Hepatitis C Virus Infection Down - regulates miR - 29 : Effects on Viral Fitness and Hepatic Stellate Cell Activation

Background. Chronic Hepatitis C Virus (HCV) induced liver fibrosis is mediated by upregulation of Transforming Growth Factor (TGF)-beta and subsequent hepatic stellate cell (HSC) activation. MicroRNAs (miRNAs) regulate HCV infection and HSC activation. Methods. TaqMan miRNA profiling identified 12 miRNA families differentially expressed between chronically HCV-infected human livers and uninfected controls. To identify pathways affected by miRNAs, we developed a new algorithm (PACT, Pathway Analysis of Conserved Targets), based on the probability of conserved targeting. Results. This analysis suggested a role for miR-29 during HCV infection. Intriguingly, miR-29 was down-regulated in most HCV-infected patients. miR-29 regulates expression of extracellular matrix (ECM) proteins. In culture, HCV infection down-regulated miR-29 and miR-29 over-expression reduced HCV RNA abundance. miR-29 also appears to play a role in HSCs. Hepatocytes and HSCs contribute similar amounts of miR-29 to bulk liver. Primary HSC activation and TGF-β treatment of immortalized HSCs both down-regulated miR-29. miR-29 over-expression in LX-2 cells decreased proliferation and collagen expression. miR-29 down-regulation by HCV may derepress ECM synthesis during HSC activation. Conclusions. HCV infection down-regulates miR-29 in hepatocytes and may potentiate collagen synthesis by reducing miR-29 levels in activated HSCs. Treatment with miR-29 mimics in vivo might inhibit HCV while reducing fibrosis.