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Antimicrobial Agents and Chemotherapy, August 1999, p. 1947-1954, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Emergence of Drug-Resistant Populations of Woodchuck Hepatitis Virus in Woodchucks Treated with the Antiviral Nucleoside Lamivudine

Tianlun Zhou,1,2 Jeffry Saputelli,1 Carol E. Aldrich,1 Manon Deslauriers,3 Lynn D. Condreay,3 and William S. Mason1,*

Fox Chase Cancer Center, Philadelphia, Pennsylvania 191111; Biomedical Graduate Studies, University of Pennsylvania, Philadelphia, Pennsylvania 191042; and Department of Virology, Glaxo Wellcome, Inc., Research Triangle Park, North Carolina 277093

Received 1 February 1999/Returned for modification 31 March 1999/Accepted 24 May 1999

Lamivudine [(-)-beta -L-2',3'-dideoxy-3'-thiacytidine] reduces woodchuck hepatitis virus (WHV) titers in the sera of chronically infected woodchucks by inhibiting viral DNA synthesis. However, after 6 to 12 months, WHV titers begin to increase toward pretreatment levels. Three WHV variants with mutations in the active site of the DNA polymerase gene are present at this time (W. S. Mason et al., Virology 245:18-32, 1998). We have asked if these mutant viruses were responsible for the lamivudine resistance and if their emergence caused an immediate rise in virus titers. Cell cultures studies implied that the mutants were resistant to lamivudine. Emergence of mutant WHV was not always associated, however, with an immediate rise in virus titers in the serum. One of the three types of mutant viruses became prominent in serum up to 7 months before titers in serum actually began to increase, at a time when wild-type virus was still predominant in the liver. The two other mutants did not show this behavior but were detected in serum and liver later, just at the time that virus titers began to rise. A factor linking all three mutants was that a similar duration of drug administration preceded the rise in titers, irrespective of which mutant ultimately prevailed. A simple explanation for these results is that the increase in virus titers following emergence of drug-resistant mutants can occur only as the preexisting wild-type virus is cleared from the hepatocyte population, allowing spread of the mutants. Thus, prolonged suppression of virus titers in the serum may sometimes be a measure of the stability of hepatocyte infection rather than of a successful therapeutic outcome.

* Corresponding author. Mailing address: Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111. Phone: (215) 728-2402. Fax: (215) 728-3616. E-mail: ws_mason{at}fccc.edu.

Antimicrobial Agents and Chemotherapy, August 1999, p. 1947-1954, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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