New insight in the pathobiology of hepatitis B virus infection
ABSTRACT Chronic hepatitis B virus (HBV) infection remains a major health burden and the main risk factor for the development of hepatocellular carcinoma worldwide. However, HBV is not directly cytopathic and liver injury appears to be mostly caused by repeated attempts of the host's immune responses to control the infection. Recent studies have shown that the unique replication strategy adopted by HBV enables it to survive within the infected hepatocyte while complex virus-host interplays ensure the virus is able to fulfil its replication requirements yet is still able to evade important host antiviral innate immune responses. Clearer understanding of the host and viral mechanisms affecting HBV replication and persistence is necessary to design more effective therapeutic strategies aimed at improving the management of patients with chronic HBV infection to eventually achieve viral eradication. This article focuses on summarising the current knowledge of factors influencing the course of HBV infection, giving emphasis on the use of novel assays and quantitative serological and intrahepatic biomarkers as tools for predicting treatment response and disease progression.
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ABSTRACT: The major histocompatibility complex (MHC)-containing genes are among the most polymorphic in vertebrates. MHC genes code for proteins that are critical in the immune system response. In this study, the polymorphism of the second exon of the MHC class II DRB gene was characterized in the Eastern woodchuck (Marmota monax). Woodchucks chronically infected with the woodchuck hepatitis virus (WHV) represent the best available animal model for the study of chronic hepatitis B infection in humans. In the genotyped animals we found fifteen alleles, which were expressed in two independent loci and that were named DRB1A and DRB1B in this work. The 15 alleles investigated showed an elevated divergence. A significant excess of non-synonymous substitutions was detected, which could indicate that a historical positive selection is acting in the woodchuck DRB1 genes. This hypothesis was confirmed in our study by the high variability in or near the antigen binding sites (ABS) and by the results obtained in sequence variability analyses. This analysis identified the presence of a microsatellite sequence that is located at the start of the second intron, which could further allow the development of a fast and cheap semiautomatic sequencing method.Molecular Immunology 10/2014; 63(2). DOI:10.1016/j.molimm.2014.10.011 · 3.00 Impact Factor
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ABSTRACT: Hepatitis B virus (HBV) poses a threat to global public health mainly because of complications of HBV-related chronic liver disease. HBV exhibits a narrow host range, replicating primarily in hepatocytes by a still poorly understood mechanism. For the generation of progeny virions, HBV depends on interactions with specific host factors through its life cycle. Revealing and characterizing these interactions are keys to identifying novel antiviral targets, and to developing specific treatment strategies for HBV patients. In this review, recent insights into the HBV-host interactions, especially on virus entry, intracellular trafficking, genome transcription and replication, budding and release, and even cellular restriction factors were reviewed. J. Med. Virol. © 2014 Wiley Periodicals, Inc.Journal of Medical Virology 06/2014; 86(6):925-32. DOI:10.1002/jmv.23916 · 2.22 Impact Factor
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ABSTRACT: The infection of hepatitis B virus (HBV) is closely associated with the development of hepatocellular carcinoma (HCC), in which HBV X protein (HBx) plays crucial roles. MicroRNAs are involved in diverse biologic functions and in carcinogenesis by regulating gene expression. In the present study, we aim to investigate the underlying mechanism by which HBx enhances hepatocarcinogenesis. We found that miR-205 was downregulated in 33 clinical HCC tissues in comparison with adjacent noncancerous hepatic tissues. The expression levels of miR-205 were inversely correlated with those of HBx in abovementioned tissues. Then, we demonstrated that HBx was able to suppress miR-205 expression in hepatoma and liver cells. We validated that miR-205 directly targeted HBx mRNA. Ectopic expression of miR-205 downregulated HBx, whereas depletion of endogenous miR-205 upregulated HBx in hepatoma cells. Notably, our data revealed that HBx downregulated miR-205 through inducing hypermethylation of miR-205 promoter in the cells. In terms of function, the forced miR-205 expression remarkably inhibited the HBx-enhanced proliferation of hepatoma cells in vitro and in vivo, suggesting that miR-205 is a potential tumor-suppressive gene in HCC. HBx-transgenic mice showed that miR-205 was downregulated in the liver. Importantly, HBx was able to abrogate the effect of miR-205 on tumor suppression in carcinogenesis. Therefore, we conclude that HBx is able to inhibit tumor suppressor miR-205 to enhance hepatocarcinogenesis through inducing hypermethylation of miR-205 promoter during their interaction. Therapeutically, miR-205 may be useful in the treatment of HCC.Neoplasia (New York, N.Y.) 11/2013; 15(11):1282-91. DOI:10.1593/neo.131362 · 5.40 Impact Factor