Institut für Klinische und Molekulare Virologie, Universitätsklinikum, Friedrich Alexander Universität, Erlangen, Germany.
J Virol. 2012 Apr;86(7):3528-40. doi: 10.1128/JVI.06713-11. Epub 2012 Feb 1.
The interferon (IFN)-mediated antiviral response is a major defense of the host immune system. In order to complete their life cycle, viruses must modulate host IFN-mediated immune responses. Herpes simplex virus 1 (HSV-1) is a large DNA virus containing more than 80 genes, many of which encode proteins that are involved in virus-host interactions and show immune modulatory capabilities. In this study, we demonstrate that the US11 protein, an RNA binding tegument protein of HSV-1, is a novel antagonist of the beta IFN (IFN-β) pathway. US11 significantly inhibited Sendai virus (SeV)-induced IFN-β production, and its double-stranded RNA (dsRNA) binding domain was indispensable for this inhibition activity. Additionally, wild-type HSV-1 coinfection showed stronger inhibition than US11 mutant HSV-1 in SeV-induced IFN-β production. Coimmunoprecipitation analysis demonstrated that the US11 protein in HSV-1-infected cells interacts with endogenous RIG-I and MDA-5 through its C-terminal RNA-binding domain, which was RNA independent. Expression of US11 in both transfected and HSV-1-infected cells interferes with the interaction between MAVS and RIG-I or MDA-5. Finally, US11 dampens SeV-mediated IRF3 activation. Taken together, the combined data indicate that HSV-1 US11 binds to RIG-I and MDA-5 and inhibits their downstream signaling pathway, preventing the production of IFN-β, which may contribute to the pathogenesis of HSV-1 infection.
干扰素（IFN）介导的抗病毒反应是宿主免疫系统的主要防御机制。为了完成其生命周期，病毒必须调节宿主 IFN 介导的免疫反应。单纯疱疹病毒 1（HSV-1）是一种含有 80 多个基因的大型 DNA 病毒，其中许多基因编码参与病毒-宿主相互作用的蛋白质，并表现出免疫调节能力。在这项研究中，我们证明 HSV-1 的 US11 蛋白是一种新型的β干扰素（IFN-β）途径拮抗剂。US11 显著抑制仙台病毒（SeV）诱导的 IFN-β产生，其双链 RNA（dsRNA）结合域对于这种抑制活性是必不可少的。此外，野生型 HSV-1 共感染在 SeV 诱导的 IFN-β产生中比 US11 突变型 HSV-1 显示出更强的抑制作用。共免疫沉淀分析表明，HSV-1 感染细胞中的 US11 蛋白通过其 C 末端 RNA 结合域与内源性 RIG-I 和 MDA-5 相互作用，这种相互作用不依赖于 RNA。在转染和 HSV-1 感染的细胞中表达 US11 会干扰 MAVS 和 RIG-I 或 MDA-5 之间的相互作用。最后，US11 减弱了 SeV 介导的 IRF3 激活。总之，综合数据表明 HSV-1 US11 结合 RIG-I 和 MDA-5 并抑制其下游信号通路，从而阻止 IFN-β的产生，这可能有助于 HSV-1 感染的发病机制。
