Toll-Like Receptor 7 Agonist GS-9620 Induces HIV Expression and HIV-Specific Immunity in Cells from HIV-Infected Individuals on Suppressive Antiretroviral Therapy

Abstract

Antiretroviral therapy can suppress HIV replication to undetectable levels but does not eliminate latent HIV, thus necessitating lifelong therapy. Recent efforts to target this persistent reservoir have focused on inducing the expression of latent HIV so that infected cells may be recognized and eliminated by the immune system. Toll-like receptor (TLR) activation stimulates antiviral immunity and has been shown to induce HIV from latently infected cells. Activation of TLR7 leads to the production of several stimulatory cytokines, including type I interferons (IFNs). In this study, we show that the selective TLR7 agonist GS-9620 induced HIV in peripheral blood mononuclear cells (PBMCs) from HIV-infected individuals on suppressive antiretroviral therapy. GS-9620 increased extracellular HIV RNA 1.5- to 2-fold through a mechanism that required type I IFN signaling. GS-9620 also activated HIV-specific T cells and enhanced antibody-mediated clearance of HIV-infected cells. Activation by GS-9620 in combination with HIV peptide stimulation increased CD8 T cell degranulation, production of intracellular cytokines, and cytolytic activity. T cell activation was again dependent on type I IFNs produced by plasmacytoid dendritic cells. GS-9620 induced phagocytic cell maturation and improved effector-mediated killing of HIV-infected CD4 T cells by the HIV envelope-specific broadly neutralizing antibody PGT121. Collectively, these data show that GS-9620 can activate HIV production and improve the effector functions that target latently infected cells. GS-9620 may effectively complement orthogonal therapies designed to stimulate antiviral immunity, such as therapeutic vaccines or broadly neutralizing antibodies. Clinical studies are under way to determine if GS-9620 can target HIV reservoirs.IMPORTANCE Though antiretroviral therapies effectively suppress viral replication, they do not eliminate integrated proviral DNA. This stable intermediate of viral infection is persistently maintained in reservoirs of latently infected cells. Consequently, lifelong therapy is required to maintain viral suppression. Ultimately, new therapies that specifically target and eliminate the latent HIV reservoir are needed. Toll-like receptor agonists are potent enhancers of innate antiviral immunity that can also improve the adaptive immune response. Here, we show that a highly selective TLR7 agonist, GS-9620, activated HIV from peripheral blood mononuclear cells isolated from HIV-infected individuals with suppressed infection. GS-9620 also improved immune effector functions that specifically targeted HIV-infected cells. Previously published studies on the compound in other chronic viral infections show that it can effectively induce immune activation at safe and tolerable clinical doses. Together, the results of these studies suggest that GS-9620 may be useful for treating HIV-infected individuals on suppressive antiretroviral therapy.

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“…TLR- and STING-mediated signaling profiles are also different that could contribute to their differential antiretroviral capacity. Interestingly, TLR agonist enhances latent HIV reactivation in vitro (24, 25) whereas we found cGAMP-NP inhibits HIV replication and possibly reactivation in PBMCs isolated from HIV positive individuals.…”

Bioimaging predictors of rilpivirine biodistribution and antiretroviral activities

“…The ability to deliver therapeutics to the exact subcellular site of HIV infection provides opportunities for disease prevention and treatment. Further optimization opens the possibility of combining multiple ARVs into a single particle, encapsulating CRISPR Cas9 for excision of integrated HIV DNA from tissue sites of latent infection [87] or delivering latency reversal agents like toll-like receptor (TLR) 7 agonists which were shown to be capable of reducing viral reservoirs in simian immunodeficiency virus-infected rhesus macaques [88], while simultaneously imaging the real time ARV particle biodistribution and therapeutic efficacy.…”

Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV

“…Various LRAs can increase viral gene expression from latency in vitro, including: histone deacetylase inhibitor/s (HDACi/s), histone methyltransferase (HMT) inhibitors, DNA methyltransferase inhibitors, bromodomain inhibitors, protein kinase C (PKC) agonists (reviewed in (Rasmussen & Lewin, 2016), as well as PI3K/Akt pathway inhibitors that affect cell survival and agonists for the innate immune receptors TLR7 or TLR9 (Offersen et al, 2016; Tsai et al, 2017) (Figure 2). Only a limited number of these agents have been studied in clinical trials.…”