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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / genetics
  • Acetyltransferases / immunology
  • Cell Line
  • Cytokines / genetics
  • Cytokines / immunology
  • Hepacivirus / genetics
  • Hepacivirus / physiology*
  • Hepatitis C / genetics
  • Hepatitis C / immunology*
  • Humans
  • Interleukins / genetics
  • Interleukins / immunology*
  • 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


  • Cytokines
  • IFI27 protein, human
  • IFNL4 protein, human
  • Interleukins
  • Membrane Proteins
  • Proteins
  • Transcription Factors
  • Ubiquitins
  • ISG15 protein, human
  • Oxidoreductases Acting on CH-CH Group Donors
  • RSAD2 protein, human
  • Acetyltransferases
  • HTATIP2 protein, human