New Findings from Germany, Japan and the United States in the Area of Hepatitis B Virus Described
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Hepatitis Weekly - Aug. 21, 2006
2006 AUG 21 - (NewsRx.com) -- Investigators in Germany, Japan and the United States have published new hepatitis B virus data.
Study 1: A study from Germany has reported on the interferon-inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus (HBV) replication. "Hypermutations in HBV DNA by APOBEC3 cytidine deaminases have been detected in vitro and in vivo, and APOBEC3G (A3G) and A-POBEC3F (A3F) have been shown to inhibit the replication of HBV in vitro, but the presumably low or even absent hepatic expression of these enzymes has raised the question as to their physiological impact on HBV replication. We show that normal human liver expresses the mRNAs of APOBEC3B (A3B), APOBEC3C (A3C), A3F, and A3G," wrote M. Bonvin and colleagues, St. Vincenz Hospital. "In primary human hepatocytes, interferon alpha (IFN-alpha) stimulated the expression of these cytidine deaminases up to 14-fold, and the mRNAs of A3G, A3F, and A3B reached expression levels of 10%, 3%, and 3%, respectively, relative to GAPDH mRNA abundance. "On transfection, the full-length protein A3B(L) inhibited HBV replication in vitro as efficiently as A3G or A3F, whereas the truncated splice variant A3B(S) and A3C had no effect. A3B(L) and A3B(S) were detected predominantly in the nucleus of uninfected cells; however, in HBV-expressing cells both proteins were found also in the cytoplasm and were associated with HBV viral particles, similarly to A3G and A3F. Moreover, A3G, A3F, and A3B(L), but not A3B(S), induced extensive G-to-A hypermutations in a fraction of the replicated HBV genomes," the authors reported. The researchers concluded, "The editing enzymes A3B(L), A3F, and most markedly A3G, which are expressed in liver and up-regulated by IFN-alpha in hepatocytes, are candidates to contribute to the noncytolytic clearance of HBV." Bonvin and colleagues published their study in Hepatology (Interferon-inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication. Hepatology, 2006;43(6):1364-1374). Additional information can be obtained by contacting J. Greeve, St. Vincenz Hospital, Department of Medicine, D-33098 Paderborn, Germany. Study 2: According to a study from Japan, chronic hepatitis B virus (HBV) replication utilizes covalently closed circular DNA (cccDNA). "The lack of small animal models supporting chronic HBV infection impedes the assessment of anti-viral drugs in the whole animal. Although transgenic mice have been used for this purpose, these models are clearly different from natural infection, because HBV is produced from the integrated HBV sequence harbored in all hepatocytes," wrote T. Takehara and colleagues, Osaka University. "Balb/cA nude mice were hydrodynamically injected with a plasmid having 1.5-fold over-length of HBV DNA and analyzed for HBV replication. Hydrodynamically injected mice showed substantial levels of antigenemia and viremia for more than 1 year." The researchers observed, "Covalently closed circular DNA (cccDNA), the template of viral replication in natural infection, was produced in the livers and was critically involved in the long-term HBV production, because disruption of the pol gene of the inoculated DNA resulted in transient expression of HBV genes for less than 2 months. "Administration of the IFN alpha gene transiently suppressed HBV DNA replication, but was not capable of eliminating HBV in this model." "In vivo gene transfer of a plasmid encoding HBV DNA can establish chronic viral replication in mice, which involves, at least in part, new synthesis of the HBV cccDNA episome, thus recapitulating a part of human HBV infection," concluded the authors. Takehara and colleagues published the results of their research in the Journal of Hepatology (Viral covalently closed circular DNA in a non-transgenic mouse model for chronic hepatitis B virus replication. J Hepatol, 2006;44(2):267-274). For additional information, contact N. Hayashi, Osaka University, Graduate School of Medicine, Department of Gastroenterology & Hepatology, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan. Study 3: According to research from the United States, hepatitis B virus (HBV) infection may alter liver function. "Hepatitis B virus X (HBX) is essential for the productive infection of HBV in vivo and has a pleiotropic effect on host cells. We have previously demonstrated that the proteasome complex is a cellular target of HBX, that HBX alters the proteolytic activity of proteasome in vitro, and that inhibition of proteasome leads to enhanced viral replication, suggesting that HBX and proteasome interaction plays a crucial role in the life cycle and pathogenesis of HBV. "In the present study," wrote Z.Y. Hu and colleagues, U.S. National Institute of Diabetes & Digestive & Kidney Diseases, "we tested the effect of HBX on the proteasome activities in vivo in a transgenic mouse model in which HBX expression is developmentally regulated by the mouse major urinary promoter in the liver. "In addition, microarray analysis was performed to examine the effect of HBX expression on the global gene expression profile of the liver. The results showed that the peptidase activities of the proteasome were reduced in the HBX transgenic mouse liver, whereas the activity of another cellular protease was elevated, suggesting a compensatory mechanism in protein degradation." The researchers wrote, "In the microarray analysis, diverse genes were altered in the HBX mouse livers and the number of genes with significant changes increased progressively with age. Functional clustering showed that a number of genes involved in transcription and cell growth were significantly affected in the HBX mice, possibly accounting for the observed pleiotropic effect of HBX." "In particular, insulin-like growth factor-binding protein I was down-regulated in the HBX mouse liver. The down-regulation was similarly observed during acute woodchuck hepatitis virus infection. "Other changes including up-regulation of proteolysis-related genes may also contribute to the profound alterations of liver functions in HBV infection," the authors concluded. Hu and colleagues published their study in the Journal of Virology (Altered proteolysis and global gene expression in hepatitis B virus X transgenic mouse liver. J Virol, 2006;80(3):1405-1413). For additional information, contact T.J. Liang, U.S. National Institute of Diabetes & Digestive Kidney Diseases, Liver Diseases Branch, U.S. National Institutes of Health, Bldg 10, Rm 9B16, Bethesda, MD 20892, USA. This article was prepared by Hepatitis Weekly editors from staff and other reports.
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发表于 2006-8-28 02:45
