PKR protein kinase is activated by hepatitis C virus and inhibits viral replication through translational control

Hepatitis C virus (HCV) infection is currently treated with IFN alpha-based therapy but little is known how IFN alpha inhibits HCV replication. We show here that HCV JFH1 infection of human hepatoma Huh-7 cells leads to the activation of IFN-inducible protein kinase PKR and phosphorylation of the translation initiation factor eIF2 alpha. Compared to a control cell HCV replication was significantly elevated in a PKR-knockdown cell, giving rise to a 10-fold higher viral titer, and was less sensitive to IFN alpha treatment. Conversely, transient expression of PKR inhibited HCV replication in a kinase-dependent manner with concomitant increase of eIF2 alpha phosphorylation. Further, expression of a phospho-mimetic eIF2 alpha mutant moderately inhibited HCV replication. Together, these results demonstrate that PKR is activated by HCV infection and plays a critical antiviral role through inhibition of viral protein translation. (C) 2009 Elsevier B.V. All rights reserved.