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

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.

FIG. 1.

Location of the interferon (IFN)-λ gene family and genome-wide association study markers rs12979860 and rs8099917 on chromosome 19 (a); exonic structure of IFNL4 with the location of the IFNL4 rs12979860 (“IL28B”) and IFNL4 rs368234815 (IFNL4–ΔG) polymorphisms (b).

FIG. 2.

Median decrease in hepatitis C virus (HCV) RNA (log10 IU/mL) in African American participants in Virahep-C study during the first 28 days of treatment with pegylated IFN-α and ribavirin. P=0.015 for a comparison of mean differences in HCV RNA levels at day 28 for each of the 3 genotype groups for ss469415590 (ie, rs368234815, IFNL4–ΔG) with the respective groups for IFNL4 rs12979860 (“IL28B”). From Prokunina-Olsson and others (2013) [By permission, Nature Publishing].

FIG. 3.

Recombinant IFN-λ4 signals through the IFN-λ receptor complex. HEK293 cells were, as indicated, transfected with IFN-λR1 and/or treated with silencing RNA against IL-10R2. The cells were also transfected with luciferase reporter constructs for Renilla, which is constitutively expressed, and Firefly, which is IFN inducible. Adapted from Hamming and others (2013) [By permission, Nature Publishing].