1 Department of Molecular Biology and Genetics - Structural Biology, Department of Molecular Biology and Genetics, Science and Technology, Aarhus University2 Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne3 Department of Biomedicine, University of Basel4 Institute of Social and Preventive Medicine, University Hospital (CHUV) and University of Lausanne5 Service of Immunology and Allergology, Department of Medicine, University Hospital and University of Lausanne6 Fondazione Epatocentro Ticino7 Laboratory of Virology, Division of Infectious Diseases and Division of Laboratory Medicine, University Hospitals of Geneva and Medical School, University of Geneva8 Pourtalès Hospital9 Liver Unit, Scientific Research Institute Casa Sollievo della Sofferenza10 Division of Gastroenterology and Hepatology, University Hospital and University of Lausanne11 Division of Gastroenterology and Hepatology, University Hospital of Zurich12 Division of Clinical Pathology and Division of Gastroenterology and Hepatology, University Hospitals13 Division of Gastroenterology, Canton Hospital, St Gallen14 Service of Hepatology, Department of Clinical Research, University of Bern15 unknown16 Department of Molecular Biology and Genetics - Structural Biology, Department of Molecular Biology and Genetics, Science and Technology, Aarhus University
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.