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

• 来源期刊: 中国病毒学
• 年，卷（期）: 2019,（2）
• 页码范围: 197-210
• 页数: 14页
• 语种: 英文

摘要

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.