Buitendijk Maarten, Eszterhas Susan K, Howell Alexandra L
1 Department of Veterans Affairs, Veterans Health Administration , Biomedical Laboratory Research and Development, White River Junction, Vermont.
AIDS Res Hum Retroviruses. 2014 May;30(5):457-67. doi: 10.1089/AID.2013.0199. Epub 2014 Jan 20.
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 48 h or 72 h, 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.
对微生物病原体的先天性免疫反应是在配体与特定模式识别受体结合后启动的。每种模式识别受体，包括Toll样受体（TLR）家族的成员，对特定类型的病原体相关分子模式具有特异性，确保生物体能够对包括细菌、病毒和真菌在内的多种病原体迅速做出反应。我们研究了内体TLR激动剂在外周血单核细胞（PBMC）中诱导抗HIV-1活性的程度。当在感染HIV-1之前添加TLR3、TLR7、TLR8和TLR9的激动剂时，它们显著降低了外周血单核细胞的感染率。有趣的是，TLR8和TLR9的激动剂即使在HIV-1感染后分别迟至48小时或72小时添加，也能高效阻断HIV复制，这表明抗病毒作用持久且长效。对TLR激动剂激活后抗病毒基因诱导情况的分析表明，所有激动剂均诱导了I型干扰素和干扰素刺激基因的表达，尽管诱导水平因所用激动剂而异。有趣的是，只有TLR9的激动剂ODN2395 DNA诱导了II型干扰素以及抗HIV蛋白载脂蛋白B mRNA编辑酶催化多肽样蛋白3G（Apobec3G）和SAM域和HD结构域包含蛋白1（SAMHD1）的表达。通过使用髓样分化因子88（MyD88）衔接蛋白抑制剂阻断TLR活性，我们证明，至少对于TLR8和TLR9而言，抗HIV活性并非完全由TLR激活介导，而是可能由HIV靶细胞中其他抗病毒传感器的激活介导。这些发现表明，内体TLR激动剂通过TLR介导和非TLR介导的机制发挥作用，诱导抗HIV分子的表达。此外，这些激动剂诱导的非TLR介导机制可能被用于阻断近期暴露于HIV个体中的HIV-1复制。
