Toll-Like Receptor Agonists Are Potent Inhibitors of Human Immunodeficiency Virus-Type 1 Replication in Peripheral Blood Mononuclear Cells
Toll-Like Receptor Agonists Are Potent Inhibitors of Human Immunodeficiency Virus-Type 1 Replication in Peripheral Blood Mononuclear Cells
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DOI：
10.1089/aid.2013.0199
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发表时间：
2014-05-01
影响因子：
1.5
通讯作者：
Howell, Alexandra L.
中科院分区：
文献类型：
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作者：
Buitendijk, Maarten;Eszterhas, Susan K.;Howell, Alexandra L.
在配体与特定的模式识别受体结合后，启动了对微生物病原体的先天免疫反应。每个模式识别受体包括Toll样受体(TLR)家族的成员，针对特定类型的病原体相关分子模式，确保有机体能够对包括细菌、病毒和真菌在内的广泛病原体做出快速反应。我们研究了内涵体TLR激动剂在多大程度上诱导外周血单个核细胞(PBMC)抗HIV-1活性。在感染HIV-1前加入TLR3、TLR7、TLR8和TLR9激动剂，可显著减少外周血单核细胞的感染。有趣的是，TLR8和TLR9的激动剂即使在HIV-1感染后48小时或72小时才分别加入，也能非常有效地阻止HIV的复制，表明抗病毒作用是持久和持久的。对激动剂激活TLR后抗病毒基因诱导的分析表明，所有激动剂都能诱导I型干扰素和干扰素刺激基因的表达，但程度因激动剂的使用而异。有趣的是，只有TLR9的激动剂ODN2395 DNA诱导了II型干扰素和抗HIV蛋白APOBEC3G和SAMHD1的表达。通过使用MyD88接头蛋白的抑制剂阻断TLR的活性，我们证明，至少对于TLR8和TLR9，抗HIV活性不是完全由TLR激活介导的，而可能是通过激活HIV靶细胞中的额外抗病毒传感器来实现的。这些发现表明，内体TLR激动剂通过TLR介导和非TLR介导的机制来诱导抗HIV分子的表达。此外，这些激动剂诱导的非TLR介导的机制可能被用来阻止最近感染HIV的个人的HIV-1复制。
Innate immune responses to microbial pathogens are initiated following the binding of ligand to specific pattern recognition receptors. Each pattern recognition receptor, which includes members of the Toll-like receptor (TLR) family, is specific for a particular type of pathogen associated molecular pattern ensuring that the organism can respond rapidly to a wide range of pathogens including bacteria, viruses, and fungi. We studied the extent to which agonists to endosomal TLR could induce anti-HIV-1 activity in peripheral blood mononuclear cells (PBMCs). When agonists to TLR3, TLR7, TLR8 and TLR9 were added prior to infection with HIV-1, they significantly reduced infection of peripheral blood mononuclear cells. Interestingly, agonists to TLR8 and TLR9 were highly effective at blocking HIV replication even when added as late as 48h or 72h, respectively, after HIV-1 infection, indicating that the anti-viral effect was durable and long lasting. Analysis of the induction of anti-viral genes after agonist activation of TLR indicated that all of the agonists induced expression of the type I interferons and interferon stimulated genes, although to variable levels that depended on the agonist used. Interestingly, only the agonist to TLR9, ODN2395 DNA, induced expression of type II interferon and the anti-HIV proteins Apobec3G and SAMHD1. By blocking TLR activity using an inhibitor to the MyD88 adaptor protein, we demonstrated that, at least for TLR8 and TLR9, the anti-HIV activity was not entirely mediated by TLR activation, but likely by the activation of additional anti-viral sensors in HIV target cells. These findings suggest that agonists to the endosomal TLR function to induce expression of anti-HIV molecules by both TLR-mediated and non-TLR-mediated mechanisms. Moreover, the non-TLR-mediated mechanisms induced by these agonists could potentially be exploited to block HIV-1 replication in recently HIV-exposed individuals.