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

Publication

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

Journal Paper/Review - Dec 23, 2014

Terczyńska-Dyla Ewa, Moradpour Darius, Mullhaupt Beat, Negro Francesco, Santoro Rosanna, Semela David, Semmo Nasser, Swiss Hepatitis C Cohort Study Group, Heim Markus H, Bochud Pierre-Yves, Mangia Alessandra, Malinverni Raffaele, Bibert Stéphanie, Duong Francois H T, Krol Ilona, Jørgensen Sanne, Collinet Emilie, Kutalik Zoltán, Aubert Vincent, Cerny Andreas, Kaiser Laurent, Hartmann Rune

Citation

Terczyńska-Dyla E, Moradpour D, Mullhaupt B, Negro F, Santoro R, Semela D, Semmo N, Swiss Hepatitis C Cohort Study Group, Heim M, Bochud P, Mangia A, Malinverni R, Bibert S, Duong F, Krol I, Jørgensen S, Collinet E, Kutalik Z, Aubert V, Cerny A, Kaiser L, Hartmann R. Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes. Nat Commun 2014; 5:5699.

Type

Journal Paper/Review (English)

Journal

Nat Commun 2014; 5

Publication Date

Dec 23, 2014

Issn Electronic

2041-1723

Pages

5699

Brief description/objective

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.