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Journal of Virology, June 2003, p. 6367-6375, Vol. 77, No. 11
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.11.6367-6375.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Gene Expression Profiling of the Cellular Transcriptional Network Regulated by Alpha/Beta Interferon and Its Partial Attenuation by the Hepatitis C Virus Nonstructural 5A Protein

Gary K. Geiss,1,{dagger} Victoria S. Carter,1 Yupeng He,1,{ddagger} Bartlomiej K. Kwieciszewski,1 Ted Holzman,1 Marcus J. Korth,1 Catherine A. Lazaro,2 Nelson Fausto,2 Roger E. Bumgarner,1 and Michael G. Katze1,3*

Departments of Microbiology,1 Pathology, School of Medicine,2 Washington National Primate Research Center, University of Washington, Seattle, Washington 981953

Received 26 December 2002/ Accepted 13 March 2003

Alpha/beta interferons (IFN-{alpha}/ß) induce potent antiviral and antiproliferative responses and are used to treat a wide range of human diseases, including chronic hepatitis C virus (HCV) infection. However, for reasons that remain poorly understood, many HCV isolates are resistant to IFN therapy. To better understand the nature of the cellular IFN response, we examined the effects of IFN treatment on global gene expression by using several types of human cells, including HeLa cells, liver cell lines, and primary fetal hepatocytes. In response to IFN, 50 of the approximately 4,600 genes examined were consistently induced in each of these cell types and another 60 were induced in a cell type-specific manner. A search for IFN-stimulated response elements (ISREs) in genomic DNA located upstream of IFN-stimulated genes revealed both previously identified and novel putative ISREs. To determine whether HCV can alter IFN-regulated gene expression, we performed microarray analyses on IFN-treated HeLa cells expressing the HCV nonstructural 5A (NS5A) protein and on IFN-treated Huh7 cells containing an HCV subgenomic replicon. NS5A partially blocked the IFN-mediated induction of 14 IFN-stimulated genes, an effect that may play a role in HCV resistance to IFN. This block may occur through repression of ISRE-mediated transcription, since NS5A also inhibited the IFN-mediated induction of a reporter gene driven from an ISRE-containing promoter. In contrast, the HCV replicon had very little effect on IFN-regulated gene expression. These differences highlight the importance of comparing results from multiple model systems when investigating complex phenomena such as the cellular response to IFN and viral mechanisms of IFN resistance.

* Corresponding author. Mailing address: Department of Microbiology, University of Washington, Box 358070, Seattle, WA 98195-8070. Phone: (206) 732-6136. Fax: (206) 732-6056. E-mail: honey{at}u.washington.edu.

{dagger} Present address: Rexagen Corporation, Seattle, WA 98103.

{ddagger} Present address: Abbott Laboratories, Abbott Park, IL 60064.

Journal of Virology, June 2003, p. 6367-6375, Vol. 77, No. 11
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.11.6367-6375.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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