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 Walter, H.
Right arrow Articles by Korn, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Walter, H.
Right arrow Articles by Korn, K.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, January 2002, p. 89-94, Vol. 46, No. 1
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.1.89-94.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Prediction of Abacavir Resistance from Genotypic Data: Impact of Zidovudine and Lamivudine Resistance In Vitro and In Vivo

Hauke Walter, Barbara Schmidt,* Marianne Werwein, Eva Schwingel, and Klaus Korn

Institute of Clinical and Molecular Virology, German National Reference Centre for Retroviruses, University of Erlangen-Nürnberg, Erlangen, Germany

Received 26 April 2001/ Returned for modification 12 July 2001/ Accepted 1 October 2001

Abacavir is frequently used in antiretroviral combination therapies as a potent nucleoside reverse transcriptase inhibitor (NRTI). Four mutations are selected for by abacavir in vitro and in vivo: K65R, L74V, Y115F, and M184V. Abacavir resistance has also been observed in NRTI multidrug-resistant samples. Furthermore, abacavir resistance has been described in the context of zidovudine resistance. To evaluate the genetic basis of abacavir resistance, the viral genotype and phenotypic resistance were analyzed for 307 patient samples. Low- and high-level resistances were defined as 2.5- to 5.5-fold- and >5.5-fold-reduced susceptibility, respectively. If all samples with abacavir-selected and NRTI multidrug resistance-associated mutations were scored as resistant, 27.6% of the samples were misclassified, mainly due to samples falsely scored as susceptible. Therefore, the relative frequencies of other mutations were evaluated. Mutations at codons 44 and 118 were rarely detected in abacavir-susceptible samples but were overrepresented in resistant samples. Site-directed mutagenesis of E44D, V118I, and M184V resulted in low-level resistance for the double mutant 44/184 and the triple mutant. Low-level abacavir resistance was also detected for a viral clone carrying zidovudine mutations only. Additional insertion of M184V into the zidovudine background doubled the resistance, whereas 44/118 did not lead to a further increase. Incorporating combinations of zidovudine mutations and M184V into the scoring system markedly reduced the number of misclassified samples, whereas 44/118 did not improve the prediction. In conclusion, the combination of M184V with zidovudine mutations gives rise to high-level abacavir resistance, which may be clinically relevant. Thus, options for useful sequential combinations of NRTI are limited.

* Corresponding author. Present address: Institute of Clinical and Molecular Virology, German National Reference Centre for Retroviruses, University of Erlangen-Nürnberg, Schlossgarten 4, D-91054 Erlangen, Germany. Phone: 49-9131-85-24010. Fax: 49-9131-85-26485. E-mail: baschmid{at}viro.med.uni-erlangen.de.

Antimicrobial Agents and Chemotherapy, January 2002, p. 89-94, Vol. 46, No. 1
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.1.89-94.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Yang, G., Paintsil, E., Dutschman, G. E., Grill, S. P., Wang, C.-J., Wang, J., Tanaka, H., Hamasaki, T., Baba, M., Cheng, Y.-C. (2009). Impact of Novel Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutations P119S and T165A on 4'-Ethynylthymidine Analog Resistance Profile. Antimicrob. Agents Chemother. 53: 4640-4646 [Abstract] [Full Text]  
  • Margot, N. A., Waters, J. M., Miller, M. D. (2006). In Vitro Human Immunodeficiency Virus Type 1 Resistance Selections with Combinations of Tenofovir and Emtricitabine or Abacavir and Lamivudine. Antimicrob. Agents Chemother. 50: 4087-4095 [Abstract] [Full Text]  
  • Wainberg, M. A., Brenner, B. G., Turner, D. (2005). Changing Patterns in the Selection of Viral Mutations among Patients Receiving Nucleoside and Nucleotide Drug Combinations Directed against Human Immunodeficiency Virus Type 1 Reverse Transcriptase. Antimicrob. Agents Chemother. 49: 1671-1678 [Full Text]  
  • Turner, D., Brenner, B., Wainberg, M. A. (2004). Relationships among various nucleoside resistance-conferring mutations in the reverse transcriptase of HIV-1. J Antimicrob Chemother 53: 53-57 [Abstract] [Full Text]  
  • Wolf, K., Walter, H., Beerenwinkel, N., Keulen, W., Kaiser, R., Hoffmann, D., Lengauer, T., Selbig, J., Vandamme, A.-M., Korn, K., Schmidt, B. (2003). Tenofovir Resistance and Resensitization. Antimicrob. Agents Chemother. 47: 3478-3484 [Abstract] [Full Text]  
  • Girouard, M., Diallo, K., Marchand, B., McCormick, S., Gotte, M. (2003). Mutations E44D and V118I in the Reverse Transcriptase of HIV-1 Play Distinct Mechanistic Roles in Dual Resistance to AZT and 3TC. J. Biol. Chem. 278: 34403-34410 [Abstract] [Full Text]  
  • Ray, A. S., Basavapathruni, A., Anderson, K. S. (2002). Mechanistic Studies to Understand the Progressive Development of Resistance in Human Immunodeficiency Virus Type 1 Reverse Transcriptase to Abacavir. J. Biol. Chem. 277: 40479-40490 [Abstract] [Full Text]  
  • Shafer, R. W. (2002). Genotypic Testing for Human Immunodeficiency Virus Type 1 Drug Resistance. Clin. Microbiol. Rev. 15: 247-277 [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»