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

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  • Ewa Terczynska-Dyla
  • Stephanie Bibert, Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Schweiz
  • Francois H T Duong, Department of Biomedicine, University of Basel, Division of Gastroenterology and Hepatology, University Hospital Basel, Schweiz
  • Ilona Krol, Department of Biomedicine, University of Basel, Division of Gastroenterology and Hepatology, University Hospital Basel, Schweiz
  • Sanne Jørgensen, Danmark
  • Emilie Collinet, Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Schweiz
  • Zoltán Kutalik, Institute of Social and Preventive Medicine, University Hospital (CHUV) and University of Lausanne, Swiss Institute of Bioinformatics, Schweiz
  • Vincent Aubert, Service of Immunology and Allergology, Department of Medicine, University Hospital and University of Lausanne, Schweiz
  • Andreas Cerny, Fondazione Epatocentro Ticino, Schweiz
  • Laurent Kaiser, Laboratory of Virology, Division of Infectious Diseases and Division of Laboratory Medicine, University Hospitals of Geneva and Medical School, University of Geneva, Schweiz
  • Raffaele Malinverni, Pourtalès Hospital, Schweiz
  • Alessandra Mangia, Liver Unit, Scientific Research Institute Casa Sollievo della Sofferenza, Italien
  • Darius Moradpour, Division of Gastroenterology and Hepatology, University Hospital and University of Lausanne, Schweiz
  • Beat Müllhaupt, Division of Gastroenterology and Hepatology, University Hospital of Zurich, Schweiz
  • Francesco Negro, Division of Clinical Pathology and Division of Gastroenterology and Hepatology, University Hospitals, Schweiz
  • Rosanna Santoro, Liver Unit, Scientific Research Institute Casa Sollievo della Sofferenza, Italien
  • David Semela, Division of Gastroenterology, Canton Hospital, St Gallen, Schweiz
  • Nasser Semmo, Service of Hepatology, Department of Clinical Research, University of Bern, Schweiz
  • Swiss Hepatitis C Cohort Study Group
  • ,
  • Markus H Heim, Department of Biomedicine, University of Basel, Division of Gastroenterology and Hepatology, University Hospital Basel, Schweiz
  • Pierre-Yves Bochud, Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Schweiz
  • Rune Hartmann

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.

OriginalsprogEngelsk
Artikelnummer5699
TidsskriftNature Communications
Vol/bind5
Antal sider8
ISSN2041-1723
DOI
StatusUdgivet - 2014

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