Interferon-alpha inhibits hepatitis C virus subgenomic RNA replication by an MxA-independent pathway

Hepatitis C virus (HCV) persists in the majority of infected individuals an d is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Chronic hepatitis C is currently treated with interferon (IFN)- alpha or with a combination of IFN-alpha and ribavirin. The availability of an HCV replicon system (Lohmann et al,, Science 285, 110-113, 1999) allowe d the investigation of the effects of IFN on genuine HCV replication in cul tured cells. It is shown here that IFN-alpha inhibits subgenomic HCV RNA re plication in HuH-7 human hepatoma cells. Immunofluorescence, Western blot a nd Northern blot analysis revealed that levels of both HCV protein and repl icon RNA were reduced after treatment with IFN-a in a dose-dependent manner . In further experiments, it was investigated whether MxA plays a role in t he inhibition of HCV. The human MxA protein is an IFN-induced GTPase that h as antiviral activity against various RNA viruses. However, HCV RNA replica tion was not affected in transfected HuH-7 cells that transiently overexpre ssed MxA. Moreover, a dominant-negative mutant of MxA did not interfere wit h the antiviral activity of IFN-alpha against HCV RNA replication. Taken to gether, these results demonstrate that IFN-alpha inhibits HCV replicons via an MxA-independent pathway.