Working Toward Effective Treatment for Hepatitis B
Despite the existence of safe and efficient vaccines, hepatitis B virus is one of the most deadly viruses in the world, killing about 1.2 million people every year. To better understand the direct liver disease induced by hepatitis B virus, recent research brought us one step closer to an effective treatment for HBV infection.
This dreadful HBV is small in size. The genome of this virus is a partial double stranded circle. When made fully double stranded, this genome carries about 3000 base pairs, compared to 200 kilo base pairs of the genome of the smallpox virus. These 3000 base pairs encode an envelope protein, a core protein, a polymerase essential for virus replication and a very special X protein, named such because its function was not known when it was named.
Dr Dina Kremsdorf of INSERM (Institut National de la Sante et de la Recherche Medicale) and her associates have been trying to elucidate some of the functions of this X protein involved in liver pathogenesis during HBV infection. They first established a system in which the gene for X protein is permanently incorporated into mouse genome. With transgenic mice expressing X protein, they could research many different impacts of the protein on the host.
Their first exciting discovery was the inhibition of liver cell proliferation by X protein. This discovery raised a novel mechanism on how HBV causes liver diseases. Recently, the team further investigated how X protein inhibited the liver cell proliferation. In a new report,* Dr Kremsdorf et al looked at the expression level of 5376 genes in the transgenic mice.
This seemingly daunting work was made possible when Dr Kremsdorf took advantage of the DNA microarray technique, which allowed simultaneous analysis of all 5376 genes. Their results indicated a decreased activity of those genes required for gene transcription and cholesterol metabolic pathway. This not only confirmed the previous observation, but showed how the molecular mechanism of how Hepatitis B virus X protein inhibits the liver regeneration.
These new discoveries should improve our knowledge of the implication of the viral proteins in the pathogenesis of HBV infection. This should allow participation in the design of new and more effective treatments for HBV patients.World J Gastroenterol. 2008 Jan 28;14(4):574-81.
INSERM (Institut National de la Sante et de la Recherche Medicale) U845, CHU Necker; 156 rue de Vaugirard, Paris 75015, France. firstname.lastname@example.org.
AIM: To analyze the modulation of gene expression profile associated with inhibition of liver regeneration in hepatitis B X (HBx)-expressing transgenic mice. METHODS: Microarray technology was performed on liver tissue obtained from 4 control (LacZ) and 4 transgenic mice (HBx-LacZ), 48 h after partial hepatectomy. The significance of the normalized log-ratios was assessed for each gene, using robust t-tests under an empirical Bayes approach. Microarray hybridization data was verified on selected genes by quantitative PCR. RESULTS: The comparison of gene expression patterns showed a consistent modulation of the expression of 26 genes, most of which are implicated in liver regeneration. Up-regulated genes included DNA repair proteins (Rad-52, MSH6) and transmembrane proteins (syndecan 4, tetraspanin), while down-regulated genes were connected to the regulation of transcription (histone deacetylase, Zfp90, MyoD1) and were involved in the cholesterol metabolic pathway and isoprenoid biosynthesis (farnesyl diphosphate synthase, Cyp7b1, geranylgeranyl diphosphate synthase, SAA3). CONCLUSION: Our results provide a novel insight into the biological activities of HBx, implicated in the inhibition of liver regeneration