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-alpha), is effective in a limited percentage of patients. The mechanisms by which IFN-alpha interferes with the HCV life cycle and the reasons for limited effectiveness of IFN-alpha 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-alpha-mediated HCV clearance. We reported that conventional protein kinase C (cPKC) activity is important for the effectiveness of IFN-alpha treatment. In cells treated with a cPKC-specific inhibitor, IFN-alpha failed to induce an efficient HCV RNA degradation. The lack of cPKC activity leads to a broad reduction of IFN-alpha-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-alpha-mediated antiviral therapies.
Fimia
Gian Maria
GM
Gene Expression Laboratory, National Institute for Infectious Diseases "L. Spallanzani" IRCCS, Via Portuense 292, 00149 Rome, Italy.
Evangelisti
Cristina
C
Alonzi
Tonino
T
Romani
Marta
M
Fratini
Federica
F
Paonessa
Giacomo
G
Ippolito
Giuseppe
G
Tripodi
Marco
M
Piacentini
Mauro
M
D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D012367:RNA, Viral / Q000378:metabolism; D012093:Replicon / Q000187:drug effects*; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*
D000998:Antiviral Agents; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D012367:RNA, Viral; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D011493:Protein Kinase C