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Nat Commun. 2014 Dec 23;5:5699. doi: 10.1038/ncomms6699.

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

Author information

1
Department of Molecular Biology and Genetics, Aarhus University, Aarhus DK-8000, Denmark.
2
Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne CH-1011, Switzerland.
3
1] Department of Biomedicine, University of Basel, Basel CH-4031, Switzerland [2] Division of Gastroenterology and Hepatology, University Hospital Basel, Basel CH-4031, Switzerland.
4
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.
5
Service of Immunology and Allergology, Department of Medicine, University Hospital and University of Lausanne, Lausanne 1011, Switzerland.
6
Fondazione Epatocentro Ticino, Sede Moncucco, Lugano 6900, Switzerland.
7
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.
8
Pourtalès Hospital, Neuchâtel 2000, Switzerland.
9
Liver Unit, Scientific Research Institute Casa Sollievo della Sofferenza, San Giovanni Rotondo 71013, Italy.
10
Division of Gastroenterology and Hepatology, University Hospital and University of Lausanne, Lausanne CH-1011, Switzerland.
11
Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich 8091, Switzerland.
12
Division of Clinical Pathology and Division of Gastroenterology and Hepatology, University Hospitals, Geneva 1211, Switzerland.
13
Division of Gastroenterology, Canton Hospital, St Gallen CH-9007, Switzerland.
14
Service of Hepatology, Department of Clinical Research, University of Bern, Bern CH-3010, Switzerland.

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.

PMID:
25534433
DOI:
10.1038/ncomms6699
[Indexed for MEDLINE]

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