Molecular Mechanism Of Hepatitis B And C Virus Gene Expression And Replication Modulated By MicroRNA

Regulated gene expression and progeny production are essential for persistent and chronic infection by human pathogens, such as hepatitis B virus (HBV), which affects>400million people worldwide and is a major cause of liver disease. In this study, we provide the first direct evidence that a liver-specific microRNA, miR-122, binds to a highly conserved HBV pregenomic RNA sequence via base-pairing interactions and inhibits HBV gene expression and replication. The miR-122target sequence is located at the coding region of the mRNA for the viral polymerase and the3’untranslated region of the mRNA for the core protein. In cultured cells, HBV gene expression and replication reduces with increased expression of miR-122, and the expression of miR-122decreases in the presence of HBV infection and replication. Furthermore, analyses of clinical samples demonstrated an inverse linear correlation in vivo between the miR-122level and the viral loads in the peripheral blood mononuclear cells of HBV-positive patients. Our results suggest that miR-122may down-regulate HBV replication by binding to the viral target sequence, contributing to the persistent/chronic infection of HBV, and that HBV-induced modulation of miR-122expression may represent a mechanism to facilitate viral pathogenesis.Upon recognition of viral components by pattern recognition receptors, including Toll-like receptors (TLRs) and retinoic acid-inducible gene Ⅰ (RIG-Ⅰ)-like helicases, cells are activated to produce type Ⅰ interferon (IFN) and proinflammatory cytokines. These pathways are tightly regulated by the host to prevent an inappropriate cellular response, but viruses can modulate these pathways to proliferate and spread. Hepatitis C virus (HCV) infection induces a wide range of chronic liver injuries; nevertheless, the mechanism through how HCV evades the immune surveillances system remains obscure. Recently, identification of negative regulators for cytoplasmic RNA-mediated antiviral signaling attracts much attention. In the present study, we found that HCV infection of human hepatocytes upregulated microRNA21(miR-21), which in turn suppressed HCV-triggered type Ⅰ IFN production, thus promoting HCV replication. Furthermore, we demonstrated that miR-21targets two important factors in the TLR signaling pathway, myeloid differentiation factor88(MYD88) and interleukin-1receptor-associated kinase1(IRAK1), which are involved in HCV-induced type Ⅰ IFN production. Taken together, our results indicate that miR-21is upregulated during HCV infection and negatively regulates IFN-a signaling through MYD88and IRAK1and may be a potential therapeutic target for antiviral intervention.