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Journal of Virology, February 1999, p. 1492-1502, Vol. 73, No. 2
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Double-Stranded Linear Duck Hepatitis B Virus (DHBV) Stably Integrates at a Higher Frequency than Wild-Type DHBV in LMH Chicken Hepatoma Cells

Shih S. Gong,1,dagger Anne D. Jensen,1 C. J. Chang,2 and Charles E. Rogler1,*

Marion Bessin Liver Research Center, Department of Medicine,1 and Department of Epidemiology and Social Medicine,2 The Jack and Pearl Resnick Campus of the Albert Einstein College of Medicine, Bronx, New York 10461

Received 22 June 1998/Accepted 10 November 1998

Integration of hepadnavirus DNAs into host chromosomes can have oncogenic consequences. Analysis of host-viral DNA junctions of DHBV identified the terminally duplicated r region of the viral genome as a hotspot for integration. Since the r region is present on the 5' and 3' ends of double-stranded linear (DSL) hepadnavirus DNAs, these molecules have been implicated as integration precursors. We have produced a LMH chicken hepatoma cell line (LMH 66-1 DSL) which replicates exclusively DSL duck hepatitis B virus (DHBV) DNA. To test whether linear DHBV DNAs integrate more frequently than the wild type open circular DHBV DNAs, we have characterized the integration frequency in LMH 66-1 DSL cells by using a subcloning approach. This approach revealed that 83% of the LMH 66-1 DSL subclones contained new integrations, compared to only 16% of subclones from LMH-D2 cells replicating wild-type open circular DHBV DNA. Also, a higher percentage of the LMH 66-1 DSL subclones contained two or more new integrations. Mathematical analysis suggests that the DSL DHBV DNAs integrated stably once every three generations during subcloning whereas wild-type DHBV integrated only once every four to five generations. Cloning and sequencing of new integrations confirmed the r region as a preferred integration site for linear DHBV DNA molecules. One DHBV integrant was associated with a small deletion of chromosomal DNA, and another DHBV integrant occurred in a telomeric repeat sequence.

* Corresponding author. Mailing address: Marion Bessin Liver Research Center, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461-1602. Phone: (718) 430-2607. Fax: (718) 430-8975. E-mail: crogler{at}aecom.yu.edu.

dagger Present address: Interferon Sciences, Inc., New Brunswick, NJ 08901-3660.

Journal of Virology, February 1999, p. 1492-1502, Vol. 73, No. 2
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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