title: 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.
authors: Department of Biology, Gilead Sciences, Inc., Foster City, California, USA.
authors: Rujuta A
authors: RA
authors: Bam
authors: Department of Biology, Gilead Sciences, Inc., Foster City, California, USA.
authors: Derek
authors: D
authors: Hansen
authors: Department of Biology, Gilead Sciences, Inc., Foster City, California, USA.
authors: Alivelu
authors: A
authors: Irrinki
authors: Department of Biology, Gilead Sciences, Inc., Foster City, California, USA.
authors: Andrew
authors: A
authors: Mulato
authors: Department of Biology, Gilead Sciences, Inc., Foster City, California, USA.
authors: Gregg S
authors: GS
authors: Jones
authors: Department of Biology, Gilead Sciences, Inc., Foster City, California, USA.
authors: Joseph
authors: J
authors: Hesselgesser
authors: Department of Biology, Gilead Sciences, Inc., Foster City, California, USA.
authors: Christian R
authors: CR
authors: Frey
authors: Department of Biology, Gilead Sciences, Inc., Foster City, California, USA.
authors: Tomas
authors: T
authors: Cihlar
authors: Department of Biology, Gilead Sciences, Inc., Foster City, California, USA stephen.yant@gilead.com.
authors: Stephen R
authors: SR
authors: Yant
mesh_terms: D000906:Antibodies / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000472:pathogenicity; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors; D007372:Interferons / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000821:virology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D011621:Pteridines / Q000627:therapeutic use*; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000906:Antibodies; D000998:Antiviral Agents; D016898:Interferon-alpha; D015850:Interleukin-6; D011621:Pteridines; D051199:Toll-Like Receptor 7; D007372:Interferons; C582524:vesatolimod
keywords: GS-9620; TLR7; antiviral agents; human immunodeficiency virus; interferons