title: Long-term expression of the hepatitis B virus core-e- and X-proteins does not cause pathologic changes in transgenic mice.
abstract: OBJECTIVE
  Chronic infections with the human hepatitis B virus can result in liver cirrhosis and primary hepatocellular carcinoma. The reasons for these long-term effects are unclear. The aim of this study was to generate transgenic mice expressing the HBV X- and c/e-gene under authentic and foreign promoter control and to test whether the respective gene products can cause pathologic effects during the lifespan of a mouse. Moreover, the temporal and the tissue-specific regulation of the crucial HBV c/e-gene promoter was analyzed.
  
  
  METHODS
  Eight transgenic mouse lines were generated. Four contained the c/e- and X-gene and two contained only the X-gene under authentic promoter control. Two lines expressed only the X-gene under control of the rat insulin promoter/enhancer. Gene expression was tested by protein and mRNA analyses. During an observation period of 2 years, mice were sacrificed and organs subjected to histologic examination. Mice expressing the X-gene in pancreatic beta cells were tested for the development of diabetes.
  
  
  RESULTS
  In the liver, slight histopathologic alterations but no neoplastic changes could be observed in mice expressing the X-gene. Activity of the c/e-gene promoter/enhancer was age dependent and was not restricted to hepatocytes.
  
  
  CONCLUSIONS
  No evidence was obtained that long-term expression of the HBV c/e- and X-gene products can cause neoplasia during the lifespan of a mouse.
authors.affiliation: Laboratory Animal Research Unit, University of Ulm, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Reifenberg
authors.forename: J
authors.initials: J
authors.lastname: Löhler
authors.forename: H P
authors.initials: HP
authors.lastname: Pudollek
authors.forename: E
authors.initials: E
authors.lastname: Schmitteckert
authors.forename: G
authors.initials: G
authors.lastname: Spindler
authors.forename: J
authors.initials: J
authors.lastname: Köck
authors.forename: H J
authors.initials: HJ
authors.lastname: Schlicht
mesh_terms: D000818:Animals; D004742:Enhancer Elements, Genetic; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D006511:Hepatitis B Antigens / Q000235:genetics / Q000276:immunology*; D006512:Hepatitis B Core Antigens / Q000235:genetics / Q000276:immunology*; D006513:Hepatitis B e Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D011401:Promoter Regions, Genetic
chemical_list: D006511:Hepatitis B Antigens; D006512:Hepatitis B Core Antigens; D006513:Hepatitis B e Antigens