Combination of CD8β depletion and IL-15 superagonist N-803 induces virus reactivation in SHIV-infected, long-term ART-treated rhesus macaques.

The "shock and kill" strategy predicates that virus reactivation in latently infected cells is required to eliminate the HIV reservoir. In a recent study, we show robust and persistent induction of plasma viremia in ART-treated SIV-infected rhesus macaques (RMs) undergoing CD8α depletion and treated with the IL-15 superagonist N-803 (McBrien, J.B. et alNature 578, 154-159 (2020), https://doi.org/10.1038/s41586-020-1946-0) Of note, in the study we used an antibody targeting CD8α, therefore depleting NK cells, NKT cells, and γδ T cells in addition to CD8+ T-cells. In the current proof-of-concept study, we tested whether virus reactivation can be induced by administration of N-803 to SHIV-infected, ART-treated RMs that are selectively depleted of CD8+ T cells via the CD8β-targeting antibody CD8b255R1. CD8β depletion was performed in five SHIVSF162P3-infected RMs treated with ART for 12 months and with plasma viremia consistently below 3 copies/ml. All animals received four weekly doses of N-803 starting at the time of CD8b255R1 administration. Induction of detectable plasma viremia was observed in three out of five RMs, with the level of virus reactivation seemingly correlated to the frequency of CD8+ T-cells following CD8β depletion as well as the level of virus reactivation observed when the same animals underwent CD8α depletion and N-803 administration after 24 weeks of ART. These data indicate that CD8β depletion and N-803 administration can induce virus reactivation in SHIVSF162P3-infected RMs despite suboptimal depletion of CD8+ T cells and profound ART-induced suppression of virus replication, thus confirming a critical role for these cells in suppressing virus production and/or reactivation in vivo under ART.Importance The "shock and kill" HIV cure strategy attempts to reverse and eliminate the latent viral infection that prevents eradication of the virus. Latency-reversing agents tested in clinical trials to date have failed to impact on the HIV viral reservoir. IL-15 superagonist N-803, currently involved in a clinical trial for HIV cure, was recently shown by our lab to induce robust and persistent induction of plasma viremia during ART in three in vivo animal models of HIV infection. These results suggest a substantial role for CD8+ lymphocytes in suppressing the latency-reversal effect of N-803 by promoting the maintenance of viral latency. In this study, we tested whether the use of a CD8β-targeting antibody, which would specifically deplete CD8+ T cells, would yield similar levels of virus reactivation. We observed induction of plasma viremia which correlated with the efficacy of the CD8 depletion strategy.