This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ladner, S. K.
Right arrow Articles by King, R. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ladner, S. K.
Right arrow Articles by King, R. W.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, August 1998, p. 2128-2131, Vol. 42, No. 8
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The M539V Polymerase Variant of Human Hepatitis B Virus Demonstrates Resistance to 2'-Deoxy-3'-Thiacytidine and a Reduced Ability to Synthesize Viral DNA

Stephanie K. Ladner, Thomas J. Miller, and Robert W. King*

Avid Therapeutics, Inc., Philadelphia, Pennsylvania 19104

Received 13 August 1997/Returned for modification 3 November 1997/Accepted 21 May 1998

The cytosine analog 2'-deoxy-3'-thiacytidine (3TC) has been shown to be an effective treatment for chronic hepatitis B virus (HBV) infection. However, several liver transplant patients who were undergoing treatment with 3TC for HBV infection experienced a breakthrough of virus while on 3TC. The predominant virus found in these patients' sera contained either a valine or isoleucine for the methionine in the highly conserved YMDD nucleotide binding site in the HBV polymerase. To determine the biological relevance of the Met-to-Val substitution, we mutated a plasmid that contained a cDNA copy of the HBV pregenomic RNA such that when virus replication occurred during transient transfection of HepG2 cells, an M539V polymerase variant was produced. We found that in transiently transfected cells, this variant was approximately 330-fold less sensitive to the antiviral effects of 3TC and produced 7-fold less viral DNA than the wild type.

* Corresponding author. Mailing address: The DuPont Merck Pharmaceutical Co., The Experimental Station, P.O. Box 80336, Wilmington, DE 19880-0336. Phone: (302) 695-9354. Fax: (302) 695-3934. E-mail: robert.w.king{at}dupontmerck.com. [Requests for all research reagents should be sent through Phil Furman, Triangle Pharmaceuticals, 4 University Place, 4611 University Dr, Durham, NC 27707. Phone: (919) 493-5980.]

Antimicrobial Agents and Chemotherapy, August 1998, p. 2128-2131, Vol. 42, No. 8
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Lim, S. G., Krastev, Z., Ng, T. M., Mechkov, G., Kotzev, I. A., Chan, S., Mondou, E., Snow, A., Sorbel, J., Rousseau, F., for the FTCB-204 Study Group, (2006). Randomized, Double-Blind Study of Emtricitabine (FTC) plus Clevudine versus FTC Alone in Treatment of Chronic Hepatitis B.. Antimicrob. Agents Chemother. 50: 1642-1648 [Abstract] [Full Text]  
  • Lim, S. G., Ng, T. M., Kung, N., Krastev, Z., Volfova, M., Husa, P., Lee, S. S., Chan, S., Shiffman, M. L., Washington, M. K., Rigney, A., Anderson, J., Mondou, E., Snow, A., Sorbel, J., Guan, R., Rousseau, F., for the Emtricitabine FTCB-301 Study Group, (2006). A Double-blind Placebo-Controlled Study of Emtricitabine in Chronic Hepatitis B. Arch Intern Med 166: 49-56 [Abstract] [Full Text]  
  • Pai, S. B., Bozdayi, A. M., Pai, R. B., Beker, T., Sarioglu, M., Turkyilmaz, A. R., Grier, J., Yurdaydin, C., Schinazi, R. F. (2005). Emergence of a Novel Mutation in the FLLA Region of Hepatitis B Virus during Lamivudine Therapy. Antimicrob. Agents Chemother. 49: 2618-2624 [Abstract] [Full Text]  
  • Ying, C., Holy, A., Hockova, D., Havlas, Z., De Clercq, E., Neyts, J. (2005). Novel Acyclic Nucleoside Phosphonate Analogues with Potent Anti-Hepatitis B Virus Activities. Antimicrob. Agents Chemother. 49: 1177-1180 [Abstract] [Full Text]  
  • Walters, K.-A., Tipples, G. A., Allen, M. I., Condreay, L. D., Addison, W. R., Tyrrell, L. (2003). Generation of Stable Cell Lines Expressing Lamivudine-Resistant Hepatitis B Virus for Antiviral-Compound Screening. Antimicrob. Agents Chemother. 47: 1936-1942 [Abstract] [Full Text]  
  • Levine, S., Hernandez, D., Yamanaka, G., Zhang, S., Rose, R., Weinheimer, S., Colonno, R. J. (2002). Efficacies of Entecavir against Lamivudine-Resistant Hepatitis B Virus Replication and Recombinant Polymerases In Vitro. Antimicrob. Agents Chemother. 46: 2525-2532 [Abstract] [Full Text]  
  • Gaillard, R. K., Barnard, J., Lopez, V., Hodges, P., Bourne, E., Johnson, L., Allen, M. I., Condreay, P., Miller, W. H., Condreay, L. D. (2002). Kinetic Analysis of Wild-Type and YMDD Mutant Hepatitis B Virus Polymerases and Effects of Deoxyribonucleotide Concentrations on Polymerase Activity. Antimicrob. Agents Chemother. 46: 1005-1013 [Abstract] [Full Text]  
  • Delaney, W. E. IV, Edwards, R., Colledge, D., Shaw, T., Torresi, J., Miller, T. G., Isom, H. C., Bock, C. T., Manns, M. P., Trautwein, C., Locarnini, S. (2001). Cross-Resistance Testing of Antihepadnaviral Compounds Using Novel Recombinant Baculoviruses Which Encode Drug-Resistant Strains of Hepatitis B Virus. Antimicrob. Agents Chemother. 45: 1705-1713 [Abstract] [Full Text]  
  • Stuyver, L., Van Geyt, C., De Gendt, S., Van Reybroeck, G., Zoulim, F., Leroux-Roels, G., Rossau, R. (2000). Line Probe Assay for Monitoring Drug Resistance in Hepatitis B Virus-Infected Patients during Antiviral Therapy. J. Clin. Microbiol. 38: 702-707 [Abstract] [Full Text]  
  • Allen, M. I., Gauthier, J., DesLauriers, M., Bourne, E. J., Carrick, K. M., Baldanti, F., Ross, L. L., Lutz, M. W., Condreay, L. D. (1999). Two Sensitive PCR-Based Methods for Detection of Hepatitis B Virus Variants Associated with Reduced Susceptibility to Lamivudine. J. Clin. Microbiol. 37: 3338-3347 [Abstract] [Full Text]  
  • Ling, R, Harrison, T. (1999). Functional analysis of mutations conferring lamivudine resistance on hepatitis B virus. J. Gen. Virol. 80: 601-606 [Abstract]  
  • King, R. W., Ladner, S. K., Miller, T. J., Zaifert, K., Perni, R. B., Conway, S. C., Otto, M. J. (1998). Inhibition of Human Hepatitis B Virus Replication by AT-61, a Phenylpropenamide Derivative, Alone and in Combination with (-)beta -L-2',3'-Dideoxy-3'-Thiacytidine. Antimicrob. Agents Chemother. 42: 3179-3186 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»