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

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, Alessandra Mangia, Darius Moradpour, Beat Müllhaupt, Francesco Negro, Rosanna Santoro, David Semela, Nasser Semmo, Markus H. Heim (), Pierre-Yves Bochud () and Rune Hartmann ()
Additional contact information
Ewa Terczyńska-Dyla: Aarhus University
Stephanie Bibert: Infectious Diseases Service, University Hospital and University of Lausanne
Francois H. T. Duong: University of Basel
Ilona Krol: University of 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
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
Pierre-Yves Bochud: Infectious Diseases Service, University Hospital and University of Lausanne
Rune Hartmann: Aarhus University

Nature Communications, 2014, vol. 5, issue 1, 1-9

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6699

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