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

作者：Ashma Chakrawarti, Ross Cromarty, Christopher M. Basting, Jodi Anderson, Ty Schroeder, Kevin Escandón-Vargas, Robin Shields‐Cutler, Robert Langat, E. R. Swanson, Patrick Soon‐Shiong, Jeffrey T. Safrit, Leonard S. Sender, Sandeep K. Reddy, Jeffrey S. Miller, Joshua Rhein, Timothy W. Schacker, Nichole R. Klatt · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.10.01.679827 · 被引用次数：4 · 研究领域：Gut microbiota and health、Reproductive tract infections research、Clostridium difficile and Clostridium perfringens research

Abstract 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.