Long-term expression of the hepatitis B virus core-e- and X-proteins does not cause pathologic changes in transgenic mice

• Published in: Journal of hepatology Vol. 26; no. 1; pp. 119 - 130
• Main Authors: Reifenberg, Kurt, Löhler, Jürgen, Pudollek, Hans-Peter, Schmitteckert, Eva, Spindler, Gabriele, Köck, Josef, Schlicht, Hans-Jürgen
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier B.V 1997; Elsevier
• Subjects: Animals; Biological and medical sciences; Core-gene; Enhancer Elements, Genetic; Gene Expression Regulation, Viral - physiology; Hepatitis B Antigens - genetics; Hepatitis B Antigens - immunology; Hepatitis B Core Antigens - genetics; Hepatitis B Core Antigens - immunology; Hepatitis B e Antigens - genetics; Hepatitis B e Antigens - immunology; Hepatitis B virus; Human viral diseases; Humans; Infectious diseases; Islets of Langerhans - metabolism; Liver; Medical sciences; Mice; Mice, Transgenic; Organ Specificity; Pathogenesis; Promoter Regions, Genetic; Transgenic mice; Viral diseases; Viral hepatitis; X-gene; Hepatitis B virus; Pathogenesis; Core-gene; Liver; X-gene; Transgenic mice; Measurement; Tumor promotor; Hepatic disease; Hepatocellular carcinoma; Viral hepatitis B; Messenger RNA; Gene; Hepadnaviridae; Malignant transformation; Complication; Rodentia; Malignant tumor; Experimental study; Gene expression; Infection; Virus; Vertebrata; Chronic; Mammalia; Mouse; Viral disease; Animal; Risk factor; Digestive diseases
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/S0168-8278(97)80018-9

Background/Aims: 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.
Conclusion: 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.