CONVERGENT COMBINATION THERAPY CAN SELECT VIABLE MULTIDRUG-RESISTANT HIV-1 IN-VITRO
CONVERGENT COMBINATION THERAPY CAN SELECT VIABLE MULTIDRUG-RESISTANT HIV-1 IN-VITRO
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DOI：
10.1038/365451a0
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发表时间：
1993-09-30
期刊：
影响因子：
64.8
通讯作者：
KEMP, SD
中科院分区：
文献类型：
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作者：
LARDER, BA;KELLAM, P;KEMP, SD
人类免疫缺陷病毒1型（HIV-1）的逆转录酶是许多病原体的靶标1。酶功能区的氨基酸取代可消除逆转录酶活性，也可防止HIV-1复制2，3。但是诸如AZT（3'-叠氮基-3'-脱氧胸苷，齐多夫定）4 - 6、ddI（2'，3'-双脱氧肌苷）7，8和非核苷逆转录酶抑制剂（NNRTI）9 - 14等药物的选择压力由于酶中的非致命突变而导致耐药变体的生长7，9 - 16。关于逆转录酶抑制剂之间的协同作用17 - 19和缺乏交叉耐药性的报告（参考文献7、9、10、12 - 14、17、18、20、21），加上ddI 7和NNRTI诱导的突变逆转AZT耐药性14，表明针对逆转录酶的特定药物组合可能会减少耐药性。Chow等人22在一份报告中扩展了这一概念，即逆转录酶中耐药突变的特定多重组合可显著损害HIV-1复制。他们的结论是，可能存在进化限制，以防止逆转录酶抑制剂的多药耐药性的出现22。我们在此报告，从AZT和ddI双重耐药病毒开始，在细胞培养中可以很容易地选择对AZT、ddI和NNRTI奈韦拉平23共耐药的HIV-1。我们没有发现耐药突变“复制不相容”组合的证据，尽管逆转录酶中赋予氧硫杂环戊烷-胞嘧啶核苷耐药性的突变（M184--> V）24，25完全抑制了三重耐药背景中的AZT耐药性。这些体外观察结果表明，三联药物联合治疗可能最终导致共耐药HIV-1，尽管它们并不排除评估此类联合治疗HIV-1疾病。
THE reverse transcriptase enzyme of human immunodeficiency virus type 1 (HIV-1) is the target for many inhibitors1. Amino-acid substitutions in functional regions of the enzyme that abolish reverse transcriptase activity also prevent HIV-1 replication2,3. But selection pressure by drugs such as AZT (3'-azido-3'-deoxythymidine, zidovudine)4-6, ddI(2',3'-dideoxyinosine)7,8 and non-nucleoside reverse transcriptase inhibitors (NNRTIs)9-14 causes outgrowth of resistant variants due to non-lethal mutations in the enzyme7,9-16. Reports of synergy17-19 and lack of cross-resistance between reverse transcriptase inhibitors (refs 7, 9, 10, 12-14, 17, 18, 20, 21), plus the reversal of AZT resistance by mutations induced by ddI7 and NNRTIs14, have indicated that specific drug combinations directed at reverse transcriptase might curtail resistance. Chow et al.22 extended this concept in a report that specific multiple combinations of resistance mutations in the reverse transcriptase can significantly impair HIV-1 replication. They concluded that evolutionary limitations may exist to prevent the emergence of multidrug resistance to inhibitors of reverse transcriptase22. We report here that HIV-1 co-resistant to AZT, ddI and the NNRTI nevirapine23 can be readily selected in cell culture starting with dual AZT- and ddI-resistant virus. We found no evidence for 'replication incompatible' combinations of resistance mutations, although a mutation (M184-->V) conferring oxathiolane-cytosine nucleoside resistance in reverse transcriptase24,25 completely suppressed AZT resistance in a triple-resistant background. These in vitro observations suggest that triple drug combination therapy might ultimately result in co-resistant HIV-1, although they do not preclude assessment of such combinations for treatment of HIV-1 disease.