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Journal of Virology, February 2002, p. 1213-1223, Vol. 76, No. 3
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.3.1213-1223.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Mutations of the Woodchuck Hepatitis Virus Polymerase Gene That Confer Resistance to Lamivudine and 2'-Fluoro-5-Methyl-ß-L-Arabinofuranosyluracil

Toshiki Yamamoto,1 Samuel Litwin,1 Tianlun Zhou,1 Yuao Zhu,1 Lynn Condreay,2 Phillip Furman,3 and William S. Mason1*

Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111,1 Department of Virology, Glaxo Wellcome, Inc., Research Triangle Park, North Carolina 27709,2 Triangle Pharmaceuticals, Inc., Durham, North Carolina 277073

Received 27 August 2001/ Accepted 31 October 2001

Administration of either lamivudine (2'-deoxy-3'-thiacytidine) or L-FMAU (2'-fluoro-5-methyl-ß-L-arabinofuranosyluracil) to woodchucks chronically infected with woodchuck hepatitis virus (WHV) induces a transient decline in virus titers. However, within 6 to 12 months, virus titers begin to increase towards pretreatment levels. This is associated with the emergence of virus strains with mutations of the B and C regions of the viral DNA polymerase (T. Zhou et al., Antimicrob. Agents Chemother. 43:1947–1954, 1999; Y. Zhu et al., J. Virol. 75:311–322, 2001). The present study was carried out to determine which of the mutants that we have identified conferred resistance to lamivudine and/or to L-FMAU. When inserted into a laboratory strain of WHV, each of the mutations, or combinations of mutations, of regions B and C produced a DNA replication-competent virus and typically conferred resistance to both nucleoside analogs in cell culture. Sequencing of the polymerase active site also occasionally revealed other mutations, but these did not appear to contribute to drug resistance. Moreover, in transfected cells, most of the mutants synthesized viral DNA nearly as efficiently as wild-type WHV. Computational models suggested that persistence of several of the WHV mutants as prevalent species in the serum and, by inference, liver for up to 6 months following drug withdrawal required a replication efficiency of at least 10 to 30% of that of the wild type. However, their delayed emergence during therapy suggested replication efficiency in the presence of the drug that was still well below that of wild-type WHV in the absence of the drug.

* Corresponding author. Mailing address: Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111. Phone: (215) 728-2462. Fax: (215) 728-3105. E-mail: ws_mason{at}fccc.edu.

Journal of Virology, February 2002, p. 1213-1223, Vol. 76, No. 3
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.3.1213-1223.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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