Persistent pneumococcal colonisation in antiretroviral-treated HIV infection is associated with nasal inflammation.

Despite systemic viral suppression, people living with HIV (PLHIV) on antiretroviral therapy (ART) remain highly susceptible to pneumococcal colonisation and disease. Here, we show that long-term ART does not restore nasal mucosal immunity. Using flow cytometry, single-cell transcriptomics, and neutrophil functional assays, we identify a persistent mucosal immune signature in PLHIV-ART > 1 yr marked by epithelial-driven neutrophilic inflammation, T cell exhaustion, and cellular senescence. Neutrophils exhibit mitochondrial stress, senescence-associated secretory phenotype (SASP) gene expression, and impaired oxidative burst, particularly in individuals with pneumococcal carriage. Epithelial cells express elevated neutrophil-recruiting ligand genes, while nasal T cells display pro-apoptotic and exhaustion gene profiles. Neutrophilic inflammation is strongly associated with pneumococcal carriage density, implicating a feedforward loop between inflammation and microbial persistence. Our findings reveal tissue-specific immune dysregulation despite ART and suggest that targeting epithelial-immune signalling or neutrophil senescence may offer novel therapeutic avenues to reduce respiratory pathogen burden in PLHIV.