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Antimicrobial Agents and Chemotherapy, June 2001, p. 1705-1713, Vol. 45, No. 6
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.6.1705-1713.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Cross-Resistance Testing of Antihepadnaviral Compounds Using Novel Recombinant Baculoviruses Which Encode Drug-Resistant Strains of Hepatitis B Virus

William E. Delaney IV,1,dagger Ros Edwards,1 Danni Colledge,1 Tim Shaw,1 Joseph Torresi,1 Thomas G. Miller,2 Harriet C. Isom,2 C. Thomas Bock,3 Michael P. Manns,3 Christian Trautwein,3 and Stephen Locarnini1,*

Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria 3051, Australia1; The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 170332; and Medical School Hannover, 30625 Hannover, Germany3

Received 9 October 2000/Returned for modification 20 December 2000/Accepted 8 March 2001

Long-term nucleoside analog therapy for hepatitis B virus (HBV)-related disease frequently results in the selection of mutant HBV strains that are resistant to therapy. Molecular studies of such drug-resistant variants are clearly warranted but have been difficult to do because of the lack of convenient and reliable in vitro culture systems for HBV. We previously developed a novel in vitro system for studying HBV replication that relies on the use of recombinant baculoviruses to deliver greater than unit length copies of the HBV genome to HepG2 cells. High levels of HBV replication can be achieved in this system, which has recently been used to assess the effects of lamivudine on HBV replication and covalently closed circular DNA accumulation. The further development of this novel system and its application to determine the cross-resistance profiles of drug-resistant HBV strains are described here. For these studies, novel recombinant HBV baculoviruses which encoded the L526M, M550I, and L526M M550V drug resistance mutations were generated and used to examine the effects of these substitutions on viral sensitivity to lamivudine, penciclovir (the active form of famciclovir), and adefovir, three compounds of clinical importance. The following observations were made: (i) the L526M mutation confers resistance to penciclovir and partial resistance to lamivudine, (ii) the YMDD mutations M550I and L526M M550V confer high levels of resistance to lamivudine and penciclovir, and (iii) adefovir is active against each of these mutants. These findings are supported by the limited amount of clinical data currently available and confirm the utility of the HBV-baculovirus system as an in vitro tool for the molecular characterization of clinically significant HBV strains.

* Corresponding author. Mailing address: Victorian Infectious Diseases Reference Laboratory (VIDRL), 10 Wreckyn St., North Melbourne, Victoria 3051, Australia. Phone: (61 3) 9342 2614. Fax: (61 3) 9342 2666. E-mail: stephenlocarnini{at}compuserve.com.

dagger Present address: Gilead Sciences, Foster City, CA 94404.

Antimicrobial Agents and Chemotherapy, June 2001, p. 1705-1713, Vol. 45, No. 6
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.6.1705-1713.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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