Latent reservoirs of replication-competent HIV-1 persist in patients on anti-retroviral therapy (ART) and represent the major obstacle to HIV eradication efforts. Considerable effort has been directed to develop and evaluate novel remission strategies to enhance virus-specific immune responses in ART-suppressed patients.
We conducted 2 studies in SHIV-infected ART-suppressed rhesus macaques (RM) to evaluate the IL-15 superagonist, N-803 to enhance virus-specific effector cells, in conjunction with broadly neutralizing antibodies (bNAbs, 10-1074 and 3BNC117). Thirty-six RMs were rectally infected with SHIV-AD8. RMs received ART at ~50 days post infection (Study 1, n=20 and Study 2, n=16) and virologic suppression was maintained for 65 or 60 weeks PI for each study, respectively. In Study 1, ART-suppressed monkeys received 6 doses of N-803 alone (n=5), 2 doses of 10-1074 alone (n=5), a combination of N-803 and 10-1074 (n=5), or vehicle control (n=5). In Study 2, ART-suppressed RMs received 6 doses of N-803 and 3 doses of both 10-1074 and 3BNC117 (n=8) or the vehicle control (n=8). Plasma SHIV RNA levels were measured and viral DNA were quantified in PBMC, colon and lymph node (LN) biopsies taken pre- and post- treatment. Modulation of immune populations, including T, B and NK cells, were monitored longitudinally. After monitored washout of bNAbs in plasma, ART was discontinued.
In both studies, blood NK cells showed peak activation at 48hrs post N-803 administration throughout the dosing period. Memory T cells were preferentially activated by N-803, and CD8+ T cells demonstrated more robust expansion during the dosing period. No immune activation of PBMC was associated with bNAb treatment. We observed no change in integrated SHIV DNA between pre- and post- treatment timepoints in either PBMC or LN tissues (Study 1). In Study 1, plasma viral rebound kinetics in RMs treated with either N-803 or 10-1074 alone, or in combination, were comparable to the control group after ART discontinuation. However, 3 of 5 combination treated RMs showed durable control of viremia after initial low-level rebound. In Study 2, 6 of 8 combination-treated (N-803/bNAbs) RMs exhibited durable control of viremia beyond week 25 following initial low-level rebound.
Repeated co-dosing of N-803 and bNAbs is safe and may facilitate long-term viral control and remission in the absence of ART.