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Journal of Virology, January 2007, p. 202-214, Vol. 81, No. 1
0022-538X/07/$08.00+0     doi:10.1128/JVI.01011-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Repression of Interferon Regulatory Factor 1 by Hepatitis C Virus Core Protein Results in Inhibition of Antiviral and Immunomodulatory Genes

Anna R. Ciccaglione,^1, Emilia Stellacci,^1, Cinzia Marcantonio,¹ Valentina Muto,¹ Michele Equestre,² Giulia Marsili,¹ Maria Rapicetta,¹ and Angela Battistini^1*

Department of Infectious, Parasitic and Immunomediated Diseases,¹ Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy²

Received 17 May 2006/ Accepted 9 October 2006

Hepatitis C virus (HCV) proteins are known to interfere at several levels with both innate and adaptive responses of the host. A key target in these effects is the interferon (IFN) signaling pathway. While the effects of nonstructural proteins are well established, the role of structural proteins remains controversial. We investigated the effect of HCV structural proteins on the expression of interferon regulatory factor 1 (IRF-1), a secondary transcription factor of the IFN system responsible for inducing several key antiviral and immunomodulatory genes. We found substantial inhibition of IRF-1 expression in cells expressing the entire HCV replicon. Suppression of IRF-1 synthesis was mainly mediated by the core structural protein and occurred at the transcriptional level. The core protein in turn exerted a transcriptional repression of several interferon-stimulated genes, targets of IRF-1, including interleukin-15 (IL-15), IL-12, and low-molecular-mass polypeptide 2. These data recapitulate in a unifying mechanism, i.e., repression of IRF-1 expression, many previously described pathogenetic effects of HCV core protein and suggest that HCV core-induced IRF-1 repression may play a pivotal role in establishing persistent infection by dampening an effective immune response.

Published ahead of print on 18 October 2006.

A.R.C. and E.S. contributed equally to this work.

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