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Journal of Virology, December 2004, p. 12809-12816, Vol. 78, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.23.12809-12816.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Conventional Protein Kinase C Inhibition Prevents Alpha Interferon-Mediated Hepatitis C Virus Replicon Clearance by Impairing STAT Activation

Gian Maria Fimia,^1, Cristina Evangelisti,^1, Tonino Alonzi,^1, Marta Romani,¹ Federica Fratini,¹ Giacomo Paonessa,² Giuseppe Ippolito,¹ Marco Tripodi,^1,3* and Mauro Piacentini^1,4

National Institute for Infectious Diseases "L. Spallanzani" IRCCS,¹ Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Biotecnologie Cellulari ed Ematologia, Sezione di Genetica Molecolare, University of Rome "La Sapienza,",³ Department of Biology, University of Rome "Tor Vergata," Rome,⁴ Istituto di Ricerche di Biologia Molecolare "P. Angeletti," Pomezia, Italy²

Received 26 May 2004/ Accepted 23 June 2004

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-), is effective in a limited percentage of patients. The mechanisms by which IFN- interferes with the HCV life cycle and the reasons for limited effectiveness of IFN- 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--mediated HCV clearance. We reported that conventional protein kinase C (cPKC) activity is important for the effectiveness of IFN- treatment. In cells treated with a cPKC-specific inhibitor, IFN- failed to induce an efficient 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 therapies.

G.M.F., C.E., and T.A. contributed equally to this work.

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