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Double-stranded RNA-activated protein kinase inhibits hepatitis C virus replication but may be not essential in interferon treatment.

Chang J.H., Kato N., Muroyama R., Taniguchi H., Guleng B., Dharel N., Shao R.X., Tateishi K., Jazag A., Kawabe T., Omata M.

BACKGROUND: Double-stranded RNA-activated protein kinase (PKR), an interferon (IFN)-stimulated gene, is activated by binding with double-stranded RNA, a putative replicative intermediate of the hepatitis C virus (HCV). Activated PKR phosphorylates the alpha subunit of eukaryotic initiation factor-2 to inhibit the translation of viral protein. AIMS/METHODS: We established stable PKR knockdown Huh7 cells using RNA interference and investigated the effect of PKR against HCV replication using a subgenomic replicon that expressed luciferase reporter protein and the JFH1 full-length HCV genome. RESULTS: In stable PKR knockdown cells that harboured a subgenomic replicon, luciferase activity was approximately three times higher than that of control cells, indicating that the subgenomic replicon replicated with a higher efficiency in stable PKR knockdown cells than that in control cells. Furthermore, stable PKR knockdown cells secreted significantly more HCV particles than did control cells after transfection with the full-length HCV genome. The replication of the subgenomic replicon was suppressed by the addition of IFN-alpha in both cells. Although the extent of suppression was significantly lower in stable PKR knockdown than control cells using a low concentration (2.5-5 U/ml) of IFN-alpha, even 10 U/ml IFN-alpha suppressed the replication of subgenomic replicon by >98% in both cells. CONCLUSIONS: Double-stranded RNA-activated protein kinase plays an important role in suppressing HCV replication in an innate state, but may not be essential in IFN therapy.

Liver Int. 30:311-318(2010) [PubMed] [Europe PMC]

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