This Article Full Text Full Text (PDF) Other Versions of this Article: AAC.00816-06v1 50/12/4087    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Margot, N. A. Articles by Miller, M. D. Search for Related Content PubMed PubMed Citation Articles by Margot, N. A. Articles by Miller, M. D.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, December 2006, p. 4087-4095, Vol. 50, No. 12
0066-4804/06/$08.00+0     doi:10.1128/AAC.00816-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

In Vitro Human Immunodeficiency Virus Type 1 Resistance Selections with Combinations of Tenofovir and Emtricitabine or Abacavir and Lamivudine

Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404

Received 5 July 2006/ Returned for modification 8 August 2006/ Accepted 8 September 2006

Human immunodeficiency virus type 1 (HIV-1) resistance development was evaluated in vitro by using combinations of the drugs tenofovir and emtricitabine or abacavir and lamivudine, as well as by using the compounds individually. Emtricitabine- and lamivudine-resistant HIV-1 isolates with the M184I or M184V mutation in reverse transcriptase were readily selected in the cultures with emtricitabine alone, lamivudine alone, and the two drug combinations and conferred high-level resistance to emtricitabine and lamivudine. Tenofovir-resistant HIV-1 isolates with the K65R mutation occurred in both the culture with tenofovir alone and the culture with the combination of emtricitabine and tenofovir. The S68N and S68K mutations were also observed in the tenofovir cultures, with no detectable impact on resistance, suggesting a possible compensatory role in viral fitness. At low concentrations of emtricitabine and tenofovir, the M184I mutation appeared first, followed by the K65R mutation, in a subset of viruses. At intermediate concentrations of emtricitabine and tenofovir, viruses harboring the K65R mutation or a novel K65N and K70R double mutation grew before they gave rise to mutants with K65R and M184V/I double mutations at higher emtricitabine concentrations. Abacavir resistance was characterized by the accumulation of the M184V, Y115F, and K65R mutations in the abacavir culture, while the M184V and L74V mutations were selected in combination with lamivudine. In the presence of the abacavir resistance mutations, viral growth was strong even in the presence of high concentrations of abacavir. In contrast, viral growth was markedly impaired in the cultures with high tenofovir concentrations, even in the presence of K65R. In conclusion, these studies show that HIV-1 mutants with a K65R and M184V genotype are generated under maximum selection pressure from the combination of tenofovir and emtricitabine.

Published ahead of print on 18 September 2006.