title: Distinct and overlapping genomic profiles and antiviral effects of Interferon-λ and -α on HCV-infected and noninfected hepatoma cells.
abstract: Recently, several SNPs in the region of the IL28B (IFN-λ) 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-λ and the ability to clear HCV. To understand the mechanism of IFN-λ's as compared to IFN-α's antiviral activity, we performed a comprehensive analysis of their anti-HCV effects, whole genome transcriptome profiling with validation, and signalling of IFN-α and IFN-λ using J6/JFH-1 and Huh7.5 cells in vitro. IFN-λ and IFN-α exhibited comparable anti-HCV activity and gene expression profiles in Huh7.5 cells. While the majority of genes induced by IFN-α and IFN-λ were similar, IFN-λ exhibits profound, but delayed kinetics of IFN-stimulated genes (ISG) induction, while IFN-α induced more rapid induction of ISGs. Furthermore, the increased induction of ISG expression by IFN-λ correlated with up-regulation of IFN-λ receptor (IL-28RA) expression and more prolonged activation of the Jak-STAT signalling pathway. The findings from our comparative analysis of IFN-α and IFN-λ in HCV-infected and noninfected cells support the clinical use of IFN-λ as a potential alternative to IFN-α in the treatment of chronic hepatitis C.
authors.affiliation: Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA. kohlia@niaid.nih.gov
authors.forename: A
authors.initials: A
authors.lastname: Kohli
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.forename: R S
authors.initials: RS
authors.lastname: Russell
authors.forename: R P
authors.initials: RP
authors.lastname: Donnelly
authors.forename: F
authors.initials: F
authors.lastname: Sheikh
authors.forename: A
authors.initials: A
authors.lastname: Sherman
authors.forename: H
authors.initials: H
authors.lastname: Young
authors.forename: T
authors.initials: T
authors.lastname: Imamichi
authors.forename: R A
authors.initials: RA
authors.lastname: Lempicki
authors.forename: H
authors.initials: H
authors.lastname: Masur
authors.forename: S
authors.initials: S
authors.lastname: Kottilil
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D016174:Hepacivirus / Q000145:classification* / Q000235:genetics / Q000254:growth & development* / Q000276:immunology; D022781:Hepatocytes / Q000187:drug effects* / Q000821:virology*; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology*; D007372:Interferons; D007378:Interleukins / Q000276:immunology*; D059467:Transcriptome; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda