Microbiome-derived metabolites shape CD4+ T cell differentiation and immune aging in HIV-1 infection.

The role of aromatic gut-derived bacterial metabolites (GDBMs) in shaping immune cell metabolism and function remains poorly explored. Using ex vivo metabolomic profiling of paired plasma and CD4+ T cells from people living with HIV-1 (PLWH), we identified a network of aromatic GDBMs whose cell-associated abundance, rather than systemic levels, was linked to broad alterations in CD4+ T cell metabolic and functional states. Among these, p-cresol sulfate (PCS) emerged as a mechanistic prototype. Ex vivo flow cytometry and scRNA-seq of CD4+ T cells stratified by cell-associated PCS levels revealed dose-dependent enrichment of transcriptional programs associated with impaired differentiation, regulatory-like identity, and cellular senescence. In vitro transcriptomic and proteomic analyses of PCS-exposed CD4+ T cells demonstrated induction of cell-cycle arrest, mitochondrial dysfunction, and senescence-associated programs, including upregulation of p16 and p21. Integration of these immunometabolic findings with HIV-1 reservoir measurements revealed that CD4+ T cell states defined by cell-associated GDBMs track with intact proviral DNA levels in vivo. These findings define a microbiome-derived axis that reshapes CD4+ T cell metabolism and fate, promotes immune aging in PLWH, and may foster immunometabolic states linked to long-term HIV-1 reservoir persistence.