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首页> 外文期刊>AIDS Research and Human Retroviruses >Gardiquimod: A toll-like receptor-7 agonist that inhibits HIV type 1 infection of human macrophages and activated T cells
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Gardiquimod: A toll-like receptor-7 agonist that inhibits HIV type 1 infection of human macrophages and activated T cells

机译：Gardiquimod：一种收费型受体7激动剂，可抑制人类巨噬细胞和活化T细胞的HIV 1型感染

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摘要

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.
机译：免疫应答调节剂正在研究作为病毒感染和癌症的治疗剂。这些分子包括Toll样受体（TLR）（一种先天免疫受体家族）的激动剂。位于细胞内体中的TLR7和8，结合病毒基因组的特征性单链RNA，并触发诱导炎症细胞因子和抗病毒先天免疫因子的细胞内信号传导途径。我们在巨噬细胞和活化的外周血单核细胞（PBMC）中研究了加地喹莫特（一种浓度低于10μM的特异TLR7激动剂）的抗HIV-1效应。在感染HIV-1的X4，R5或双嗜性（R5 / X4）菌株之前或之后的2天之内添加的加地喹莫特可显着减少这些细胞的感染。加到加迪基莫德治疗和暴露于HIV-1的巨噬细胞中的活化PBMC的共培养物在长达10天的时间内显示出最小的HIV-1复制，这表明加迪基莫德抑制了从暴露于HIV-1的巨噬细胞中活化的PBMC的病毒扩增。加地喹莫特对活化的PBMC和巨噬细胞的处理在添加后的数小时内诱导了干​​扰素-α（IFN-α）的转录，并持续几天的IFN-α蛋白分泌。用针对MyD88衔接子蛋白的肽抑制剂处理细胞可阻止加迪基莫德对IFN-α的诱导，并部分逆转了活化PBMC中的抗HIV作用。用中和抗体阻断IFN-α受体也降低了加地莫德的抗HIV作用。加地喹莫特抑制HIV-1逆转录酶，这是HIV-1生命周期的第一步。这些发现表明，既可以作为免疫系统调节剂又可以作为逆转录酶抑制剂的加地喹莫特，可以作为一种新型治疗剂来阻断HIV-1的全身和粘膜传播。

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