TLR7 Agonist GS-9620 Is a Potent Inhibitor of Acute HIV-1 Infection in Human Peripheral Blood Mononuclear Cells

Abstract

GS-9620 is a potent and selective oral Toll-like receptor 7 (TLR7) agonist that directly activates plasmacytoid dendritic cells (pDCs). GS-9620 suppressed hepatitis B virus (HBV) in animal models of chronic infection and transiently activated HIV expression ex vivo in latently infected peripheral blood mononuclear cells (PBMCs) from virally suppressed patients. Currently, GS-9620 is under clinical evaluation for treating chronic HBV infection and for reducing latent reservoirs in virally suppressed HIV-infected patients. Here, we investigated the in vitro anti-HIV-1 activity of GS-9620. GS-9620 potently inhibited viral replication in PBMCs, particularly when it was added 24 to 48 h prior to HIV infection (50% effective concentration = 27 nM). Depletion of pDCs but not other immune cell subsets from PBMC cultures suppressed GS-9620 antiviral activity. Although GS-9620 was inactive against HIV in purified CD4+ T cells and macrophages, HIV replication was potently inhibited by conditioned medium derived from GS-9620-treated pDC cultures when added to CD4+ T cells prior to infection. This suggests that GS-9620-mediated stimulation of PBMCs induced the production of a soluble factor(s) inhibiting HIV replication in trans. GS-9620-treated PBMCs primarily showed increased production of interferon alpha (IFN-α), and cotreatment with IFN-α-blocking antibodies reversed the HIV-1-inhibitory effect of GS-9620. Additional studies demonstrated that GS-9620 inhibited a postentry event in HIV replication at a step coincident with or prior to reverse transcription. The simultaneous activation of HIV-1 expression and inhibition of HIV-1 replication are important considerations for the clinical evaluation of GS-9620 since these antiviral effects may help restrict potential local HIV spread upon in vivo latency reversal.

Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection

“…In addition to TLR9 agonists, TLR7 agonists are also being investigated in HIV cure-related research [41]. The TLR7 agonist GS-9620 induce a pDC-dependent anti-HIV activity in vitro but also leads to an increase in the proinflammatory cytokines such as IL-6 [42]. Interestingly, a recent nonhuman primate study suggested that the TLR7 agonist GS-986 in combination with Ad26/MVA vectored therapeutic simian immunodeficiency virus vaccination improved immunologic control and delayed viral rebound compared to placebo-treated animals whereas animals receiving GS-986 alone appeared to have no improvement in virological control or change in the size of the viral reservoir.…”

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

“…Moreover, GS-9620 is able in vitro to inhibit HIV-1 infection in human peripheral blood mononuclear cells [151]. It was also demonstrated that GS-9620 induced HIV RNA expression ex vivo in PBMC isolated from patients on suppressive antiretroviral therapy [152e154].…”

Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection

“…Some novel methods and therapeutic strategies that can overcome viral latency have been developed such as HDAC, disulfiram, galectin-9, ingenol-3-angelate, prostratin, 5-azadC, bryostatin-1, and Runx1 [100, 101]. TLR7/8 agonists induce production of IFN-α that effectively inhibits HIV-1 replication in activated lymphocytes, macrophages or latently infected monocytic cell lines [102, 103]. Because HIV eradication is not achieved by highly active antiretroviral therapy, a strong rationale to investigate the curative potential of IFN-α is needed.…”