MicroRNA-135a Modulates Hepatitis C Virus Genome Replication through Downregulation of Host Antiviral Factors

Cellular microRNAs (miRNAs) have been shown to modulate HCV infection via directly acting on the viral genome or indirectly through targeting the virus-associated host factors. Recently we generated a comprehensive map of HCV–miRNA interactions through genome-wide miRNA functional screens and transc...

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Bibliographic Details
Published in:Virologica Sinica 2019-04, Vol.34 (2), p.197-210
Main Authors: Sodroski, Catherine, Lowey, Brianna, Hertz, Laura, Jake Liang, T., Li, Qisheng
Format: Article
Language:English
Subjects:
Biochemistry
Bioinformatics
Biomedical and Life Sciences
Biomedicine
Chemokines
CXCL12 protein
Genomes
Hepatitis C
Hepatocytes
Infections
Life cycles
Liver
Malignancy
Medical Microbiology
Microbial Genetics and Genomics
Microbiology
miRNA
MyD88 protein
Oncology
Protein-serine/threonine kinase
Replication
Research Article
Virology
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Summary:Cellular microRNAs (miRNAs) have been shown to modulate HCV infection via directly acting on the viral genome or indirectly through targeting the virus-associated host factors. Recently we generated a comprehensive map of HCV–miRNA interactions through genome-wide miRNA functional screens and transcriptomics analyses. Many previously unappreciated cellular miRNAs were identified to be involved in HCV infection, including miR-135a, a human cancer-related miRNA. In the present study, we investigated the role of miR-135a in regulating HCV life cycle and showed that it preferentially enhances viral genome replication. Bioinformatics-based integrative analyses and subsequent functional assays revealed three antiviral host factors, including receptor interacting serine/threonine kinase 2 (RIPK2), myeloid differentiation primary response 88 (MYD88), and C-X-C motif chemokine ligand 12 (CXCL12), as bona fide targets of miR-135a. These genes have been shown to inhibit HCV infection at the RNA replication stage. Our data demonstrated that repression of key host restriction factors mediated the proviral effect of miR-135a on HCV propagation. In addition, miR-135a hepatic abundance is upregulated by HCV infection in both cultured hepatocytes and human liver, likely mediating a more favorable environment for viral replication and possibly contributing to HCV-induced liver malignancy. These results provide novel insights into HCV–host interactions and unveil molecular pathways linking miRNA biology to HCV pathogenesis.
ISSN:1674-0769
1995-820X
DOI:10.1007/s12250-018-0055-9