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Journal of Virology, February 2009, p. 1778-1789, Vol. 83, No. 4
0022-538X/09/$08.00+0 doi:10.1128/JVI.01587-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
The Amount of Hepatocyte Turnover That Occurred during Resolution of Transient Hepadnavirus Infections Was Lower When Virus Replication Was Inhibited with Entecavir
,
William S. Mason,1*
Chunxiao Xu,1,
Huey Chi Low,2,3
Jeffry Saputelli,1
Carol E. Aldrich,1
Catherine Scougall,2,3
Arend Grosse,2,3
Richard Colonno,4,
Sam Litwin,1 and
Allison R. Jilbert2,3*
Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111,1 Infectious Diseases Laboratories, SA Pathology, Adelaide SA 5000, Australia,2 School of Molecular and Biomedical Science, University of Adelaide, Adelaide SA 5005, Australia,3 Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 064924
Received 25 July 2008/ Accepted 27 November 2008
Transient hepadnavirus infections can involve spread of virus to the entire hepatocyte population. In this situation hepatocytes present following recovery are derived from infected hepatocytes. During virus clearance antiviral cytokines are thought to block virus replication and formation of new covalently closed circular DNA (cccDNA), the viral transcriptional template. It remains unclear if existing cccDNA is eliminated noncytolytically or if hepatocyte death and proliferation, to compensate for killing of some of the infected hepatocytes, are needed to remove cccDNA from surviving infected hepatocytes. Interpreting the relationship between hepatocyte death and cccDNA elimination requires knowing both the amount of hepatocyte turnover and whether cccDNA synthesis is effectively blocked during the period of immune destruction of infected hepatocytes. We have addressed these questions by asking if treatment of woodchucks with the nucleoside analog inhibitor of viral DNA synthesis entecavir (ETV) reduced hepatocyte turnover during clearance of transient woodchuck hepatitis virus (WHV) infections. To estimate hepatocyte turnover, complexity analysis was carried out on virus-cell DNA junctions created by integration of WHV and present following recovery in the livers of WHV-infected control or ETV-treated woodchucks. We estimated that, on average, 2.2 to 4.8 times less hepatocyte turnover occurred during immune clearance in the ETV-treated woodchucks. Computer modeling of the complexity data suggests that mechanisms in addition to hepatocyte death were responsible for elimination of cccDNA during recovery from transient infections.
* Corresponding author. Mailing address for William S. Mason: Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111. Phone: (215) 728-2462. Fax: (215) 728-2412. E-mail: ws_mason{at}fccc.edu. Mailing address for Allison R. Jilbert: School of Molecular and Biomedical Science, University of Adelaide, Adelaide SA 5005, Australia. Phone: 61-8-8303 5399. Fax: 61-8-8303 7532. E-mail: allison.jilbert{at}adelaide.edu.au
Published ahead of print on 10 December 2008.
Supplemental material for this article may be found at http://jvi.asm.org/.
Present address: Drexel Institute for Biotechnology and Virology Research of Drexel University College of Medicine, Pennsylvania Biotechnology Center, 3805 Old Easton Road, Doylestown, PA 18902.
Present address: Presidio Pharmaceuticals, Inc., 1700 Owens Street, Suite 585, San Francisco, CA 94158.
Journal of Virology, February 2009, p. 1778-1789, Vol. 83, No. 4
0022-538X/09/$08.00+0 doi:10.1128/JVI.01587-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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