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Journal of Virology, June 2001, p. 5108-5118, Vol. 75, No. 11
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.11.5108-5118.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Transfer of Hepatitis B Virus Genome by Adenovirus Vectors into Cultured Cells and Mice: Crossing the Species Barrier

Martin Franz Sprinzl, Heike Oberwinkler,dagger Heinz Schaller, and Ulrike Protzer*

Zentrum für Molekulare Biologie Heidelberg (ZMBH), University of Heidelberg, D-69120 Heidelberg, Federal Republic of Germany

Received 10 November 2000/Accepted 1 March 2001

For the study of hepatitis B virus infection, no permissive cell line or small animal is available. Stably transfected cell lines and transgenic mice which contain hepadnavirus genomes produce virus, but---unlike in natural infection---from an integrated viral transcription template. To transfer hepadnavirus genomes across the species barrier, we developed adenovirus vectors in which 1.3-fold-overlength human and duck hepatitis B virus genomes were inserted. The adenovirus-mediated genome transfer efficiently initiated hepadnavirus replication from an extrachromosomal template in established cell lines, in primary hepatocytes from various species, and in the livers of mice. Following the transfer, hepatitis B virus proteins, genomic RNA, and all replicative DNA intermediates were detected. Detection of covalently closed circular DNA in hepatoma cell lines and in primary hepatocytes indicated that an intracellular replication cycle independent from the transferred linear viral genome was established. High-titer hepatitis B virions were released into the culture medium of hepatoma cells and the various primary hepatocytes. In addition, infectious virions were secreted into the sera of mice. In conclusion, adenovirus-mediated genome transfer initiated efficient hepatitis B virus replication in cultured liver cells and in the experimental animals from an extrachromosomal template. This will allow development of small-animal systems of hepatitis B virus infection and will facilitate study of pathogenicity of wild-type and mutant viruses as well as of virus-host interaction and new therapeutic approaches.

* Corresponding author. Present address: Hygiene Institut, Abteilung Virologie, Im Neuenheimer Feld 324, D-69120 Heidelberg, Federal Republic of Germany. Phone: 49-69221-565015. Fax: 49-69221-565003. E-mail: u.protzer{at}zmbh.uni-heidelberg.de.

dagger Present address: Department of Virology, Hygiene Institute, University of Heidelberg, D-69120 Heidelberg, Federal Republic of Germany.

Journal of Virology, June 2001, p. 5108-5118, Vol. 75, No. 11
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.11.5108-5118.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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