TLR7 agonist, N6-LS and PGT121 delayed viral rebound in SHIV-infected macaques after antiretroviral therapy interruption

Abstract

Toll-like receptor 7 (TLR7) agonist and PGT121 (broadly neutralizing antibody, bnAb) administration previously delayed viral rebound and induced SHIV remission. We evaluated the impact of GS-986 (TLR7 agonist) and dual bnAbs on viral rebound after antiretroviral therapy (ART) interruption. Rhesus macaques inoculated with SHIV-1157ipd3N4 were initiated on daily suppressive ART from Day 14 post SHIV inoculation. Active arm animals (n = 8) received GS-986, N6-LS and PGT121 after plasma viral suppression, starting from week 14. GS-986 induced immune activation and SHIV-specific T cell responses but not viral expression in all the active arm animals. After ART interruption, median time to viral rebound was 6 weeks in the active and 3 weeks in the control arm (p = 0.024). In this animal model, the administration of the combination of GS-986 and dual bnAbs was associated with a modest delay in viral rebound. This strategy should be further evaluated to better understand the underlying mechanisms for the induction of virus-specific immune responses and delay in viral rebound. We evaluated the impact of TLR7 agonist (GS-986) and two broadly neutralizing antibodies (bnAbs) targeting different regions of the HIV envelope (CD4 binding site by N6-LS and V3 glycan by PGT121) in delaying viral rebound during ART interruption in rhesus macaques that were initiated on viral suppressive antiretroviral therapy (ART) 14 days post SHIV-1157ipd3N4 infection. We found that the combination of TLR7 agonist and dual bnAbs delayed viral rebound after ART interruption by 2-fold (from 3 wks in the control arm to 6 wks in the active arm, p = 0.024). This encouraging result independently validated prior findings of delay in viral rebound with TLR7 agonist and a single bnAb (PGT121) by Borducchi et al, Nature, 2018. Importantly, findings were in concurrence despite the performance of the study by an independent research group, in a different macaque colony, with a different strain of SHIV. Moreover, this study intentionally deferred ART initiation by a week, i.e. on day 14 post inoculation to mirror what is logistically feasible in acute HIV infection. Thus, data from this study may potentially more closely reflect the impact of the combination of TLR7 agonist and dual bnAbs on viral rebound in HIV-infected individuals.