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Journal of Virology, October 1999, p. 8469-8475, Vol. 73, No. 10
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Expression of Hepatitis C Virus Proteins Inhibits Signal Transduction through the Jak-STAT Pathway

Markus H. Heim,1,2 Darius Moradpour,2 and Hubert E. Blum2,*

Department of Research, University Hospital Basel, CH-4031 Basel, Switzerland,1 and Department of Medicine II, University Hospital Freiburg, D-79106 Freiburg, Germany2

Received 1 February 1999/Accepted 30 June 1999

Hepatitis C virus (HCV) infection is a leading cause of liver disease worldwide. Alpha interferon (IFN-alpha ) therapy of chronic hepatitis C leads to a sustained response in 10 to 20% of patients only. The mechanisms of viral persistence and the pathogenesis of hepatitis C are poorly understood. We established continuous human cell lines, allowing the tightly regulated expression of the entire HCV open reading frame under the control of a tetracycline-responsive promoter. Using this in vitro system, we analyzed the effect of HCV proteins on IFN-induced intracellular signaling. Expression of HCV proteins in these cells strongly inhibited IFN-alpha -induced signal transduction through the Jak-STAT pathway. Inhibition occurred downstream of STAT tyrosine phosphorylation. Inhibition of the Jak-STAT pathway was not restricted to IFN-alpha -induced signaling but was observed in leukemia inhibitory factor-induced signaling through Stat3 as well. By contrast, tumor necrosis factor alpha-induced activation of the transcription factor NF-kappa B was not affected. Interference of HCV with IFN-alpha -induced signaling through the Jak-STAT pathway could contribute to the resistance to IFN-alpha therapy observed in the majority of patients and may represent a general escape strategy of HCV contributing to viral persistence and pathogenesis of chronic liver disease.

* Corresponding author. Mailing address: Department of Medicine II, University Hospital Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany. Phone: 49-761-270-3403. Fax: 49-761-270-3610. E-mail: heblum{at}ukl.uni-freiburg.de.

Journal of Virology, October 1999, p. 8469-8475, Vol. 73, No. 10
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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