Phenotypic and genotypic analysis of clinical HIV-1 isolates reveals extensive protease inhibitor cross-resistance: a survey of over 6000 samples

被引:155
作者
Hertogs, K
Bloor, S
Kemp, SD
Van den Eynde, C
Alcorn, TM
Pauwels, R
Van Houtte, M
Staszewski, S
Miller, V
Larder, BA
机构
[1] Virco NV, Mechelen, Belgium
[2] Virco Ltd, Cambridge, England
[3] Klinikum JW Goethe Univ, Zentrum Inneren Med Infektiol, Frankfurt, Germany
[4] LabCorp, Ctr Mol Biol & Pathol, Res Triangle Pk, NC USA
关键词
phenotypic drug resistance; genotypic evaluation; cross-resistance; mutations; protease inhibitors;
D O I
10.1097/00002030-200006160-00018
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Objective: To evaluate in HIV-1 the extent of phenotypic and genotypic antiretroviral drug resistance and cross-resistance towards the protease inhibitors (PIs) saquinavir, ritonavir, indinavir and nelfinavir among a set of patient samples originating from European and US routine clinical practice and submitted for phenotypic drug resistance testing and/or genotypic analysis. The mutational pattern(s) underlying both resistance and cross-resistance to Pls was investigated. Method: Over 6000 patient isolates with plasma viral load greater than 1000 copies/ mi plasma were analysed. Phenotypic resistance was evaluated by a recombinant virus assay. Phenotypic resistance is expressed as the fold-increase of the 50% inhibitory concentration (IC50) value of a compound for a patient-derived recombinant virus isolate compared with that for a wild-type laboratory virus. Genotypic analysis is reported as amino acid changes at positions in the HIV-1 protease compared to a wild-type reference. Results: Phenotypic resistance to any single PI was observed in 17 to 25% of the clinical isolates investigated. Phenotypic cross-resistance among Pls (> 10-fold increase in IC50 value) was detected in 59 to 80% of the samples resistant (> 10-fold increase in IC50 value) to at least one PI. The prevalent mutations in PI-resistant isolates involved substitutions at codons 10, 36, 46, 54, 71, 77, 82 and 90. The most frequent mutational pattern in samples with Pi cross-resistance involved combined substitutions at positions 10 and 90, extended with substitutions at positions 54, 71, 77, 82 or 84. Conclusions: Extensive use of first-generation Pls leads to the emergence of HIV-1 isolates possessing cross-resistance to all members of this class. Identification of particular mutational profiles among these isolates may assist in the design of new generation inhibitors with specific activity against protease-mutant HIV strains. (C) 2000 Lippincott Williams & Wilkins.
引用
收藏
页码:1203 / 1210
页数:8
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