Pre-treatment Microbiome Diversity and Function is associated with Expansion of Cytotoxic and Regulatory Immune Populations after N-803 treatment in People with HIV

Background: N-803, an IL-15 superagonist, is currently being studied in clinical trials as a treatment to reverse HIV latency. However, its effects on the gut microbiome are not well understood. Methods: In this longitudinal metagenomic study, we analyzed fecal microbiomes from ART-suppressed people with HIV at four different timepoints before, during, and after N-803 treatment. Results: Overall taxonomic and functional diversity did not change significantly, yet beneficial microbial taxa and pathways were enriched after N-803. Specifically, the relative abundance of Faecalibacterium prausnitzii increased significantly after N-803, whereas histidine degradation pathways, often associated with pro-inflammatory mucosal state, decreased. A higher baseline microbial diversity correlated with stronger CD8⁺ and natural killer (NK) cells activation and reduced frequency of rectal HIV RNA+ cells. MaAsLin2 analyses further associated short-chain fatty acid (SCFA)-producing taxa and pathways with increased immune activation markers. Conclusions: These results indicate that gut microbiome diversity prior to immunotherapy influences host response and suggest that microbiome-based strategies could improve efforts to cure HIV.