期刊
NATURE IMMUNOLOGY
卷 15, 期 1, 页码 72-79出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.2758
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- Department of Immunology of the University of Washington
- US National Institutes of Health [AI060389, AI88778, CA148068]
- Frederick National Laboratory for Cancer Research of the US National Institutes of Health [HHSN261200800001E]
- Intramural Research Program of the US National Institutes of Health, Frederick National Laboratory for Cancer Research and the National Cancer Institute, Center for Cancer Research
IFNL3, which encodes interferon-lambda 3 (IFN-lambda 3), has received considerable attention in the hepatitis C virus (HCV) field, as many independent genome-wide association studies have identified a strong association between polymorphisms near IFNL3 and clearance of HCV. However, the mechanism underlying this association has remained elusive. In this study, we report the identification of a functional polymorphism (rs4803217) in the 3' untranslated region (UTR) of IFNL3 mRNA that dictated transcript stability. We found that this polymorphism influenced AU-rich element (ARE)-mediated decay (AMD) of IFNL3 mRNA, as well as the binding of HCV-induced microRNAs during infection. Together these pathways mediated robust repression of the unfavorable IFNL3 polymorphism. Our data reveal a previously unknown mechanism by which HCV attenuates the antiviral response and indicate new potential therapeutic targets for HCV treatment.
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