Antiapoptotic and oncogenic potentials of hepatitis C virus are linked to interferon resistance by viral repression of the PKR protein kinase

Hepatitis C virus (HCV) is prevalent worldwide and has become a major cause of liver dysfunction and hepatocellular carcinoma. The high prevalence of HCV reflects the persistent nature of infection and the large frequency of cases that resist the current interferon (IFN)-based anti-HCV therapeutic r egimens. HCV resistance to IFN has been attributed, in part, to the functio n of the viral nonstructural 5A (NS5A) protein. NS5A from IFN-resistant str ains of HCV can repress the PKR protein kinase, a mediator of the IFN-induc ed antiviral and apoptotic responses of the host cell and a tumor suppresso r. Here we examined the relationship between HCV persistence and resistance to IFN therapy, When expressed in mammalian cells, NS5A from IFN-resistant HCV conferred IFN resistance to vesicular stomatitis virus (VSV), which no rmally is sensitive to the antiviral actions of IFN. NS5A blocked viral dou ble-stranded RNA (dsRNA)-induced PKR activation and phosphorylation of eIF- 2 alpha in IFN-treated cells, resulting in high levels of VSV mRNA translat ion. Mutations within the PKR-binding domain of NS5A restored PKR function and the IFN-induced block to viral mRNA translation. The effects due to NS5 A inhibition of PKR were not limited to the rescue of viral mRNA translatio n but also included a block in PKR-dependent host signaling pathways. Cells expressing NS5A exhibited defective PKR signaling and were refractory to a poptosis induced by exogenous dsRNA. Resistance to apoptosis was attributed to an NS5A-mediated block in eIF-2 alpha phosphorylation. Moreover, cells expressing NS5A exhibited a transformed phenotype and formed solid tumors i n vivo. Disruption of apoptosis and tumorogenesis required the PKR-binding function of NS5A, demonstrating that these properties may be linked to the IFN-resistant phenotype of HCV.