Conventional protein kinase C inhibition prevents alpha interferon-mediated hepatitis C virus replication clearance

Alpha interferon (IFNa), alone in combination vith ribavirin, represents the only available treatment for HCV infections, with a moderate percentage of virus eradication (30-40 % ot the patoents). The mechanisms by which IFNa interferes with HCV replication have not been elucidated, nor are the reasons for limited effectiveness of INFa therapy known. Using a cell-based HCV replication system and specific kinase inhibitors we examined the role played by various signalling pathways in the IFNa-mediated HCV clearance. We have found thet conventional PKC activity is important for the effectiveness of IFNa treatment. In cells treated with a cPKC specific inhibitor, IFNa failed to induce an effective HCV RNA degradation. The lack of cPKC activity leads to a broad reduction of IFN-stimulated gene expression due to a significant impairment of STAT1 and STAT3 tyrosine phosphorylation. Thus, modulation of cPKC function, by either host or viral factors, could influence the positive outcome of IFN-mediated antiviral therapy