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Journal of Virology, July 2001, p. 6095-6106, Vol. 75, No. 13
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.13.6095-6106.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Hepatitis C Virus Nonstructural 5A Protein Induces Interleukin-8, Leading to Partial Inhibition of the Interferon-Induced Antiviral Response

Stephen J. Polyak,1,* Khalid S. A. Khabar,2 Denise M. Paschal,1 Heather J. Ezelle,3 Gilles Duverlie,4 Glen N. Barber,3 David E. Levy,5 Naofumi Mukaida,6 and David R. Gretch1

Department of Laboratory Medicine, University of Washington, Seattle, Washington1; Departments of Biological and Medical Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia2; Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida3; Department of Virology, CHU-Hôpital Sud, Amiens, France4; Department of Pathology, New York University School of Medicine, New York, New York5; and Department of Molecular Oncology, Kanazawa University, Kanazawa, Japan6

Received 27 September 2000/Accepted 2 April 2001

Hepatitis C virus (HCV), a major cause of liver disease worldwide, is frequently resistant to the antiviral alpha interferon (IFN). The HCV nonstructural 5A (NS5A) protein has been implicated in HCV antiviral resistance in many studies. NS5A antagonizes the IFN antiviral response in vitro, and one mechanism is via inhibition of a key IFN-induced enzyme, the double-stranded-RNA-activated protein kinase (PKR). In the present study we determined if NS5A uses other strategies to subvert the IFN system. Expression of full-length NS5A proteins from patients who exhibited a complete response (FL-NS5A-CR) or were nonresponsive (FL-NS5A-NR) to IFN therapy in HeLa cells had no effect on IFN induction of IFN-stimulated gene factor 3 (ISGF-3). Expression of mutant NS5A proteins lacking 110 (NS5A-Delta N110), 222 (NS5A-Delta N222), and 334 amino-terminal amino acids and mutants lacking 117 and 230 carboxy-terminal amino acids also had no effect on ISGF-3 induction by IFN. Expression of FL-NS5A-CR and FL-NS5A-NR did not affect IFN-induced STAT-1 tyrosine phosphorylation or upregulation of PKR and major histocompatibility complex class I antigens. However, NS5A expression in human cells induced interleukin 8 (IL-8) mRNA and protein, and this effect correlated with inhibition of the antiviral effects of IFN in an in vitro bioassay. NS5A induced transcription of a reporter gene driven by the IL-8 promoter, and the first 133 bp of the IL-8 promoter made up the minimal domain required for NS5A transactivation. NS5A-Delta N110 and NS5A-Delta N222 stimulated the IL-8 promoter to higher levels than did the full-length NS5A protein, and this correlated with increased nuclear localization of the proteins. Additional mutagenesis of the IL-8 promoter suggested that NF-kappa B and AP-1 were important in NS5A-Delta N222 transactivation in the presence of tumor necrosis factor alpha and that NF-IL-6 was inhibitory to this process. This study suggests that NS5A inhibits the antiviral actions of IFN by at least two mechanisms and provides the first evidence for a biological effect of the transcriptional activity of the NS5A protein. During HCV infection, viral proteins may induce chemokines that contribute to HCV antiviral resistance and pathogenesis.

* Corresponding author. Mailing address: Virology Division, Box 359690, 325 9th Ave., Seattle, WA 98104-2499. Phone: (206) 341-5224. Fax: (206) 341-5203. E-mail: polyak{at}u.washington.edu.

Journal of Virology, July 2001, p. 6095-6106, Vol. 75, No. 13
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.13.6095-6106.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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