Pre-treatment Gut Microbiome Diversity and Function Linked to Cytotoxic and Natural Killer Cell Immune Responses 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 exploratory longitudinal metagenomic study, we analyzed fecal microbiomes from 10 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 nominally enriched after N-803. Specifically, the relative abundance of Faecalibacterium prausnitzii showed a nominal increase 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 identified potentially important associations between short-chain fatty acid (SCFA)-producing taxa and pathways with increased immune activation markers. CONCLUSIONS: These findings in a limited Phase 1B clinical study suggest that gut microbiome diversity prior to immunotherapy may influence host response. These results provide a basis for further investigation into microbiome-based strategies to improve efforts to cure HIV.