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 Colonno, R. J.
Right arrow Articles by Parkin, N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Colonno, R. J.
Right arrow Articles by Parkin, N.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, April 2003, p. 1324-1333, Vol. 47, No. 4
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.4.1324-1333.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Activities of Atazanavir (BMS-232632) against a Large Panel of Human Immunodeficiency Virus Type 1 Clinical Isolates Resistant to One or More Approved Protease Inhibitors

Richard J. Colonno,1* Alexandra Thiry,1 Kay Limoli,2 and Neil Parkin2

Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut,1 ViroLogic Inc., South San Francisco, California2

Received 9 October 2002/ Returned for modification 23 December 2002/ Accepted 7 January 2003

To evaluate the cross-resistance profile of the human immunodeficiency virus type 1 protease inhibitor (PI) atazanavir (BMS-232632), a panel of 551 clinical isolates exhibiting a wide array of PI resistance profiles and a variety of genotypic patterns were assayed for susceptibility to atazanavir and six other PIs: amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir. In general, reductions in atazanavir susceptibility in vitro required several amino acid changes and were relatively modest in degree, and susceptibility was retained among isolates resistant to one or two of the currently approved PIs. There was a clear trend toward loss of susceptibility to atazanavir, as isolates exhibited increasing levels of cross-resistance to multiple PIs. Atazanavir appeared to have a distinct resistance profile relative to each of the other six PIs tested based on susceptibility comparisons against this panel of resistant isolates. Analysis of the genotypic profiles of 943 PI-susceptible and -resistant clinical isolates identified a strong correlation between the presence of amino acid changes at specific residues (10I/V/F, 20R/M/I, 24I, 33I/F/V, 36I/L/V, 46I/L, 48V, 54V/L, 63P, 71V/T/I, 73C/S/T/A, 82A/F/S/T, 84V, and 90M) and decreased susceptibility to atazanavir. While no single substitution or combination of substitutions was predictive of atazanavir resistance (change, >3.0-fold), the presence of at least five of these substitutions correlated strongly with loss of atazanavir susceptibility. Mutations associated with reduced susceptibility to each of the other six PIs were also determined.

* Corresponding author. Mailing address: Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660. Phone: (203) 677-7779. Fax: (203) 677-7994. E-mail: richard.colonno{at}bms.com.

Antimicrobial Agents and Chemotherapy, April 2003, p. 1324-1333, Vol. 47, No. 4
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.4.1324-1333.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Klei, H. E., Kish, K., Lin, P.-F. M., Guo, Q., Friborg, J., Rose, R. E., Zhang, Y., Goldfarb, V., Langley, D. R., Wittekind, M., Sheriff, S. (2007). X-Ray Crystal Structures of Human Immunodeficiency Virus Type 1 Protease Mutants Complexed with Atazanavir. J. Virol. 81: 9525-9535 [Abstract] [Full Text]  
  • Ford, J., Boffito, M., Maitland, D., Hill, A., Back, D., Khoo, S., Nelson, M., Moyle, G., Gazzard, B., Pozniak, A. (2006). Influence of atazanavir 200 mg on the intracellular and plasma pharmacokinetics of saquinavir and ritonavir 1600/100 mg administered once daily in HIV-infected patients. J Antimicrob Chemother 58: 1009-1016 [Abstract] [Full Text]  
  • Colombo, S., Buclin, T., Cavassini, M., Decosterd, L. A., Telenti, A., Biollaz, J., Csajka, C. (2006). Population Pharmacokinetics of Atazanavir in Patients with Human Immunodeficiency Virus Infection. Antimicrob. Agents Chemother. 50: 3801-3808 [Abstract] [Full Text]  
  • Lemey, P., Derdelinckx, I., Rambaut, A., Van Laethem, K., Dumont, S., Vermeulen, S., Van Wijngaerden, E., Vandamme, A.-M. (2005). Molecular Footprint of Drug-Selective Pressure in a Human Immunodeficiency Virus Transmission Chain. J. Virol. 79: 11981-11989 [Abstract] [Full Text]  
  • Weinheimer, S., Discotto, L., Friborg, J., Yang, H., Colonno, R. (2005). Atazanavir Signature I50L Resistance Substitution Accounts for Unique Phenotype of Increased Susceptibility to Other Protease Inhibitors in a Variety of Human Immunodeficiency Virus Type 1 Genetic Backbones. Antimicrob. Agents Chemother. 49: 3816-3824 [Abstract] [Full Text]  
  • Yanchunas, J. Jr., Langley, D. R., Tao, L., Rose, R. E., Friborg, J., Colonno, R. J., Doyle, M. L. (2005). Molecular Basis for Increased Susceptibility of Isolates with Atazanavir Resistance-Conferring Substitution I50L to Other Protease Inhibitors. Antimicrob. Agents Chemother. 49: 3825-3832 [Abstract] [Full Text]  
  • Orrick, J. J, Steinhart, C. R (2004). Atazanavir. The Annals of Pharmacotherapy 38: 1664-1674 [Abstract] [Full Text]  
  • Koh, Y., Nakata, H., Maeda, K., Ogata, H., Bilcer, G., Devasamudram, T., Kincaid, J. F., Boross, P., Wang, Y.-F., Tie, Y., Volarath, P., Gaddis, L., Harrison, R. W., Weber, I. T., Ghosh, A. K., Mitsuya, H. (2003). Novel bis-Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI) UIC-94017 (TMC114) with Potent Activity against Multi-PI-Resistant Human Immunodeficiency Virus In Vitro. Antimicrob. Agents Chemother. 47: 3123-3129 [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»