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
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
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DOI：
10.1128/aac.47.4.1324-1333.2003
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发表时间：
2003-04-01
影响因子：
4.9
通讯作者：
Parkin, N
中科院分区：
文献类型：
--
作者：
Colonno, RJ;Thiry, A;Parkin, N
为了评价人类免疫缺陷病毒1型蛋白酶抑制剂（PI）阿扎那韦（BMS-232632）的交叉耐药谱，对一组551株显示广泛PI耐药谱和多种基因型模式的临床分离株进行了阿扎那韦和其他6种PI（安普那韦、茚地那韦、洛匹那韦、奈非那韦、利托那韦和沙奎那韦）敏感性测定。一般而言，阿扎那韦体外敏感性的降低需要几个氨基酸的变化，并且在程度上相对温和，并且在对目前批准的一种或两种PI耐药的分离株中保留了敏感性。对阿扎那韦的敏感性有明显的丧失趋势，因为分离株对多种PI的交叉耐药水平不断增加。基于对该组耐药分离株的敏感性比较，阿扎那韦相对于检测的其他6种PI似乎具有不同的耐药特征。对943株PI敏感和耐药临床分离株的基因型谱进行分析，发现特定残基的氨基酸变化与PI耐药之间存在强相关性。（10 I/V/F、20 R/M/I、24 I、33 I/F/V、36 I/L/V、46 I/L、48 V、54 V/L、63 P、71 V/T/I、73 C/S/ T/A、82 A/F/S/T、84 V和90 M），并降低对阿扎那韦的敏感性。虽然没有单一取代或取代组合预测阿扎那韦耐药（变化>3.0倍），但这些取代中至少5个的存在与阿扎那韦敏感性的丧失强烈相关。还确定了与对其他6种PI的敏感性降低相关的突变。
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.