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.

Fighting HIV-1 Persistence: At the Crossroads of “Shoc-K and B-Lock”

“…The combination of GS-9620 with the vaccine AD26/MVA led to innate and adaptive immune stimulation, a delay in viral rebound after ART cessation, and reduced viral DNA in lymph nodes and the peripheral blood of SIV-infected monkeys [187]. Similar results were obtained in rhesus macaques infected with Simian Human Chimeric Immunodeficiency virus (SHIV), receiving GS-986 together with two bnAbs, N6-LS and PGT121, where a modest delay in the viral rebound after ART interruption was observed [188]. However, in a double-blind, multicenter, placebo-controlled trial, no changes in plasma viral loads were observed in HIV-1 positive patients under ART treated with GS-9620, despite a consistent induction in IFN response and lymphocyte activation [189].…”

“…In animal models, TLR agonists induced the expression of viral RNA, and activation of both innate and adaptive immune response [181]. These effects were further enhanced when combining the agonists with therapeutic vaccines or bnAbs [187,188]. Recently, RLRs and STING agonists have emerged as a promising new class of LRAs, with the capacity to induce the latent provirus and stimulate the selective apoptosis of reactivated cells [199].…”

Broadly neutralizing anti-HIV-1 antibodies tether viral particles at the surface of infected cells

“…They target conserved sites of vulnerability at the surface of Env: the CD4 binding site (CD4bs), the N-glycans associated with the V1/V2 and V3 loops, the silent face of gp120, the membrane proximal external region (MPER) of gp41 and a larger site spanning the interface between gp41 and gp120. In both nonhuman primates and humanized mice, infusion of bNAbs decreases viral loads 2,3 , prevents infection [4][5][6] and delays viral rebound 7,8 . Several bNAbs are under clinical evaluation 9,10 .…”

Can Broadly Neutralizing HIV-1 Antibodies Help Achieve an ART-Free Remission?

“…ART was discontinued after antibody washout. Though TLR7 agonist and dual bnAbs delayed viral rebound by 2-fold (3 vs 6 wks, p=0.024), viral rebound occurred in all animals ( 70 ). The delay in ART initiation, the shorter duration of ART and the lower number of doses of bnAbs administered (ranging from 2-5 doses, limited by the development of anti-drug antibody) may have contributed to the reduction in efficacy when compared with the Borducchi et al.…”