The IFN-λ4 Conundrum: When a Good Interferon Goes Bad

Since its discovery in 2013, interferon lambda 4 (IFN-lambda 4) has received a reputation as a paradoxical type III IFN. Difficulties in detecting IFN-lambda 4, especially in secreted form even led to questions about its existence. However, the genetic ability to generate IFN-lambda 4, determined by the presence of the rs368234815-Delta G allele, is the strongest predictor of impaired clearance of hepatitis C virus (HCV) infection in humans. Significant modulation of IFN-lambda 4 activity by a genetic variant (P70S) supports IFN-lambda 4, and not other type III IFNs encoded in the same genomic locus, as the primary functional cause of the association with HCV clearance. Although the ability to produce IFN-lambda 4 is associated with decreased HCV clearance, the recombinant IFN-lambda 4 is active against HCV and other viruses. These observations present an apparent conundrum-when and how does a presumably good IFN, with anti-HCV activity, interfere with the ability to clear HCV? In this review, we discuss findings that suggest potential mechanisms for explaining this conundrum.