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Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes

Author

Listed:
  • Ewa Terczyńska-Dyla

    (Aarhus University)

  • Stephanie Bibert

    (Infectious Diseases Service, University Hospital and University of Lausanne)

  • Francois H. T. Duong

    (University of Basel
    University Hospital Basel)

  • Ilona Krol

    (University of Basel
    University Hospital Basel)

  • Sanne Jørgensen

    (Aarhus University)

  • Emilie Collinet

    (Infectious Diseases Service, University Hospital and University of Lausanne)

  • Zoltán Kutalik

    (Institute of Social and Preventive Medicine, University Hospital (CHUV) and University of Lausanne
    Swiss Institute of Bioinformatics)

  • Vincent Aubert

    (Service of Immunology and Allergology, University Hospital and University of Lausanne)

  • Andreas Cerny

    (Fondazione Epatocentro Ticino)

  • Laurent Kaiser

    (Laboratory of Virology, University Hospitals of Geneva and Medical School, University of Geneva)

  • Raffaele Malinverni

    (Pourtalès Hospital)

  • Alessandra Mangia

    (Liver Unit, Scientific Research Institute Casa Sollievo della Sofferenza)

  • Darius Moradpour

    (University Hospital and University of Lausanne)

  • Beat Müllhaupt

    (University Hospital of Zurich)

  • Francesco Negro

    (University Hospitals)

  • Rosanna Santoro

    (Liver Unit, Scientific Research Institute Casa Sollievo della Sofferenza)

  • David Semela

    (Canton Hospital)

  • Nasser Semmo

    (Service of Hepatology, University of Bern)

  • Markus H. Heim

    (University of Basel
    University Hospital Basel)

  • Pierre-Yves Bochud

    (Infectious Diseases Service, University Hospital and University of Lausanne)

  • Rune Hartmann

    (Aarhus University)

Abstract

Hepatitis C virus (HCV) infections are the major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma worldwide. Both spontaneous and treatment-induced clearance of HCV depend on genetic variation within the interferon-lambda locus, but until now no clear causal relationship has been established. Here we demonstrate that an amino-acid substitution in the IFNλ4 protein changing a proline at position 70 to a serine (P70S) substantially alters its antiviral activity. Patients harbouring the impaired IFNλ4-S70 variant display lower interferon-stimulated gene (ISG) expression levels, better treatment response rates and better spontaneous clearance rates, compared with patients coding for the fully active IFNλ4-P70 variant. Altogether, these data provide evidence supporting a role for the active IFNλ4 protein as the driver of high hepatic ISG expression as well as the cause of poor HCV clearance.

Suggested Citation

  • Ewa Terczyńska-Dyla & Stephanie Bibert & Francois H. T. Duong & Ilona Krol & Sanne Jørgensen & Emilie Collinet & Zoltán Kutalik & Vincent Aubert & Andreas Cerny & Laurent Kaiser & Raffaele Malinverni , 2014. "Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes," Nature Communications, Nature, vol. 5(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6699
    DOI: 10.1038/ncomms6699
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