IFN-λ4 desensitizes the response to IFN-α treatment in chronic hepatitis C through long-term induction of USP18.
The recently discovered interferon lambda 4 (IFN-λ4) 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.
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, PR China.
Weiguo
W
Fan
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, PR China.
Shiqi
S
Xie
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, PR China.
Xinhao
X
Zhao
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, PR China.|School of Life Sciences and Technology, Shanghai Tech University, Shanghai 200031, PR China.
Nan
N
Li
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, PR China.
Chong
C
Chang
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, PR China.
Li
L
Li
Hepatology Section, First Hospital, University of Jilin, Changchun 130021, Jilin, PR China.
Ge
G
Yu
Hepatology Section, First Hospital, University of Jilin, Changchun 130021, Jilin, PR China.
Xiumei
X
Chi
Hepatology Section, First Hospital, University of Jilin, Changchun 130021, Jilin, PR China.
Yu
Y
Pan
Hepatology Section, First Hospital, University of Jilin, Changchun 130021, Jilin, PR China.
Junqi
J
Niu
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, PR China.
Jin
J
Zhong
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai, PR China.|Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, PR China.
Bing
B
Sun
D044466:Asian People; D010450:Endopeptidases / Q000378:metabolism*; D016174:Hepacivirus / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D007378:Interleukins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D043222:Ubiquitin Thiolesterase; D000095022:Interferon Lambda
D010450:Endopeptidases; D016898:Interferon-alpha; D007378:Interleukins; D043222:Ubiquitin Thiolesterase; C579163:IFNL4 protein, human; D000095022:Interferon Lambda; C485560:USP18 protein, human