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[1]. Gardiquimod trifluoroacetate is a specific TLR7 agonist when used at concentrations below 10 μM, which can also inhibit HIV-1 reverse transcriptase[1]. Levels of HIV-1 DNA are significantly lower in Gardiquimod trifluoroacetate-treated cells compared to untreated controls on day 9 postinfection. Significantly lower levels of HIV-1 DNA and HIV-1 p24 are observed in Gardiquimod trifluoroacetate-treated and HIV-1-exposed macrophages cocultured with activated peripheral blood mononuclear cells (PBMCs). Gardiquimod trifluoroacetate significantly increased IFN-α mRNA levels 80-, 20-, and 35-fold above the level of detection at 2, 4, and 6 h post treatment, respectively[1]. 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 macrophages and activated PBMCs. 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[1]. On day 12, the tumor volume in mice injected with PBS increased to 1770 ± 370 mm3, whereas it was only 230 ± 70 mm3 in mice treated with Gardiquimod trifluoroacetate[2].
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