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Journal of Virology, November 2005, p. 13778-13793, Vol. 79, No. 21
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.21.13778-13793.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Dissecting the Interferon-Induced Inhibition of Hepatitis C Virus Replication by Using a Novel Host Cell Line{dagger}

Marc P. Windisch,1 Michael Frese,1 Artur Kaul,1 Martin Trippler,2 Volker Lohmann,1 and Ralf Bartenschlager1*

Department of Molecular Virology, Hygiene Institute, University of Heidelberg, Im Neuenheimer Feld 345, D-69120 Heidelberg, Germany,1 Department of Gastroenterology and Hepatology, University of Essen, Virchowstrasse 171, D-45147 Essen, Germany2

Received 10 June 2005/ Accepted 6 August 2005

The Hepatitis C virus (HCV), a member of the family Flaviviridae, is a major cause of chronic liver disease. Patients are currently treated with alpha interferon (IFN-{alpha}) that is given alone or in combination with ribavirin. Unfortunately, this treatment is ineffective in eliminating the virus in a large proportion of individuals. IFN-induced antiviral activities have been intensively studied in the HCV replicon system. It was found that both IFN-{alpha} and IFN-{gamma} inhibit HCV replicons, but the underlying mechanisms have not yet been identified. Of note is that nearly all of these studies were performed with the human hepatoma cell line Huh-7. Here, we report that genotypes 1b and 2a replicons also replicate in the human hepatoblastoma cell line HuH6. Similar to what has been described for Huh-7 cells, we observed that efficient HCV replication in HuH6 cells depends on the presence of cell culture-adaptive mutations and the permissiveness of the host cell. However, three major differences exist: in HuH6 cells, viral replication is (i) independent from ongoing cell proliferation, (ii) less sensitive to certain antiviral compounds, and (iii) highly resistant to IFN-{gamma}. The latter is not due to a general defect in IFN signaling, as IFN-{gamma} induces the nuclear translocation of signal transducer and activator of transcription 1 (STAT1), the enhanced transcription of several IFN-regulated genes, and the inhibition of unrelated viruses such as influenza A virus and Semliki Forest virus. Taken together, the results establish HuH6 replicon cells as a valuable tool for IFN studies and for the evaluation of antiviral compounds.

* Corresponding author. Mailing address: Abteilung Molekulare Virologie, Hygiene Institut, Universität Heidelberg, Im Neuenheimer Feld 345, D-69120 Heidelberg, Germany. Phone: 49-6221-56-4869. Fax: 49-6221-56-4570. E-mail: ralf_bartenschlager{at}med.uni-heidelberg.de.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, November 2005, p. 13778-13793, Vol. 79, No. 21
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.21.13778-13793.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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