444 – RV550: IL-15 Superagonist N-803 With ART in Acute HIV Infection Enhances T and NK Cell Proliferation

Background

In the RV550 clinical trial, we hypothesized that IL-15 superagonist N-803 administration with ART during acute HIV infection (AHI) would limit HIV reservoir establishment and persistence. Here, we characterized the effects of N-803 on T cells and NK cells in peripheral blood (PBMC) and lymph nodes (LN).

Methods

Participants with AHI (Fiebig I-IV) were randomized in an open-label manner to receive N-803 (6ug/kg) subcutaneously at weeks 0, 3, and 6 post-ART (n=10) or no N-804 (n=4), with LN biopsies obtained at week 0 and 4 days after week 6. Immune cell dynamics in PBMC and LN were assessed by flow cytometry. Differences between groups were analyzed by Mann-Whitney U tests.

Results

N-803 induced proliferative expansion of T cells and NK cells, with a significant increase in Ki-67⁺ CD8⁺ T cells (Figure 1A) and Ki-67⁺ NK cells observed after the 2^nd dose (p=0.003 and p=0.003, respectively) in PBMC, and after the 3^rd dose in PBMC (p=0.004 and p=0.004, respectively) and  in LN (p=0.006 and p=0.03, respectively) of participants who received N-803 + ART compared to ART alone. Perforin expression in Ki-67⁺ CD8⁺ T cells after the 1^st and 2^nd dose (p=0.01 and p=0.03, respectively) and EOMES expression in NK cells after the 1^st, 2^nd and 3^rd dose (p=0.04, p=0.03, and p=0.02, respectively) in PBMC were also increased with N-803 treatment. N-803 also increased Ki-67⁺ CD4⁺ T cells after the 1^st, 2^nd and 3^rd dose in PBMC (p=0.008, p=0.003, and p=0.002, respectively) and in LN (p=0.004) after the 3^rd dose. Finally, we observed increased expression of the anti-apoptotic molecule BCL-2 in proliferating CD4⁺ T cells in PBMC after the 2^nd (p=0.02) and 3^rd dose (p=0.048) of N-820 (Figure 1B). Despite these effects, plasma viral loads were comparable between N-803-treated participants and controls.

Conclusions

N-803 induced the proliferation and effector differentiation of CD8⁺ T cells and NK cells, suggesting it may be effective at enhancing the cytolytic activity of antiviral lymphocytes. The effects of this on HIV reservoir dynamics is under evaluation.

DISCLAIMER: The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army, the Department of Defense, the National Institutes of Health, the Department of Health and Human Services, or the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. The investigators have adhered to the policies for protection of human subjects as prescribed in AR-70-25.