Interferons α and λ Inhibit Hepatitis C Virus Replication With Distinct Signal Transduction and Gene Regulation Kinetics

Background & Aims: Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma. Current therapy with pegylated interferon α (IFN-α) in combination with ribavirin is associated with adverse effects and often fails to induce a sustained response. IFN-λs, recently discovered IFN gene family members, exhibit antiviral and cell stimulatory activities similar to IFN-α. We aimed to determine whether IFN-λ exhibits antiviral activity toward HCV and to compare the signal transduction and effector gene pathways with those of IFN-α. Methods: Using the HCV replicon system and cell culture infectious reporter virus, we compared IFN-α and IFN-λ effects on HCV RNA replication and protein expression, as measured by quantitative reverse-transcriptase polymerase chain reaction, luciferase expression, and Western blot. Receptor expression and signaling pathways were explored using flow cytometry and Western blot. IFN-α- and IFN-λ-mediated gene expression changes were compared using microarray analyses. Results: IFN-λ exhibited dose- and time-dependent HCV inhibition, independent of types I and II IFN receptors. The kinetics of IFN-λ-mediated signal transducers and activators of transcription (STAT) activation and induction of potential effector genes were distinct from those of IFN-α. IFN-λ induced steady increases in levels of known interferon stimulated genes (ISGs), whereas IFN-α ISGs peaked early and declined rapidly. IFN-λ inhibited replication of HCV genotypes 1 and 2 and enhanced the antiviral efficacy of subsaturating levels of IFN-α. Conclusions: These results demonstrate distinct differences in IFN-λ- and IFN-α-induced antiviral states. Understanding these differences may prove useful for developing new HCV treatment strategies.