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IFNL3 (IL28B) favorable genotype escapes hepatitis C virus-induced microRNAs and mRNA decay

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4183367.pdf (2.73 MB)

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2014

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10.1038/ni.2758

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McFarland, A. P., S. M. Horner, A. Jarret, R. C. Joslyn, E. Bindewald, B. A. Shapiro, D. A. Delker, et al. 2014. “IFNL3 (IL28B) favorable genotype escapes hepatitis C virus-induced microRNAs and mRNA decay.” Nature immunology 15 (1): 72-79. doi:10.1038/ni.2758. http://dx.doi.org/10.1038/ni.2758.

Abstract

The IFNL3 (IL28B) gene has received immense attention in the hepatitis C virus (HCV) field as multiple independent genome-wide association studies identified a strong association between polymorphisms near the IFNL3 gene and HCV clearance. However, the mechanism underlying this association has remained elusive. In this study, we report the identification of a functional polymorphism (rs4803217) located in the 3′ untranslated region (3′ UTR) of the IFNL3 mRNA that dictates transcript stability. This polymorphism influences AU-rich element-mediated decay as well as the binding of HCV-induced microRNAs during infection. Together, these pathways mediate robust repression of the unfavorable IFNL3 genotype. These data reveal a novel mechanism by which HCV attenuates the antiviral response and uncover new potential therapeutic targets for HCV treatment.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183367/pdf/

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http://nrs.harvard.edu/urn-3:HUL.InstRepos:13347508

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