IFN-lambda 4 potently blocks IFN-alpha signalling by ISG15 and USP18 in hepatitis C virus infection

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Genetic polymorphisms in IFNL4 have been shown to predict responses to IFN-alpha-based therapy in hepatitis C virus (HCV)-infected patients. The IFNL4-Delta G genotype, which encodes functional IFN-lambda 4 protein, is associated with a poor treatment response. In the present study, we investigated the induction and biological effects of IFN-lambda 4 in HCV-infected hepatocytes and their association with responsiveness to IFN-alpha. We also studied the effects of direct-acting antiviral (DAA) treatment on IFN-lambda 4 expression and IFN-alpha responsiveness. HCV infection induced IFN-lambda 4 expression at mRNA and protein levels in primary human hepatocytes (PHHs). In hepatoma cells, IFNL4 gene transfection or recombinant IFN-lambda 4 protein treatment robustly increased the protein levels of ISG15 and USP18 in an IFNLR1-dependent manner and potently blocked IFN-alpha signalling. The ISG15/USP18-mediated IFN-alpha unresponsiveness was demonstrated by transfection of siRNAs targeting ISG15 and/or USP18. This potent IFN-lambda 4 effect was related to prolonged ISG expression after IFNL4 gene transfection. DAA treatment of HCV-infected PHHs reduced the expression of IFN-lambda s, including IFN-lambda 4, and restored IFN-alpha responsiveness. These results demonstrate that virus-induced IFN-lambda 4 potently blocks IFN-alpha signalling by inducing high protein levels of ISG15 and USP18. Moreover, the data clearly demonstrate that DAA therapy restores IFN-alpha responsiveness in HCV-infected cells.
Publisher
NATURE PUBLISHING GROUP
Issue Date
2017-06
Language
English
Article Type
Article
Keywords

INTERFERON-STIMULATED GENES; INNATE IMMUNE-RESPONSE; HCV INFECTION; LAMBDA 4; CLEARANCE; CELLS; EXPRESSION; IL28B; ASSOCIATION

Citation

SCIENTIFIC REPORTS, v.7

ISSN
2045-2322
DOI
10.1038/s41598-017-04186-7
URI
http://hdl.handle.net/10203/226674
Appears in Collection
MSE-Journal Papers(저널논문)
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