Inhibition of cytochrome c release in Fas-mediated signaling pathway in transgenic mice induced to express hepatitis C viral proteins

Persistent hepatitis C virus (HCV) infection often progresses to chronic he patitis, cirrhosis, and hepatocellular carcinoma. Numerous viruses have bee n reported to escape from apoptotic mechanism to maintain persistent infect ion. In the present study, we characterized the effect of HCV proteins on t he Fas signal using HCV transgenic mice, which expressed core, E1, E2, and NS2 proteins, regulated by the Cre/loxP switching system. The transgene exp ression of HCV transgenic mice caused resistance to Fas antibody stimulated lethality. Apoptotic cell death in the liver of HCV protein expressing mic e was significantly reduced compared with nonexpressing mice. Histopatholog ical analysis and DNA fragmentation analysis revealed that the HCV proteins suppressed Fas-mediated apoptotic cell death. To identify the target pathw ay of HCV proteins, we characterized caspase activity. The activation of ca spase-9 and -3/7 but not caspase-8 was inhibited by HCV proteins. Cytochrom e c release from mitochondria was inhibited in HCV protein expressing mice. These results indicated that the expression of HCV proteins may directly o r indirectly inhibit Fas-mediated apoptosis and death in mice by repressing the release of cytochrome c from mitochondria, thereby suppressing caspase -9 and -3/7 activation. These results suggest that HCV may cause persistent infection, as a result of suppression of Fas-mediated cell death.