Mucosal and systemic immune signatures reveal compartmentalized regulation of gut barrier integrity in virologically suppressed HIV Infection

Persistent immune activation and inflammation contribute to non–AIDS comorbidities in people living with HIV (PLWH) despite long-term virological suppression. Given the central role of the gut in immune homeostasis, we investigated whether mucosal and peripheral molecular signatures relate to clinical status, immune recovery, and antiretroviral therapy (ART) class. Sixty-eight virologically suppressed PLWH were stratified by CDC clinical stage, ART regimen (integrase strand transfer inhibitor [INSTI]–based vs. non-INSTI), and CD4/CD8 ratio. Targeted gene expression was assessed by RT-PCR in anorectal mucosal biopsies and peripheral blood mononuclear cells, while epithelial protein expression was evaluated by Western blot in mucosal biopsies. Plasma biomarkers of epithelial injury, microbial translocation, and systemic inflammation were quantified by ELISA. Group comparisons and correlation analyses were performed using non-parametric statistics. Mucosal analyses revealed distinct transcriptional and protein-level alterations associated with clinical and immunological stratifications, whereas peripheral cellular and circulating biomarkers showed limited discriminatory capacity. Notably, specific ART-related patterns emerged at the mucosal level, accompanied by coordinated associations between epithelial junctional features and local immune parameters that were not mirrored systemically. Together, these findings indicate persistent, spatially restricted epithelial–immune remodelling in treated HIV infection, underscoring the importance of direct mucosal assessment to capture residual barrier and immune perturbations under suppressive ART.