Background
The gut microbiota plays a crucial role in host immune modulation. N-803, an IL-15 superagonist primarily developed for cancer immunotherapy, has shown potential to enhance immune responses in people with HIV (PWH). This pilot study investigated the relationship between gut microbiota and immune responses during a clinical trial of N-803 in PWH.
Methods
N-803 was administered subcutaneously to 10 PWH at a dose of 6 mcg/kg on Days 0, 21, and 42. Stool samples were collected prior to day 0 (baseline), day 28, day 49-56 (postdrug) and day 137-141. Shotgun metagenomic sequencing was performed to analyze taxonomic composition and functional profiles of the gut microbiota bioinformatically. We also investigated associations between microbial diversity and immune markers, including NKG2A, viral (v)RNA levels, and CD8 T cell counts in lymph nodes (LNs), rectum, and ileum. Statistical analyses were conducted using R.
Results
Two distinct enterotypes were identified among the participants, which significantly differed in both alpha and beta diversity. A significantly positive correlation was observed between Shannon diversity and NKG2A cell counts in the LNs after treatment while a negative trend was seen with vRNA levels in the LNs. We split the individuals into two groups: viral responders (VRs) who had decreased vRNA levels in LNs from baseline to post-drug infusion and viral non-responders (VNRs) who had increased vRNA levels in LNs from baseline to post-drug infusion. VNRs had a notably higher abundance of Faecalibacterium sp. CYL33. Furthermore, microbial pathways that correlated positively with CD8 T cell counts often showed inverse correlations with vRNA levels, particularly in pathways related to lysine, colanic acid, and chorismate biosynthesis.
Conclusions
This pilot study shows that gut microbiota composition remains relatively stable during N-803 therapy in PWH. However, microbial and metabolic differences are apparent in individuals who have immune responses to N-803 therapy compared to those who do not. These differences suggest specific microbial functions may influence immune activity and/or virus control. The trends observed in this study highlight the intricate relationships between microbiota diversity and immune markers in HIV infection. Further research with larger sample sizes is necessary to better understand the role of the gut microbiome in modulating immune responses during N-803 therapy and its implications for HIV immunotherapy.
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