1. Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes.
- Author
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Terczyńska-Dyla E, Bibert S, Duong FH, Krol I, Jørgensen S, Collinet E, Kutalik Z, Aubert V, Cerny A, Kaiser L, Malinverni R, Mangia A, Moradpour D, Müllhaupt B, Negro F, Santoro R, Semela D, Semmo N, Heim MH, Bochud PY, and Hartmann R
- Subjects
- Acetyltransferases genetics, Acetyltransferases immunology, Cell Line, Cytokines genetics, Cytokines immunology, Hepacivirus genetics, Hepatitis C genetics, Humans, Interleukins genetics, Membrane Proteins genetics, Membrane Proteins immunology, Oxidoreductases Acting on CH-CH Group Donors, Proteins genetics, Proteins immunology, Transcription Factors genetics, Transcription Factors immunology, Ubiquitins genetics, Ubiquitins immunology, Hepacivirus physiology, Hepatitis C immunology, Interleukins immunology
- 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.
- Published
- 2014
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