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Journal of Virology, September 2004, p. 9713-9720, Vol. 78, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.18.9713-9720.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Regulation of Hepatitis C Virus Replication by Interferon Regulatory Factor 1

Nobuhiko Kanazawa,1,{dagger} Masayuki Kurosaki,1,{dagger} Naoya Sakamoto,1* Nobuyuki Enomoto,1,2 Yasuhiro Itsui,1 Tsuyoshi Yamashiro,1 Yoko Tanabe,1 Shinya Maekawa,1 Mina Nakagawa,1 Cheng-Hsin Chen,1 Sei Kakinuma,1 Shigeru Oshima,1 Tetsuya Nakamura,1 Takanobu Kato,3 Takaji Wakita,3 and Mamoru Watanabe1

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University,1 Department of Microbiology, Tokyo Metropolitan Institute for Neuroscience, Tokyo,3 First Department of Internal Medicine, University of Yamanashi, Yamanashi, Japan2

Received 2 February 2004/ Accepted 12 May 2004

Cellular antiviral responses are mediated partly by the expression of interferon-stimulated genes, triggered by viral genomes, their transcripts and replicative intermediates. Persistent replication of a hepatitis C virus (HCV) replicon suggests that the replicon does not elicit cellular innate antiviral responses. In the present study, we investigated regulatory factors of the interferon-mediated antiviral system in cells expressing an HCV replicon. Luciferase reporter assays revealed that the baseline activity of the interferon-stimulated response element (ISRE) was significantly lower in cells harboring the replicon than in naive cells. Among the proteins involved in the IFN/Jak/STAT pathway and in ISRE activity, the expression level of interferon regulatory factor 1 (IRF-1) was found to be significantly lower in cells harboring the replicon. Transfection of an IRF-1 expression construct into cells harboring the replicon caused an increase of ISRE activity, accompanied by suppression of expression of the HCV replicon. Moreover, in cured Huh7 cells from which the HCV replicon had been eliminated, the expression levels of IRF-1 and ISRE activity also were suppressed, demonstrating that the decrease of IRF-1 is attributable, not to active suppression by the viral proteins, but to adaptation of cells that enables replication of the HCV subgenome. The high permissiveness of the cured cells for the replicon was abolished by transgenic supplementation of IRF-1 expression. Taken together, IRF-1 is one of the key host factors that regulate intracellular HCV replication through modulation of interferon-stimulated-gene-mediated antiviral responses.

* Corresponding author. Mailing address: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Phone: 81-3-5803-5877. Fax: 81-3-5803-0268. E-mail: nsakamoto.gast{at}tmd.ac.jp.

{dagger} N.K. and M.K. contributed equally to this work.

Journal of Virology, September 2004, p. 9713-9720, Vol. 78, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.18.9713-9720.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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