HIV Reservoir Dynamics and Bacteriome Composition Along the Gut Axis.

Abstract

The gastrointestinal (GI) tract is a major reservoir of HIV and home to the body's most diverse microbiome. However, the role of gut bacteriome in modulating local HIV persistence remains uninvestigated. Leveraging rapid autopsy samples (n=113) from 24 people with HIV (PWH) in the Last Gift cohort, we performed 16S rRNA sequencing and quantified total HIV DNA and msTat/Rev RNA (ddPCR) across five GI segments (duodenum, jejunum, ileum, colon, rectum). Associations between relative abundance of bacterial taxa and reservoir characteristics were analyzed using multivariable models. HIV DNA levels were highest in the jejunum, intermediate in duodenum and ileum, and lowest in the colon and rectum (p<0.05 for all). HIV transcriptional activity was higher-than-expected relatively to the reservoir size in duodenum and ileum. Bacterial communities significantly differed in richness and composition across the segments (PERMANOVA p=0.002). Higher richness was associated with increased HIV transcriptional activity in the small bowel (ρ=0.32, p=0.015), and decreased activity in the large bowel (ρ=-0.41, p=0.013). 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. 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.