title: Gardiquimod: a Toll-like receptor-7 agonist that inhibits HIV type 1 infection of human macrophages and activated T cells.
abstract: Immune response modifiers are being studied as therapeutic agents for viral infections and cancer. These molecules include agonists for the Toll-like receptors (TLR), a family of innate immune receptors. TLR7 and 8, located in cellular endosomes, bind single-stranded RNA characteristic of viral genomes, and trigger intracellular signaling pathways that induce inflammatory cytokines and antiviral innate immune factors. We studied the anti-HIV-1 effects of gardiquimod, a specific TLR7 agonist when used at concentrations below 10 μM, in macrophages and activated peripheral blood mononuclear cells (PBMCs). Gardiquimod, added prior to or within 2 days after infection with X4, R5, or dual-tropic (R5/X4) strains of HIV-1, significantly reduced infection in these cells. Cocultures of activated PBMCs added to gardiquimod-treated and HIV-1-exposed macrophages demonstrated minimal HIV-1 replication for up to 10 days, suggesting that gardiquimod inhibited activated PBMCs viral amplification from HIV-1-exposed macrophages. Gardiquimod treatment of both activated PBMCs and macrophages induced interferon-alpha (IFN-α) transcription within hours of addition, and sustained IFN-α protein secretion for several days. Treatment of cells with a peptide inhibitor to the MyD88 adaptor protein blocked the induction of IFN-α by gardiquimod, and partially reversed the anti-HIV effects in activated PBMCs. Blocking the IFN-α receptor with a neutralizing antibody also reduced the anti-HIV effect of gardiquimod. Gardiquimod inhibited HIV-1 reverse transcriptase, an early step in the life cycle of HIV-1. These findings suggest that gardiquimod, functioning as both an immune system modifier and a reverse transcriptase inhibitor, could be developed as a novel therapeutic agent to block systemic and mucosal transmission of HIV-1.
authors: V.A. Medical Center, White River Junction, VT 05009, USA.
authors: Maarten
authors: M
authors: Buitendijk
authors: Susan K
authors: SK
authors: Eszterhas
authors: Alexandra L
authors: AL
authors: Howell
mesh_terms: D000634:Aminoquinolines / Q000627:therapeutic use*; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D002460:Cell Line; D004279:DNA, Viral / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D016898:Interferon-alpha / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D008264:Macrophages / Q000187:drug effects / Q000821:virology*; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology*; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000634:Aminoquinolines; D019380:Anti-HIV Agents; D004279:DNA, Viral; D007093:Imidazoles; D016898:Interferon-alpha; D051199:Toll-Like Receptor 7; C546771:gardiquimod