Conventional protein kinase C inhibition prevents alpha interferon-mediated hepatitis C virus replicon clearance by impairing STAT activation

Hepatitis C virus (HCV) has evolved complex strategies to evade host immune responses and establish chronic infection. The only treatment available for HCV infections, alpha interferon (IFN-α), is effective in a limited percentage of patients. The mechanisms by which IFN-α interferes with the HCV life cycle and the reasons for limited effectiveness of IFN-α therapy have not yet been fully elucidated. Using a cell-based HCV replication system and specific kinase inhibitors, we examined the role played by various signaling pathways in the IFN-α-mediated HCV clearance. We reported that conventional protein kinase C (cPKC) activity is important for the effectiveness of IFN-α treatment. In cells treated with a cPKC-specific inhibitor, IFN-α failed to induce an efficient HCV RNA degradation. The lack of cPKC activity leads to a broad reduction of IFN-α-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-α-mediated antiviral therapies.