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

Chakrawarti, A.; Cromarty, R. T.; Basting, C. M.; Anderson, J.; Schroeder, T.; Escandon, K.; Shields-Cutler, R.; Swanson, E.; Soon-Shiong, P.; Safrit, J. T.; Sender, L. S.; Reddy, S.; Miller, J.; Rhein, J.; Schacker, T.; Klatt, N. R.

2025-10-01 microbiology
10.1101/2025.10.01.679827 bioRxiv
Show abstract

BackgroundN-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. MethodsIn 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. ResultsOverall 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. ConclusionsThese results indicate that gut microbiome diversity prior to immunotherapy influences host response and suggest that microbiome-based strategies could improve efforts to cure HIV.

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