Abstract
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.
Highlights
Hepatitis C virus (HCV), a positive-sense, single-stranded RNA virus of the Flaviviridae family, chronically infects approximately 150 million people worldwide (Mohd Hanafiah et al 2013)
We investigated the effects of miR-135a on HCV life cycle and demonstrated that this miRNA modulates HCV genome replication through its actions on several critical antiviral host factors, which have been implicated in HCVmediated liver pathogenesis
To validate the effect of miR-135a on HCV infection identified from the functional genomics screen (Li et al 2017), we performed multiple virological assays using synthetic miR-135a mimic and HCV cell culture system (HCVcc)
Summary
Hepatitis C virus (HCV), a positive-sense, single-stranded RNA virus of the Flaviviridae family, chronically infects approximately 150 million people worldwide (Mohd Hanafiah et al 2013). While highly effective direct-acting antiviral (DAA) regimens have been developed, eradication of the virus does not completely eliminate the increased risk of advanced liver diseases, including fibrosis and HCC (El-Serag et al 2016). HCV depends heavily on host or cellular factors to establish persistent infection and trigger unique hepatic pathological processes (Randall et al 2007; Li et al 2009; Tai et al 2009; Lupberger et al 2011; Reiss et al 2011; Li et al 2014). Cellular microRNAs (miRNAs) represent such host dependencies and play important roles in regulating viral infection and related pathogenesis. MicroRNAs are 22-nucleotide non-coding RNAs that repress target gene expression and manipulate a multitude of pathophysiological processes in cells. miRNAs exert their effects by binding to predominantly the 30 untranslated regions
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