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Journal of Virology, March 2000, p. 2193-2202, Vol. 74, No. 5
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The Enhancer I Core Region Contributes to the Replication Level of Hepatitis B Virus In Vivo and In Vitrodagger

C.-Thomas Bock, Nisar P. Malek, Hans L. Tillmann, Michael P. Manns, and Christian Trautwein*

Department of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, D-30625 Hannover, Germany

Received 6 August 1999/Accepted 29 November 1999

Chronic hepatitis B virus (HBV) infection can lead to liver cirrhosis and hepatocellular carcinoma. Long-term interaction of the immune system with the virus results in the selection of escape mutants and viral persistence. In this work we characterize mutations in the enhancer I region isolated prior to liver transplantation from the HBV genomes of 10 patients with chronic HBV infection. The HBV-genomes were sequenced, and the enhancer I region was cloned into luciferase reporter constructs to determine the transcriptional activity. Functional studies were performed by transfecting HBV replication-competent plasmids into hepatoma cells. Analyses of the replication fitness of the mutant strains were conducted by biochemical analysis. In all HBV genomes the enhancer I region was mutated. Most of these mutations resulted in decreased transcriptional activity. The strongest effects were detectable in strains with mutations in the hepatocyte nuclear factor 3 and 4 (HNF3 and HNF4) binding sites of the enhancer I core domain. Replication-competent HBV constructs containing these mutations demonstrated up to 10-fold-reduced levels of virus replication. Before liver transplantation, when the mutant strains were detected in the patients' sera, low HBV DNA levels were found. After transplantation and reinfection with a wild-type virus, the levels of replication were up to 240-fold higher. Our results show that mutations in the enhancer I region of HBV have a major impact on HBV replication. These mutations may also determine the switch from high to low levels of viral replication which is frequently observed during chronic HBV infection.

* Corresponding author. Mailing address: Department of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Phone: 49-511-532-3489. Fax: 49-511-532-4896. E-mail: Trautwein.Christian{at}MH-Hannover.de.

dagger This work is dedicated to K. H. Meyer zum Büschenfelde on the occasion of his 70th birthday.

Journal of Virology, March 2000, p. 2193-2202, Vol. 74, No. 5
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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