| Research Abstract |
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
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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
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