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

• 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
• ISSN: 1674-0769; 1995-820X
• DOI: 10.1007/s12250-018-0055-9

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.