Cellular microRNA networks regulate host dependency of hepatitis C virus infection

Qisheng Li (), Brianna Lowey, Catherine Sodroski, Siddharth Krishnamurthy, Hawwa Alao, Helen Cha, Stephan Chiu, Ramy El-Diwany, Marc G. Ghany and T. Jake Liang ()
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Qisheng Li: National Institutes of Health
Brianna Lowey: National Institutes of Health
Catherine Sodroski: National Institutes of Health
Siddharth Krishnamurthy: National Institutes of Health
Hawwa Alao: National Institutes of Health
Helen Cha: National Institutes of Health
Stephan Chiu: National Institutes of Health
Ramy El-Diwany: National Institutes of Health
Marc G. Ghany: National Institutes of Health
T. Jake Liang: National Institutes of Health

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract Cellular microRNAs (miRNAs) have been shown to regulate hepatitis C virus (HCV) replication, yet a systematic interrogation of the repertoire of miRNAs impacting HCV life cycle is lacking. Here we apply integrative functional genomics strategies to elucidate global HCV–miRNA interactions. Through genome-wide miRNA mimic and hairpin inhibitor phenotypic screens, and miRNA–mRNA transcriptomics analyses, we identify three proviral and nine antiviral miRNAs that interact with HCV. These miRNAs are functionally linked to particular steps of HCV life cycle and related viral host dependencies. Further mechanistic studies demonstrate that miR-25, let-7, and miR-130 families repress essential HCV co-factors, thus restricting viral infection at multiple stages. HCV subverts the antiviral actions of these miRNAs by dampening their expression in cell culture models and HCV-infected human livers. This comprehensive HCV–miRNA interaction map provides fundamental insights into HCV-mediated pathogenesis and unveils molecular pathways linking RNA biology to viral infections.

Date: 2017
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DOI: 10.1038/s41467-017-01954-x

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