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This is a Quantitative Study study.

September 12, 2025Open Access

Immunometabolic defects of CD8+ T cells disrupt gut barrier integrity in people with HIV

UAUpasana Das AdhikariRagon Institute of MGH, MIT and Harvard LFLeah FroehleBoston University APAlexandra N PipkinRagon Institute of MGH, MIT and Harvard

Key Points

Immunometabolic defects in CD8+ T cells lead to intestinal epithelial apoptosis and disrupted barrier integrity.
Colon-resident CD8+ T cells in people with HIV show reduced PPARγ levels, correlating with lipid metabolism issues.
The study identifies a mechanism by which HIV contributes to intestinal epithelial dysfunction and highlights intervention strategies.
Results indicate that targeting immunometabolic processes might alleviate intestinal integrity issues in HIV and related disorders.

Abstract

A hallmark of HIV infection is disruption of intestinal barrier integrity that persists in people with HIV (PWH) despite treatment with antiretroviral therapy (ART). This disruption is central to HIV disease progression, yet the causes remain incompletely understood. We report a mechanism by which immunometabolic defects in colon-resident CD8+ T cells in PWH lead to intestinal epithelial apoptosis and disruption of intestinal barrier integrity. We show that in PWH, these cells downregulate the lipid sensor peroxisome proliferator-activated receptor-γ (PPARγ), which results in reduced intracellular lipid droplets, impaired fatty acid oxidation, and acquisition of lipids by CD8+ T cells from intestinal epithelial cells, which then contributes to epithelial cell death. Our findings indicate that HIV-associated immunometabolic dysregulation of colon CD8+ T cells leads to loss of intestinal epithelial homeostasis. These results identify potential strategies to reduce comorbidities in PWH and other disorders with disrupted intestinal barrier integrity.

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