Inhibition of innate immune system by hepatitis C virus

丙型肝炎病毒NS5B通过TLR3、TRIF和IRF-3激活干扰素-β。另一方面，丙型肝炎病毒NS3、NS4A、NS4B和NS5A抑制这种激活。结果表明，NS3与TBK1直接相互作用，这种结合抑制了TBK1与IRF-3的结合，从而抑制了IRF-3的激活。RNA干扰(RNAi)可能是宿主对病毒RNA的一种抗病毒反应，DICER可以靶向并将丙型肝炎病毒的IRES和复制中间产物消化成siRNA。然而，丙型肝炎病毒核心蛋白抑制这种RNAi，并通过与DICER的直接相互作用挽救丙型肝炎病毒的复制。RNAi是丙型肝炎病毒复制的限制因素，核心蛋白抑制基于RNA沉默的抗病毒反应。这种核心蛋白对抗宿主防御的能力可能会导致持续的病毒感染，并可能导致…的发病肿瘤抑制基因P53可能在细胞对丙型肝炎病毒的天然防御中起关键作用，当P53表达下调时，Huh7细胞中的HCVRNA复制和病毒蛋白表达水平显着升高。此外，干扰素治疗在抑制p53基因敲除的Huh7细胞中的丙型肝炎病毒RNA复制方面效果较差。事实上，在p53基因敲除的Huh7细胞中，干扰素刺激反应元件的激活和干扰素刺激基因的诱导显著减弱，并且发现P53与IRF9直接相互作用。这些观察结果强调了肿瘤抑制基因S在抗丙型肝炎病毒的细胞抗病毒免疫中的潜在贡献，可能具有治疗意义。双链核糖核酸激活的蛋白激酶是干扰素刺激的基因，通过与双链核糖核酸结合激活，双链核糖核酸是丙型肝炎病毒的复制中间产物。激活的PKR使真核细胞起始因子-2的α亚基磷酸化，从而抑制病毒蛋白的翻译。我们利用RNAi技术建立了稳定的PKR基因敲除的Huh7细胞，并研究了PKR对丙型肝炎病毒复制的影响。在含有丙型肝炎病毒亚基因组复制子的稳定的PKR基因敲除细胞中，荧光素酶活性大约是对照细胞的三倍，这表明在稳定的PKR基因敲除细胞中复制亚基因组复制子的效率比在对照细胞中高。此外，稳定的PKR基因敲除细胞在转染丙型肝炎病毒全长基因组后，比对照细胞分泌更多的丙型肝炎病毒颗粒。在两种细胞中加入干扰素-α均可抑制亚基因组复制子的复制。尽管稳定的PKR基因敲除细胞的抑制程度明显低于低浓度干扰素-α的对照细胞，但即使是10U/ml的干扰素-α也能抑制两种细胞中亚基因组复制子的复制，抑制率达98%。PKR在抑制先天状态下的丙型肝炎病毒复制方面发挥着重要作用，但在干扰素治疗中不是必需的。较少

Hepatitis C virus (HCV) NS5B activated interferon-beta through TLR3, TRIF, and IRF-3. On the other hand, HCV NS3, NS4A, NS4B, and NS5A inhibited this activation. It was revealed that NS3 interacts directly with TBK1, and this binding results in the inhibition of the association between TBK1 and IRF-3, which leads to the inhibition of IRF-3 activation. This may contribute toward the persistence of HCV.RNA interference (RNAi) may act as a host antiviral response against viral RNA Dicer can target and digest both the IRES and the replicative intermediate of HCV into siRNA In fact, Dicer can inhibit HCV replication. However, HCV core protein inhibits this RNAi and rescues HCV replication through a direct interaction with Dicer RNAi is a limiting factor for HCV replication, and the core protein suppresses the RNA silencing-based antiviral response. This ability of the core protein to counteract the host defense may lead to a persistent viral infection and may contribute to the pathogenesis … More of HCV.Tumor suppressor p53 could have a crucial role in the cellular innate defense against HCV Significantly higher levels of HCV RNA replication and viral protein expression in the Huh7 cells were observed when their p53 expressions were knocked down. Moreover, interferon treatment was less effective in inhibiting the HCV RNA replication in the p53-knocked-down Huh7 cells. In fact, the activation of the interferon stimulated response elements and the induction of interferon stimulated genes were significantly attenuated in the p53-knocked-down Huh7 cells and p53 was found to directly interact with IRF9. These observations underscore the potential contribution s of the tumor suppressor p53 in cellular antiviral immunity against HCV with possible therapeutic implication.Double-stranded-RNA-activated protein kinase (PKR), an interferon-stimulated gene, is activated by binding with double-stranded RNA, a putative replicative intermediate of HCV. Activated PKR phosphorylates the alpha subunit of eukaryotic initiation factor-2 to inhibit the translation of viral protein. We established stable PKR knockdown Huh7 cells using RNAi and investigated the effect of PKR against HCV replication. In stable PKR knockdown cells that harbored an HCV subgenomic replicon, luciferase activity was approximately three times higher than that of control cells, indicating that the subgenomic replicon replicated with higher efficiency in stable PKR knockdown cells than in control cells. Furthermore, stable PKR knockdown cells secreted significantly more HCV particles than did control cells after transfection with full-length HCV genome. The replication of subgenomic replicon was suppressed by the addition of interferon-alpha in both cells. Although the extent of suppression was significantly lower in stable PKR knockdown than control cells using a low concentration of interferon-alpha, even 10 U/ml interferon-alpha suppressed the replication of subgenomic replicon by 98% in both cells. PKR plays an important role in suppressing HCV replication in an innate state, but is not essential in interferon therapy. Less