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Microbiome-Derived Metabolites Shape CD4⁺ T-Cell Differentiation and Immune Aging in HIV-1 Infection
Amanda Cabral da Silva1, Luke Flantzer1, Jaclyn Weinberg2
1Department of Pathology and Laboratory Medicine, Emory Univerisity School of Medicine, Atlanta, United States of America.
JCI Insight
|July 21, 2026
Summary
Gut bacteria metabolites impact immune cells in people with HIV-1 (PLWH). High levels of cell-associated aromatic metabolites, like p-cresol sulfate (PCS), drive immune aging and may link to HIV persistence.
Area of Science:
- Immunometabolism
- Microbiome-host interactions
- HIV-1 pathogenesis
Background:
- The influence of gut-derived bacterial metabolites (GDBMs) on immune cell metabolism and function is not well understood.
- People living with HIV-1 (PLWH) often exhibit altered immune profiles and metabolic dysregulation.
Purpose of the Study:
- To investigate the role of aromatic GDBMs in shaping CD4+ T-cell metabolism and function in PLWH.
- To identify specific GDBMs associated with altered CD4+ T-cell states and their link to HIV-1 persistence.
Main Methods:
- Ex vivo metabolomic profiling of plasma and CD4+ T-cells from PLWH.
- Flow cytometry and single-cell RNA sequencing to analyze CD4+ T-cells stratified by cell-associated p-cresol sulfate (PCS) levels.
- In vitro transcriptomic and proteomic analyses of PCS-exposed CD4+ T-cells.
- Integration with HIV-1 reservoir measurements (intact proviral DNA).
Main Results:
- Cell-associated aromatic GDBMs, particularly PCS, were linked to significant alterations in CD4+ T-cell metabolic and functional states.
- Elevated cell-associated PCS induced dose-dependent transcriptional programs related to impaired differentiation, regulatory identity, and senescence.
- PCS exposure in vitro triggered cell-cycle arrest, mitochondrial dysfunction, and senescence markers (p16, p21).
- CD4+ T-cell states associated with GDBMs correlated with higher levels of intact proviral DNA in PLWH.
Conclusions:
- A microbiome-derived axis involving GDBMs reshapes CD4+ T-cell metabolism and promotes immune aging in PLWH.
- These immunometabolic changes may contribute to the persistence of the HIV-1 reservoir.
- Targeting GDBMs could offer novel therapeutic strategies for managing immune aging and HIV persistence.
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