Epidermal growth factor receptor signaling impairs the antiviral activity of interferon-alpha

Authors

  • Joachim Lupberger,

    1. Inserm, U1110, Institut de Virologie, Strasbourg, France
    2. Université de Strasbourg, Strasbourg, France
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    • These authors contributed equally.

  • François H.T. Duong,

    1. Inserm, U1110, Institut de Virologie, Strasbourg, France
    2. Université de Strasbourg, Strasbourg, France
    3. Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland
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    • These authors contributed equally.

  • Isabel Fofana,

    1. Inserm, U1110, Institut de Virologie, Strasbourg, France
    2. Université de Strasbourg, Strasbourg, France
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  • Laetitia Zona,

    1. Inserm, U1110, Institut de Virologie, Strasbourg, France
    2. Université de Strasbourg, Strasbourg, France
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  • Fei Xiao,

    1. Inserm, U1110, Institut de Virologie, Strasbourg, France
    2. Université de Strasbourg, Strasbourg, France
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  • Christine Thumann,

    1. Inserm, U1110, Institut de Virologie, Strasbourg, France
    2. Université de Strasbourg, Strasbourg, France
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  • Sarah C. Durand,

    1. Inserm, U1110, Institut de Virologie, Strasbourg, France
    2. Université de Strasbourg, Strasbourg, France
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  • Patrick Pessaux,

    1. Inserm, U1110, Institut de Virologie, Strasbourg, France
    2. Université de Strasbourg, Strasbourg, France
    3. Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France
    4. Institut Hospitalo-Universitaire, Strasbourg, France
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  • Mirjam B. Zeisel,

    1. Inserm, U1110, Institut de Virologie, Strasbourg, France
    2. Université de Strasbourg, Strasbourg, France
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  • Markus H. Heim,

    1. Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland
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    • These authors contributed equally.

  • Thomas F. Baumert

    Corresponding author
    1. Université de Strasbourg, Strasbourg, France
    2. Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France
    3. Institut Hospitalo-Universitaire, Strasbourg, France
    • Inserm, U1110, Institut de Virologie, Strasbourg, France
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    • These authors contributed equally.


  • See Editorial on Page 1200

  • Potential conflict of interest: Nothing to report.

  • This work was supported by the European Union (ERC-2008-AdG-233130-HEPCENT and INTERREG-IV-Rhin Supérieur-FEDER-Hepato-Regio-Net 2009 and 2012, EU FP7 HepaMab), Inserm, Laboratoire d'Excellence HEPSYS (ANR-10-LAB-28), the Agence Nationale pour la Recherche contre le SIDA et les Hépatites Virales (2008/354, 2009/183, 2011/132, and 2012/319), Université de Strasbourg, the Conseil Général du Bas Rhin, the Communauté Urbaine de Strasbourg, the Cancéropôle du Grand Est (30/03/09), INCa (2009-143), the Ligue Contre le Cancer (CA 06/12/08), and the Direction Générale de l'Offre de Soins (A12027MS). The authors thank R. Bartenschlager (University of Heidelberg, Heidelberg, Germany), T. Wakita (National Institute of Infectious Diseases, Tokyo, Japan), and F.V. Chisari (The Scripps Research Institute, La Jolla, CA) for providing HCV strain Luc-Jc1 and Huh7.5.1 cells and F. Sinicrope for providing lentiviral shRNA plasmids.

  • Inserm and the University of Strasbourg have filed a patent application on combinations of protein kinase inhibitors and interferons for the treatment and prevention of hepatitis C virus infection.

Address reprint requests to: Thomas F. Baumert, M.D., Inserm Unit 1110, University of Strasbourg, 3 rue Koeberlé, F-67000 Strasbourg, France. E-mail: Thomas.Baumert@unistra.fr; fax: +33 3 68 85 37 24.

Abstract

Interferon-alpha (IFN-α) exhibits its antiviral activity through signal transducer and activator of transcription protein (STAT) signaling and the expression of IFN response genes (IRGs). Viral infection has been shown to result in activation of epidermal growth factor receptor (EGFR)—a host cell entry factor used by several viruses, including hepatitis C virus. However, the effect of EGFR activation for cellular antiviral responses is unknown. Here, we uncover cross-talk between EGFR and IFN-α signaling that has a therapeutic effect on IFN-α-based therapies and functional relevance for viral evasion and IFN resistance. We show that combining IFN-α with the EGFR inhibitor, erlotinib, potentiates the antiviral effect of each compound in a highly synergistic manner. The extent of the synergy correlated with reduced STAT3 phosphorylation in the presence of erlotinib, whereas STAT1 phosphorylation was not affected. Furthermore, reduced STAT3 phosphorylation correlated with enhanced expression of suppressors of cytokine signaling 3 (SOCS3) in the presence of erlotinib and enhanced expression of the IRGs, radical S-adenosyl methionine domain containing 2 and myxovirus resistance protein 1. Moreover, EGFR stimulation reduced STAT1 dimerization, but not phosphorylation, indicating that EGFR cross-talk with IFN signaling acts on the STATs at the level of binding DNA. Conclusions: Our results support a model where inhibition of EGFR signaling impairs STAT3 phosphorylation, leading to enhanced IRG expression and antiviral activity. These data uncover a novel role of EGFR signaling in the antiviral activity of IFN-α and open new avenues of improving the efficacy of IFN-α-based antiviral therapies. (Hepatology 2013;58:1225–1235)

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