IFN-λ4: the paradoxical new member of the interferon lambda family

J Interferon Cytokine Res. 2014 Nov;34(11):829-38. doi: 10.1089/jir.2013.0136. Epub 2014 Apr 30.

Abstract

Interferons (IFNs) are generally considered antiviral cytokines, yet the newly discovered IFN-λ4 is linked with the failure to clear hepatitis C virus (HCV) infection either spontaneously or in response to treatment. IFN-λ4 can be generated only by individuals who carry the IFNL4-ΔG allele (rs368234815), which is the strongest known host factor for predicting clearance of HCV. The ancestral IFNL4-ΔG allele is the major variant in Africans while the minor variant in Asians, suggesting very strong negative genetic selection for this allele-most likely driven by an infectious agent other than HCV. IFN-λ4 most closely resembles IFN-λ3, but these proteins share only 29% amino-acid identity, and, in contrast to IFN-λ3, IFN-λ4 is only weakly secreted. Nevertheless, IFN-λ4 signals through the IFN-λ receptor complex and induces expression of IFN-stimulated genes via the Janus kinase-signal transducer and activator of transcription signaling pathway. Although the IFNL4-ΔG variant is strongly associated with the failure to clear HCV infection, HCV-infected patients who carry this allele have lower baseline HCV RNA levels in the absence of treatment. Resolving the paradoxical functions of IFN-λ4, which appears to induce antiviral activity yet impair effective clearance of HCV, may yield critical new insights into the immunologic response to HCV infection and IFN biology.

Publication types

  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • African Continental Ancestry Group / genetics
  • Alleles
  • Animals
  • Genetic Predisposition to Disease
  • Hepacivirus / physiology*
  • Hepatitis C / genetics
  • Hepatitis C / immunology*
  • Humans
  • Interleukins / chemistry
  • Interleukins / genetics
  • Interleukins / immunology*
  • Polymorphism, Single Nucleotide
  • RNA, Viral / immunology
  • Signal Transduction
  • Viral Load / genetics

Substances

  • IFNL4 protein, human
  • Interleukins
  • RNA, Viral