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

Ewa Terczyńska-Dyla, Stephanie Bibert, Francois H T Duong, Ilona Krol, Sanne Jørgensen, Emilie Collinet, Zoltán Kutalik, Vincent Aubert, Andreas Cerny, Laurent Kaiser, Raffaele Malinverni, Alessandra Mangia, Darius Moradpour, Beat Müllhaupt, Francesco Negro, Rosanna Santoro, David Semela, Nasser Semmo, Markus H. Heim, Pierre Yves BochudRune Hartmann, Laura Rubbia-Brandt, Gladys Martinetti, Meri Gorgievski, Jean François Dufour, Hans Hirsch, Beat Helbling, Stephan Regenass, Guenter Dollenmaier, Gieri Cathomas

Research output: Contribution to journalArticlepeer-review

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 IFNl4 protein changing a proline at position 70 to a serine (P70S) substantially alters its antiviral activity. Patients harbouring the impaired IFNl4-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 IFNl4-P70 variant. Altogether, these data provide evidence supporting a role for the active IFNl4 protein as the driver of high hepatic ISG expression as well as the cause of poor HCV clearance.

Original languageEnglish
Article numberA6699
JournalNature Communications
Volume5
DOIs
Publication statusPublished - Dec 23 2014

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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