inflammation and impairment of
gut epithelial barrier function. These defects are thought to drive HIV disease progression by allowing
translocation of luminal microbial products into the circulation, which triggers chronic systemic immune
activation and disease progression. Although antiretroviral therapy (ART) effectively suppresses viral
replication in the blood, it does not restore homeostasis in the intestine, even after years of treatment. This
contributes to increased morbidity and mortality due to inflammatory non-communicable diseases (NCDs)
such as heart disease and stroke in people with HIV (PWH). Despite the central role of intestinal barrier
function in HIV disease pathogenesis, little is known about the specific mechanisms by which HIV results in
epithelial damage. Studies of intestinal epithelial cell (IEC) dysfunction in HIV have relied primarily on
correlative observations based on histology or peripheral biomarkers. Our proposal addresses critical gaps in
knowledge by utilizing intestinal tissue samples from well-characterize cohorts of PWH and HIV-uninfected
individuals, along with novel in vivo mouse and ex vivo human cell models and state-of-the-art technologies to
explore specific mechanisms by which HIV contributes to IEC death in PWH. We hypothesize that HIV-
associated defects in CD8+ T cell fatty acid (FA) metabolism cause them to scavenge lipids from nearby
IEC, which leads to IEC death. This IEC death then results in intestinal barrier disruption. To address these
hypotheses, we are proposing two complementary aims. In Aim 1 we will characterize the in vivo and ex vivo
impact of HIV infection on IEC death in PWH using colon tissue samples obtained by endoscopy to
characterize IEC death and CD8+ T cell phenotypes. We will also utilize novel mini-gut organoid models that
incorporate autologous tissue resident immune cells and in-depth single cell sequencing analysis
leveraging a platform optimized for small sample sizes developed by collaborators at MIT. In Aim 2, we will
determine the mechanisms by which HIV-associated dysregulation of FA metabolism in intestinal CD8+ T
cells disrupts the colonic epithelial barrier. In this aim we will utilize ex vivo human organoid and in vivo murine
models to test the mechanistic role of impaired FA metabolism in CD8+ T cell mediated IEC death and
intestinal barrier dysfunction. This approach will identify specific cellular and molecular mechanisms underlying
the impact of HIV infection on intestinal barrier function and systemic immune activation. To carry out these
Aims we have assembled a team with combined expertise in HIV disease, mucosal immunology, and GI
pathology, who are well positioned to uncover specific mechanisms that underlie intestinal epithelial dysfunction
in HIV infection. This proposal will address important unknown mechanisms of IEC biology that may help in the
development of new strategies t...

## Key facts

- **NIH application ID:** 10528704
- **Project number:** 1R01DK133919-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Douglas Kwon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $708,025
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10528704

## Citation

> US National Institutes of Health, RePORTER application 10528704, Immunometabolic regulation of CD8+ T cell mediated intestinal epithelial cell death in people with HIV (PWH) (1R01DK133919-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10528704. Licensed CC0.

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