IFN-λ4: the paradoxical new member of the interferon lambda family.
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.
1 Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute , National Institutes of Health, Bethesda, Maryland.
Thomas R
TR
O'Brien
Ludmila
L
Prokunina-Olsson
Raymond P
RP
Donnelly
D000483:Alleles; D000818:Animals; D044383:Black People / Q000235:genetics; D020022:Genetic Predisposition to Disease; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007378:Interleukins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D012367:RNA, Viral / Q000276:immunology; D015398:Signal Transduction; D019562:Viral Load / Q000235:genetics; D000095022:Interferon Lambda
D007378:Interleukins; D012367:RNA, Viral; C579163:IFNL4 protein, human; D000095022:Interferon Lambda