Research conducted in Germany and the South Korea has updated our knowledge about hepatitis B virus

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Research conducted in Germany and the South Korea has updated our knowledge about hepatitis B virus

Gene Therapy Weekly - Jan. 04, 2007

2007 JAN 4 - (NewsRx.com) -- Reports outline hepatitis B virus research from Germany and the South Korea.

Study 1: According to recently published research from Germany, interferon (IFN) gamma expression inhibits large hepatitis B virus (HBV) surface protein (LHB) storage disease and ground glass hepatocyte appearance, but it exacerbates inflammation and apoptosis in HBV surface protein-accumulating transgenic livers.

"IFN gamma controls hepatitis B virus replication. As systemic application may cause severe adverse effects, approaches of liver-directed IFN gamma gene therapy may represent an attractive alternative for treatment of chronic viral hepatitis B and thus needs testing in vivo in suitable animal models.

"We therefore crossbred Alb-1HBV transgenic mice overexpressing the LHBs in their livers and developing LHBs storage disease and ground glass hepatocyte appearance with SAP-IFN gamma transgenic animals previously shown to exhibit constitutive hepatic IFN gamma expression, and analyzed the resulting double-transgenic offspring," wrote K. Reifenberg and colleagues, University of Mainz.

"We found that IFN gamma coexpression significantly reduced hepatic LHBs expression and thereby inhibited hepatocellular LHBs storage disease and ground glass hepatocyte appearance.

"The beneficial antiviral IFN gamma effects as observed in Alb1-HBV SAP-IFN gamma double-transgenic livers were associated with significantly elevated serum ALT concentrations, massive mononuclear cell infiltrates, appearance of Councilman bodies, and increased alpha-PARP (poly(ADP-ribose) polymerase cleavage)," reported the authors.

They concluded, "Exacerbation of hepatic necroinflammation and increased hepatocellular apoptosis rate in IFN gamma-expressing Alb1-HBV transgenic livers suggest that special precautions be taken for testing approaches of liver-specific IFN gamma expression in patients with chronic hepatitis B."

Reifenberg and colleagues published their study in Liver International (IFN gamma expression inhibits LHBs storage disease and ground glass hepatocyte appearance, but exacerbates inflammation and apoptosis in HBV surface protein-accumulating transgenic livers. Liver Int, 2006;26(8):986-993).

For additional information, contact K. Reifenberg, University of Mainz, Central Laboratory Animal Facility, Obere Zahlbacherstr 67, Hochhaus Augustuspl, D-55131 Mainz, Germany.

Study 2: A study from South Korea has reported on the negative regulation of hepatitis B virus (HBV) replication by cellular Hsp40/DnaJ proteins through destabilization of viral core and X proteins.

"The hepatitis B virus core protein consists of an amino-terminal capsid-assembly domain and a carboxyl-terminal RNA-binding domain. By using the yeast two-hybrid system, two Hsp40/DnaJ chaperone-family proteins, Hdj1 and hTid1, that interact with the carboxyl-terminal region (aa 94-185) of the core protein were identified," wrote S.Y. Sohn and colleagues, Korea University.

"Hdj1 is the prototype member of the family and hTid1 is the human homologue of the Drosophila tumour-suppressor protein Tid56. Binding of the viral core protein with the Hsp40 proteins was confirmed by affinity chromatography and immunoprecipitation of transiently expressed proteins. Moreover, in a sucrose gradient, the precursor form of hTid1 co-sedimented with capsid-like particles composed of the full-length core protein.

"Unlike the general perception of the role of the cellular chaperone proteins in assisting viral protein folding and thus enhancing virus replication, ectopic expression of Hdj1 and hTid1 suppressed replication of HBV in transfected human hepatoma cells," reported the authors.

"Conversely, RNA interference-mediated knock-down of hTid1 resulted in increased HBV replication. It was found that both Hsp40 proteins specifically accelerated degradation of the viral core and HBx proteins," the scientists added.

The researchers concluded, "Our results suggest that the cellular chaperones, through destabilization of viral proteins, exert inhibitory functions on virus replication and hence may play suppressive roles in hepatocellular carcinoma."

Sohn and colleagues published their study in the Journal of General Virology (Negative regulation of hepatitis B virus replication by cellular Hsp40/DnaJ proteins through destabilization of viral core and X proteins. J Gen Virol, 2006;87(Part 7):1883-1891).

For more information, contact B.Y. Ahn, Korea University, School of Life Science & Biotechnology, Anamdong 5-1, Seoul 136701, South Korea.

Study 3: According to a study from South Korea, hepatitis B virus (HBV) replication is efficiently inhibited by small interfering RNAs (siRNAs) targeted to the viral X gene in mice.

"HBV, as a major cause of acute and chronic hepatitis in humans, contains a partial double-stranded circular DNA genome of 3.2 kb that is transcribed into the 3.5-, 2.4-, 2.1-, and 0.7-kb viral transcripts by the host RNA polymerase II. The HBV X (HBx) gene is consistently expressed in all four HBV viral mRNAs and is thus an ideal target for developing viral inhibitors via a gene therapeutic approach.

"In this study, we show that two HBx-specific small interfering RNAs (siRNA), HBx1 and HBx3, significantly decrease both viral RNA and protein levels, and completely block replication in cultured cells co-transfected with a siRNA expression plasmid and an HBV replication-competent vector," wrote D. Shin and colleagues, Mogam Biotechnology Research Institute.

"To further confirm these antiviral activities of selected siRNAs in small animals, we established acute and chronic HBV mouse models by hydrodynamic injection of this plasmid containing the full-length HBV genome. Selected HBx-specific siRNAs also induced a significant antiviral effect in living animals," the authors wrote.

The investigators concluded, "Our findings should facilitate the development of an alternative therapeutic agent against HBV infection, particularly HBV-derived hepatocellular carcinoma (HCC) in which HBx has been known as one of the major pathological factors."

Shin and colleagues published the results of their research in Virus Research (Efficient inhibition of hepatitis B virus replication by small interfering RNAs targeted to the viral X gene in mice. Virus Res, 2006;119(2):146-153).

For additional information, contact M. Park, Mogam Biotechnology Research Institute, Immunology & Virology Group, 341 Pojungri, Yongin 449913, Kyonggi, South Korea.

Keywords: Kyonggi, South Korea, Chronic Infections, Genomics, Hepatitis B Virus, Hepatocellular Carcinoma, Hydrodynamic Injection, Viral Replication, RNA Interference, Small Interfering RNA.

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