Hertogs K, Bloor S, Kemp S D, Van den Eynde C, Alcorn T M, Pauwels R, Van Houtte M, Staszewski S, Miller V, Larder B A
Virco NV, Mechelen, Belgium.
AIDS. 2000 Jun 16;14(9):1203-10. doi: 10.1097/00002030-200006160-00018.
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 PIs was investigated.
Over 6000 patient isolates with plasma viral load greater than 1000 copies/ml 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.
Phenotypic resistance to any single PI was observed in 17 to 25% of the clinical isolates investigated. Phenotypic cross-resistance among PIs (> 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.
Extensive use of first-generation PIs 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.
评估在一组源自欧洲和美国常规临床实践并提交进行表型耐药性检测和/或基因型分析的患者样本中，HIV-1对蛋白酶抑制剂（PIs）沙奎那韦、利托那韦、茚地那韦和奈非那韦的表型和基因型抗逆转录病毒药物耐药性及交叉耐药性的程度。研究了对PIs耐药和交叉耐药的潜在突变模式。
分析了6000多份血浆病毒载量大于1000拷贝/毫升血浆的患者分离株。通过重组病毒试验评估表型耐药性。表型耐药性表示为化合物对患者来源的重组病毒分离株的50%抑制浓度（IC50）值相对于野生型实验室病毒的增加倍数。基因型分析报告为与野生型参考相比HIV-1蛋白酶中各位置的氨基酸变化。
在所研究的临床分离株中，17%至25%对任何一种单一PI表现出表型耐药性。在对至少一种PI耐药（IC50值增加>10倍）的样本中，59%至80%检测到PIs之间的表型交叉耐药性（IC50值增加>10倍）。PI耐药分离株中常见的突变涉及密码子10、36、46、54、71、77、82和90处的替换。PI交叉耐药样本中最常见的突变模式涉及10和90位的联合替换，并扩展到54、71、77、82或84位的替换。
第一代PIs的广泛使用导致出现对该类所有成员具有交叉耐药性的HIV-1分离株。识别这些分离株中的特定突变谱可能有助于设计对蛋白酶突变型HIV毒株具有特异性活性的新一代抑制剂。
