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Expression of hepatitis C virus proteins inhibits signal transduction through the Jak-STAT pathway
M H Heim1, D Moradpour, H E Blum
1Department of Research, University Hospital Basel, CH-4031 Basel, Switzerland.
Abstract:
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-kappaB 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.
Insights
Hepatitis C virus (HCV) proteins block interferon signaling, hindering treatment response. This viral interference with the Jak-STAT pathway may explain treatment resistance and chronic liver disease.
Area of Science:
- Hepatology
- Virology
- Immunology
Background:
- Hepatitis C virus (HCV) infection is a major global cause of liver disease.
- Current alpha interferon (IFN-alpha) therapy for chronic hepatitis C has limited efficacy, with sustained response in only 10-20% of patients.
- The mechanisms behind HCV persistence and disease pathogenesis remain largely unknown.
Purpose of the Study:
- To investigate the impact of HCV proteins on interferon-induced intracellular signaling pathways.
- To elucidate the mechanisms by which HCV may evade immune responses and establish persistent infections.
Main Methods:
- Establishment of continuous human cell lines with tetracycline-regulated expression of the entire HCV open reading frame.
- Analysis of HCV protein effects on IFN-alpha-induced signal transduction via the Jak-STAT pathway.
- Assessment of effects on leukemia inhibitory factor (LIF)-induced Stat3 signaling and tumor necrosis factor alpha (TNF-alpha)-induced NF-kappaB activation.
Main Results:
- HCV proteins significantly inhibited IFN-alpha-induced signal transduction through the Jak-STAT pathway, downstream of STAT tyrosine phosphorylation.
- This inhibition of the Jak-STAT pathway was also observed for LIF-induced signaling.
- Activation of NF-kappaB by TNF-alpha was not affected by HCV protein expression.
Conclusions:
- HCV interference with IFN-alpha-induced Jak-STAT signaling likely contributes to the poor response rates observed in patients undergoing IFN-alpha therapy.
- This interference represents a potential viral escape strategy that promotes HCV persistence and the pathogenesis of chronic liver disease.