HIV Reservoir Dynamics and Bacteriome Composition Along the Gut Axis

Background: The gastrointestinal (GI) tract is a major reservoir of HIV and home to the body's most diverse microbiome. However, the role of the gut bacteriome in modulating local HIV persistence remains uninvestigated. Methods: Leveraging rapid autopsy samples (n = 113) from 24 people with HIV in the Last Gift cohort, we performed 16S rRNA sequencing and quantified total HIV DNA and multiply spliced Tat/Rev RNA (droplet digital polymerase chain reaction) across 5 GI segments: duodenum, jejunum, ileum, colon, and rectum. Associations between the relative abundance of bacterial taxa and reservoir characteristics were analyzed via multivariable models. Results: HIV DNA levels were highest in the jejunum, intermediate in the duodenum and ileum, and lowest in the colon and rectum (P < .05 for all). HIV transcriptional activity was higher than expected relative to the reservoir size in the duodenum and ileum. Bacterial communities significantly differed in richness and composition across the segments (permutational multivariate analysis of variance, P = .002). Higher richness was associated with increased HIV transcriptional activity in the small bowel (ρ = 0.32, P = .015) and decreased activity in the large bowel (ρ = −0.41, P = .013). Segment-specific associations between taxa and HIV reservoir were observed: among these, short-chain fatty acid producers, mucin degraders, and bile acid metabolizers were consistently associated with reduced reservoir size and activity in the large bowel but with enhanced transcription in proximal segments. Sensitivity analyses by antibiotic exposure, cancer, and viral load confirmed robustness of findings. Conclusions: The gut bacteriome modulates HIV reservoir size and activity, and these effects vary along the GI tract. This regional specificity must be considered when designing bacteriome-based strategies to reduce HIV persistence and improve cure efforts.