title: Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes.
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.
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Aarhus DK-8000, Denmark.
authors.forename: Ewa
authors.initials: E
authors.lastname: Terczyńska-Dyla
authors.affiliation: Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne CH-1011, Switzerland.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bibert
authors.affiliation: 1] Department of Biomedicine, University of Basel, Basel CH-4031, Switzerland [2] Division of Gastroenterology and Hepatology, University Hospital Basel, Basel CH-4031, Switzerland.
authors.forename: Francois H T
authors.initials: FH
authors.lastname: Duong
authors.affiliation: 1] Department of Biomedicine, University of Basel, Basel CH-4031, Switzerland [2] Division of Gastroenterology and Hepatology, University Hospital Basel, Basel CH-4031, Switzerland.
authors.forename: Ilona
authors.initials: I
authors.lastname: Krol
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Aarhus DK-8000, Denmark.
authors.forename: Sanne
authors.initials: S
authors.lastname: Jørgensen
authors.affiliation: Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne CH-1011, Switzerland.
authors.forename: Emilie
authors.initials: E
authors.lastname: Collinet
authors.affiliation: 1] Institute of Social and Preventive Medicine, University Hospital (CHUV) and University of Lausanne, Lausanne 1010, Switzerland [2] Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Kutalik
authors.affiliation: Service of Immunology and Allergology, Department of Medicine, University Hospital and University of Lausanne, Lausanne 1011, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Aubert
authors.affiliation: Fondazione Epatocentro Ticino, Sede Moncucco, Lugano 6900, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Cerny
authors.affiliation: Laboratory of Virology, Division of Infectious Diseases and Division of Laboratory Medicine, University Hospitals of Geneva and Medical School, University of Geneva, Geneva 1211, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Kaiser
authors.affiliation: Pourtalès Hospital, Neuchâtel 2000, Switzerland.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Malinverni
authors.affiliation: Liver Unit, Scientific Research Institute Casa Sollievo della Sofferenza, San Giovanni Rotondo 71013, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mangia
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital and University of Lausanne, Lausanne CH-1011, Switzerland.
authors.forename: Darius
authors.initials: D
authors.lastname: Moradpour
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich 8091, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Müllhaupt
authors.affiliation: Division of Clinical Pathology and Division of Gastroenterology and Hepatology, University Hospitals, Geneva 1211, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Negro
authors.affiliation: Liver Unit, Scientific Research Institute Casa Sollievo della Sofferenza, San Giovanni Rotondo 71013, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Santoro
authors.affiliation: Division of Gastroenterology, Canton Hospital, St Gallen CH-9007, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Semela
authors.affiliation: Service of Hepatology, Department of Clinical Research, University of Bern, Bern CH-3010, Switzerland.
authors.forename: Nasser
authors.initials: N
authors.lastname: Semmo
authors.affiliation: 1] Department of Biomedicine, University of Basel, Basel CH-4031, Switzerland [2] Division of Gastroenterology and Hepatology, University Hospital Basel, Basel CH-4031, Switzerland.
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
authors.affiliation: Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne CH-1011, Switzerland.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Bochud
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Aarhus DK-8000, Denmark.
authors.forename: Rune
authors.initials: R
authors.lastname: Hartmann
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D006526:Hepatitis C / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins / Q000235:genetics / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology; D014452:Ubiquitins / Q000235:genetics / Q000276:immunology; D000095022:Interferon Lambda; D000090123:Viperin Protein
chemical_list: D000123:Acetyltransferases; D016207:Cytokines; D007378:Interleukins; D008565:Membrane Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins; D014157:Transcription Factors; D014452:Ubiquitins; C406887:IFI27 protein, human; C579163:IFNL4 protein, human; D000095022:Interferon Lambda; C074034:ISG15 protein, human; C444427:RSAD2 protein, human; D000090123:Viperin Protein; C111246:HTATIP2 protein, human