Impact of the IL-15 superagonist N-803 on lymphatic reservoirs of HIV

BACKGROUND. NK cell function is impaired in people with HIV (PWH), hindering their potential to reduce the lymphoid tissue (LT) reservoir. The IL-15 superagonist N-803 has been shown to enhance NK and T cell function and thus may reduce viral reservoirs. METHODS. To determine the impact of N-803 on LTs, we conducted a clinical trial where 10 PWH on effective antiretroviral therapy (ART) were given 3 subcutaneous 6 mcg/kg doses of N-803. We obtained PBMCs and lymph node (LN) and gut biopsies at baseline and after the last N-803 dose. RESULTS. We found a nonstatistically significant approximately 0.50 median log reduction in the frequency of viral RNA⁺ (vRNA⁺) and vDNA⁺ cells/g in the 6 participants with baseline and posttreatment LN biopsies. In the ileum, we observed reductions of vRNA⁺ cells in 8/10 participants and vDNA⁺ cells in all participants. We also found significant inverse correlations between NK cell proliferation and the frequency of vRNA⁺ cells and between NKG2A expression on NK cells and the frequency of vRNA⁺ cells. CONCLUSION. Our findings suggest N-803 may reduce the HIV reservoir in LTs of PWH on ART, an effect likely mediated by enhanced NK cell function. Controlled studies assessing the impact of NK cell therapy on HIV LTs are needed.