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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-
N110), 222 (NS5A-
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-
N110 and NS5A-
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-
B and AP-1 were important in NS5A-
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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