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‐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 o...

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Bibliographic Details
Published in:Journal of viral hepatitis 2012-12, Vol.19 (12), p.843-853
Main Authors: Kohli, A., Zhang, X., Yang, J., Russell, R. S., Donnelly, R. P., Sheikh, F., Sherman, A., Young, H., Imamichi, T., Lempicki, R. A., Masur, H., Kottilil, S.
Format: Article
Language:English
Subjects:
Antiviral Agents - pharmacology
Cell Line
Hepacivirus - classification
Hepacivirus - genetics
Hepacivirus - growth & development
Hepacivirus - immunology
hepatitis C
Hepatitis C virus
Hepatocytes - drug effects
Hepatocytes - virology
Huh7.5 cells
Humans
IFN-alpha
IL28B
Interferon-alpha - immunology
Interferons
Interleukins - immunology
JFH-1
Transcriptome
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Summary: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.
ISSN:1352-0504
1365-2893
DOI:10.1111/j.1365-2893.2012.01610.x