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Journal of Virology, January 2001, p. 311-322, Vol. 75, No. 1
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.1.311-322.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Kinetics of Hepadnavirus Loss from the Liver during Inhibition of Viral DNA Synthesis

Yuao Zhu,1,* Toshiki Yamamoto,1 John Cullen,2 Jeffry Saputelli,1 Carol E. Aldrich,1 Darren S. Miller,3 Samuel Litwin,1 Phillip A. Furman,4 Allison R. Jilbert,3 and William S. Mason1

Fox Chase Cancer Center, Philadelphia, Pennsylvania 191111; Department of Microbiology, Parasitology, and Pathology, North Carolina State University, Raleigh, North Carolina 270662; Triangle Pharmaceuticals, Inc., Durham, North Carolina 277074; and Infectious Diseases Laboratories, Institute of Medical and Veterinary Science, and Department of Microbiology and Immunology, University of Adelaide, Adelaide, SA 5000, Australia3

Received 17 April 2000/Accepted 2 October 2000

Hepadnaviruses replicate by reverse transcription, which takes place in the cytoplasm of the infected hepatocyte. Viral RNAs, including the pregenome, are transcribed from a covalently closed circular (ccc) viral DNA that is found in the nucleus. Inhibitors of the viral reverse transcriptase can block new DNA synthesis but have no direct effect on the up to 50 or more copies of cccDNA that maintain the infected state. Thus, during antiviral therapy, the rates of loss of cccDNA, infected hepatocytes (1 or more molecules of cccDNA), and replicating DNAs may be quite different. In the present study, we asked how these losses compared when woodchucks chronically infected with woodchuck hepatitis virus were treated with L-FMAU [1-(2-fluoro-5-methyl-beta -L-arabinofuranosyl) uracil], an inhibitor of viral DNA synthesis. Viremia was suppressed for at least 8 months, after which drug-resistant virus began replicating to high titers. In addition, replicating viral DNAs were virtually absent from the liver after 6 weeks of treatment. In contrast, cccDNA declined more slowly, consistent with a half-life of ~33 to 50 days. The loss of cccDNA was comparable to that expected from the estimated death rate of hepatocytes in these woodchucks, suggesting that death of infected cells was one of the major routes for elimination of cccDNA. However, the decline in the actual number of infected hepatocytes lagged behind the decline in cccDNA, so that the average cccDNA copy number in infected cells dropped during the early phase of therapy. This observation was consistent with the possibility that some fraction of cccDNA was distributed to daughter cells in those infected hepatocytes that passed through mitosis.

* Corresponding author. Mailing address: Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111. Phone: (215) 728-2402. Fax: (215) 728-3105. E-mail: y_zhu{at}fccc.edu.

Journal of Virology, January 2001, p. 311-322, Vol. 75, No. 1
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.1.311-322.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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