Linking Gut Microbiome to HIV-1 Reservoir Size in People Living with HIV

The gut microbiome is altered during HIV-1 infection contributing to immune dysfunction and inflammation in people living with HIV (PLWH) that persists despite antiretroviral therapy (ART). We explored the associations between the gut microbiome and HIV-1 reservoir size in PLWH (n = 30) on long-term ART. The intact proviral DNA assay (IPDA) and shotgun metagenomic sequencing were performed to identify microbial species and metabolic pathways associated with the size of the HIV-1 reservoir. PLWH with a smaller intact reservoir exhibited lower alpha diversity compared to individuals with a larger intact reservoir. We found that Phocaeicola plebeius and Lachnospira sp000437735 were significantly enriched in individuals with a smaller intact reservoir and lower intact-to-total proviral ratio, respectively. We observed a negative association between Fecalibacterium prausnitzi and a positive association of Prevotella copri , with the intact proviral reservoir size. Additionally, the metabolic pathways of glycolysis and branched-chain amino acid biosynthesis were enriched in individuals with larger reservoir. HIV reservoir size in blood is associated with gut microbiome diversity, specific metabolic pathways and microbial signatures, including Lachnospira, Prevotella , and Faecalibacterium . These findings underscore the potential role of the gut microbiome in viral persistence and suggest that strategies targeting microbiome modulation could disrupt the HIV reservoir.