Antibody and TLR7 agonist delay viral rebound in SHIV-infected monkeys

Abstract

The latent viral reservoir is the critical barrier for the development of an HIV-1 cure. Previous studies have shown that potent HIV-1 Env-specific broadly neutralizing antibodies (bNAbs) administered at the time of antiretroviral therapy (ART) discontinuation can exert direct antiviral effects, but whether bNAbs can target the viral reservoir during ART suppression remains unknown. Here we show that the V3 glycan-dependent bNAb PGT121 together with the TLR7 agonist vesatolimod (GS-9620) administered during ART suppression delayed viral rebound following ART discontinuation in SHIV-SF162P3-infected rhesus monkeys that initiated ART during early acute infection. Moreover, the subset of PGT121+GS-9620 treated monkeys that did not show viral rebound following ART discontinuation also did not reveal virus by highly sensitive adoptive transfer and CD8 depletion studies. These data demonstrate the potential of bNAb administration together with innate immune stimulation as a possible strategy to target the viral reservoir.

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

“…These strategies are aimed toward the reactivation of the latent reservoir using a latency-reversal agent (LRA) with the subsequent killing of the reactivated cell either by the cytotoxic arm of the immune system, including NK and CD8 T cells, or by viral cytopathic mechanisms [155,156]. Borducchi et al show that administration of the V3 glycan-dependent bNAb PGT121 together with GS-9620 during ART delayed viral rebound following discontinuation of ART in simianehuman immunodeficiency virus (SHIV)-SF162P3infected rhesus monkeys in which ART was initiated during early acute infection [157]. More contrasted results were obtained by Del Prete et al [158] GS-986, another structurally-unpublished TLR7 agonist, was also evaluated to reduce latent reservoir in SIVinfected rhesus monkeys [159].…”

Anti‐HIV‐1 antibodies trigger non‐lytic complement deposition on infected cells

“…Env exists in at least two conformations, a native "close" configuration and a CD4-bound "open" conformation (reviewed in [11]). In animal models, infusion of bNAbs protects against HIV-1 acquisition, decreases viral load [14,15], modulates host immune responses [16,17], and, when associated to latency-reversal agents, delays viral rebound after treatment interruption [18,19]. These antibodies target the CD4 binding site (CD4bs), the N-glycans of V1/V2 and V3 loops, the gp41 membrane proximal external region (MPER), and the gp120/gp41 interface [12].…”

Adaptive NK cell responses in HIV/SIV infections: A roadmap to cell-based therapeutics?

“…Recently Borducchi et al. showed that treatment with PGT121 and GS‐9620 in SHIV‐infected rhesus macaques delayed viral rebound following ART discontinuation due to activation of NK cells and monocytes leading to antibody mediated clearance of virus infected cells . Treatment with the TLR8 agonist, VTX2337, led to both direct and indirect activation of NK cells via DC mediated production of inflammatory cytokines and chemokines, including IL‐12 and TNF‐α .…”

“…Currently, two small molecule agonists of TLR7, Vesatolimod (GS-9620) and its analog, GS-986, are being used in SIV-infected/ART-treated rhesus macaques 55. This dual therapy of ART and TLR agonist showed reduction in the viral reservoir with transient viremia and immunopotentiation as demonstrated by a rapid activation of NK and T cell responses to infection.Recently Borducchi et al showed that treatment with PGT121 and GS-9620 in SHIV-infected rhesus macaques delayed viral rebound following ART discontinuation due to activation of NK cells and monocytes leading to antibody mediated clearance of virus infected cells 56. Treatment with the TLR8 agonist, VTX2337, led to both direct and indirect activation of NK cells via DC mediated production of inflammatory cytokines and chemokines, including IL-12 and TNF- 57.…”