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Volume 97, Issue 9

IFN-4 desensitizes the response to IFN- treatment in chronic hepatitis C through long-term induction of USP18 Free

Abstract

The recently discovered interferon lambda 4 (IFN-4) is a new member of the human type III interferons which could induce a strong antiviral effect through the JAK–STAT cascade. However, hepatitis C virus (HCV) patients who are capable of expressing IFN-λ4 usually have poor response to IFN-α treatment, and the mechanism behind this paradox remains unknown. Here, we reported that IFN-λ4 desensitized IFN-α-stimulated JAK–STAT signalling. Microarray analysis revealed that IFN-λ4 could induce ubiquitin specific peptidase 18 (USP18), a known inhibitor of the type I IFN signalling pathway, in a more sustained pattern compared with type I interferon induction. Moreover, only HCV genotype 1b but not 2a replicon cells pretreated with IFN-λ4 had an attenuated response to type I IFN treatment, which might be due to the different level of USP18 expression. Consistently, knockdown of USP18 in HCV genotype 1b-containing replicon cells reversed the resistance induced by IFN-λ4 and promoted viral clearance. Finally, IFN-λ4 is also strongly associated with the poor response to IFN-α in a Chinese HCV genotype 1b cohort. In conclusion, these data indicate that IFN-λ4 attenuates the response of HCV genotype 1b to IFN-α therapy and inhibits the JAK–STAT signalling pathway by inducing USP18 expression.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): Hepatitis C virus , immune regulation , Interferon , Therapy and USP18
© 2016 The Authors
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2016-09-01
2024-04-19
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IFN-λ4 desensitizes the response to IFN-α treatment in chronic hepatitis C through long-term induction of USP18
J. Gen. Virol. 97, 2210 (2016); https://doi.org/10.1099/jgv.0.000522
/content/journal/jgv/10.1099/jgv.0.000522
/content/journal/jgv/10.1099/jgv.0.000522
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