Distinct and overlapping genomic profiles and antiviral effects of Interferon-λ and -α on HCV-infected and noninfected hepatoma cells

Recently, several SNPs in the region of the IL28B (IFN-lambda) gene have been associated with spontaneous clearance of hepatitis C virus (HCV) and enhanced cure rates for IFN-alfa-based therapies, suggesting a potential correlation between IFN-lambda and the ability to clear HCV. To understand the mechanism of IFN-lambda s as compared to IFN-alpha s antiviral activity, we performed a comprehensive analysis of their anti-HCV effects, whole genome transcriptome profiling with validation, and signalling of IFN-alpha and IFN-lambda using J6/JFH-1 and Huh7.5 cells in vitro. IFN-lambda and IFN-alpha exhibited comparable anti-HCV activity and gene expression profiles in Huh7.5 cells. While the majority of genes induced by IFN-alpha and IFN-lambda were similar, IFN-lambda exhibits profound, but delayed kinetics of IFN-stimulated genes (ISG) induction, while IFN-alpha induced more rapid induction of ISGs. Furthermore, the increased induction of ISG expression by IFN-lambda correlated with up-regulation of IFN-lambda receptor (IL-28RA) expression and more prolonged activation of the Jak-STAT signalling pathway. The findings from our comparative analysis of IFN-alpha and IFN-lambda in HCV-infected and noninfected cells support the clinical use of IFN-lambda as a potential alternative to IFN-alpha in the treatment of chronic hepatitis C.