Loss of microRNA 122 expression in patients with hepatitis B enhances hepatitis B virus replication through cyclin G(1) -modulated P53 activity.
ABSTRACT Hepatitis B virus (HBV) causes chronic infection in about 350 million people worldwide. Given the important role of the most abundant liver-specific microRNA, miR-122, in hepatic function and liver pathology, here we investigated the potential role and mechanism of miR-122 in regulating HBV replication. We found that miR-122 expression in liver was significantly down-regulated in patients with HBV infection compared with healthy controls, and the miR-122 levels were negatively correlated with intrahepatic viral load and hepatic necroinflammation. The depletion of endogenous miR-122 by its antisense inhibitor led to enhanced HBV replication, whereas overexpression of miR-122 by transfection of mimic or its expression vector inhibited viral production. We next identified cyclin G(1) as an miR-122 target from multiple candidate target genes that are involved in the regulation of HBV replication. Overexpression and knockdown studies both showed that cyclin G(1) regulated viral replication in HBV transfected cells. We also observed that cyclin G(1) expression was up-regulated in HBV-infected patients, and cyclin G(1) levels were inversely associated with miR-122 expression in liver tissues. Using coimmunoprecipitation, a luciferase reporter system, and electrophoretic mobility shift assay, we further demonstrated that cyclin G(1) specifically interacted with p53, and this interaction blocked the specific binding of p53 to HBV enhancer elements and simultaneously abrogated p53-mediated inhibition of HBV transcription. Finally, we show that miR-122 suppressed HBV replication in p53 wildtype cells but not in null isogenic cells. CONCLUSION: miR-122 down-regulates its target cyclin G(1) , and thus interrupts the interaction between cyclin G(1) and p53 and abrogates p53-mediated inhibition of HBV replication. Our work shows that miR-122 down-regulation induced by HBV infection can impact HBV replication and possibly contribute to viral persistence and carcinogenesis.
- SourceAvailable from: Mala K Maini[show abstract] [hide abstract]
ABSTRACT: Hepatitis B virus (HBV) causes chronic infection in more than 350 million people worldwide. It replicates in hepatocytes but is non-cytopathic; liver damage is thought to be immune mediated. Here, we investigated the role of innate immune responses in mediating liver damage in patients with chronic HBV infection. Longitudinal analysis revealed a temporal correlation between flares of liver inflammation and fluctuations in interleukin (IL)-8, interferon (IFN)-α, and natural killer (NK) cell expression of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) directly ex vivo. A cross-sectional study confirmed these findings in patients with HBV-related liver inflammation compared with healthy carriers. Activated, TRAIL-expressing NK cells were further enriched in the liver of patients with chronic HBV infection, while their hepatocytes expressed increased levels of a TRAIL death–inducing receptor. IFN-α concentrations found in patients were capable of activating NK cells to induce TRAIL-mediated hepatocyte apoptosis in vitro. The pathogenic potential of this pathway could be further enhanced by the ability of the IFN-α/IL-8 combination to dysregulate the balance of death-inducing and regulatory TRAIL receptors expressed on hepatocytes. We conclude that NK cells may contribute to liver inflammation by TRAIL-mediated death of hepatocytes and demonstrate that this non-antigen–specific mechanism can be switched on by cytokines produced during active HBV infection.Journal of Experimental Medicine 03/2007; 204(3):667-680. · 13.21 Impact Factor
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ABSTRACT: A decade ago, standard therapy against chronic hepatitis B virus infections only consisted of lamivudine or IFN-alpha. Treatment with lamivudine and IFN has been compounded by, respectively, the emergence of drug-resistant virus strains and the appearance of serious side effects. In the last 10 years, hepatitis B treatment has made much progress. Several treatments are now licensed for the treatment of patients with chronic hepatitis B and others are under development. Here, we provide an overview of the potential and mode of action of anti-HBV agents that are currently available, and/or may become available in the near future. Foremost among these newer compounds are adefovir dipivoxil, entecavir and telbivudine.Reviews in Medical Virology 01/2008; 18(1):19-34. · 7.62 Impact Factor
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ABSTRACT: Several microRNAs (miRNAs), including liver-specific miR-122, have been implicated in the control of hepatitis C virus (HCV) RNA replication and its response to interferon (IFN) in human hepatoma cells. Our analysis of liver biopsies from subjects with chronic hepatitis C (CHC) undergoing IFN therapy revealed no correlation of miR-122 expression with viral load and markedly decreased pretreatment miR-122 levels in subjects who had no virological response during later IFN therapy; other investigated miRNAs showed only limited changes. These data have implications for the prospect of targeting miRNAs for CHC therapy.Nature medicine 02/2009; 15(1):31-3. · 27.14 Impact Factor