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Antimicrobial Agents and Chemotherapy, September 2001, p. 2495-2501, Vol. 45, No. 9
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.9.2495-2501.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

In Vitro Susceptibilities of Wild-Type or Drug-Resistant Hepatitis B Virus to (-)-beta -D-2,6-Diaminopurine Dioxolane and 2'-Fluoro-5-Methyl-beta -L-Arabinofuranosyluracil

Ruth Chin,1 Tim Shaw,1 Joseph Torresi,1 Vittina Sozzi,1 Christian Trautwein,2 Thomas Bock,2 Michael Manns,2 Harriet Isom,3 Phil Furman,4 and Stephen Locarnini1,*

Victorian Infectious Diseases Reference Laboratory, North Melbourne 3051, Australia1; Department of Gastroenterology and Hepatology, Medizinsche Hochshule, Hannover, Germany2; Department of Microbiology & Immunology, Penn State University, Pittsburg, Pennsylvania3; and Triangle Pharmaceuticals, Durham, North Carolina4

Received 30 June 2000/Returned for modification 25 October 2000/Accepted 11 June 2001

Prolonged treatment of chronic hepatitis B virus (HBV) infection with lamivudine ([-]-beta -L-2',3'-dideoxy-3' thiacytidine) or famciclovir may select for viral mutants that are drug resistant due to point mutations in the polymerase gene. Determining whether such HBV mutants are sensitive to new antiviral agents is therefore important. We used a transient transfection system to compare the sensitivities of wild-type HBV and four lamivudine- and/or famciclovir-resistant HBV mutants to adefovir [9-(2-phosphonyl-methoxyethyl)-adenine; PMEA] and the nucleoside analogues (-)-beta -D-2, 6-diaminopurine dioxolane (DAPD) and 2'-fluoro-5-methyl-beta -L-arabinofuranosyluracil (L-FMAU). The drug-resistant mutants contained amino acid substitutions in the polymerase protein. We found that the M550I and M550V plus L526M substitutions, which confer lamivudine resistance, did not confer cross-resistance to adefovir or DAPD, but conferred cross-resistance to L-FMAU. The M550V substitution in isolation conferred a similar phenotype to M550I, except that it did not confer significant resistance to L-FMAU. The L526M substitution, which is associated with famciclovir resistance, conferred cross-resistance to L-FMAU but not to adefovir or DAPD. Inhibition of HBV secretion by DAPD, L-FMAU, and adefovir did not always correlate with inhibition of the generation of intracellular HBV replicative intermediates, suggesting that these analogs may preferentially inhibit specific stages of the viral replication cycle.

* Corresponding author. Mailing address: Victorian Infectious Diseases Reference Laboratory, Locked Bag 815, Carlton South, Victoria 3053, Australia. Phone: 613 9342 2637. Fax: 613 9342 2666. E-mail: stephenlocarnini{at}compuserve.com.

Antimicrobial Agents and Chemotherapy, September 2001, p. 2495-2501, Vol. 45, No. 9
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.9.2495-2501.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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