Human immunodeficiency virus type 1 mutants resistant to nonnucleoside inhibitors of reverse transcriptase arise in tissue culture.
Human immunodeficiency virus type 1 mutants resistant to nonnucleoside inhibitors of reverse transcriptase arise in tissue culture.
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DOI：
10.1073/pnas.88.24.11241
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发表时间：
1991-12
影响因子：
11.1
通讯作者：
D. Richman;C. Shih;Israel Lowy;J. Rose;Patricia C. Prodanovich;S. Goff;J. Griffin
中科院分区：
文献类型：
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作者：
D. Richman;C. Shih;Israel Lowy;J. Rose;Patricia C. Prodanovich;S. Goff;J. Griffin
我们最近描述了一种非核苷类化合物，可以特异性抑制人类免疫缺陷病毒1型（HIV-1）的逆转录酶，HIV-1是艾滋病的病原体。该化合物nevirapine （BI-RG-587）与逆转录酶中高度保守的酪氨酸残基181和188位相互作用，在40 nM范围内以50%的抑制浓度抑制重组酶和病毒复制。耐奈韦拉平的HIV-1变异出现在药物存在的细胞培养中传代。这种耐药表型在没有药物的情况下持续传代是稳定的。这些突变体在181位的酪氨酸被半胱氨酸取代。将该突变引入重组酶后，奈韦拉平的抑制浓度增加了100倍。在野生型病毒基因组中以半胱氨酸取代残基181处的酪氨酸，可使对奈韦拉平的易感性类似地降低。突变体也对四氢咪唑[4,5,1-jk][1,4]苯二氮卓-2(1H)- 1和-硫酮衍生物和两种6-苯基硫脲嘧啶衍生物耐药，但对其他逆转录酶抑制剂3'-叠氮-3'-脱氧胸腺嘧啶和膦红酮保持敏感性。
We have recently described a nonnucleoside compound that specifically inhibits the reverse transcriptase of human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS. This compound, nevirapine (BI-RG-587), interacts with highly conserved tyrosine residues at positions 181 and 188 in the reverse transcriptase to inhibit the recombinant enzyme and virus replication in cell culture with 50% inhibitory concentrations in the 40 nM range. HIV-1 variants resistant to nevirapine emerged with passage in cell culture in the presence of drug. This resistant phenotype was stable with continued passage in the absence of drug. These mutants had a substitution of cysteine for the tyrosine at position 181. Introduction of this mutation into the recombinant enzyme increased the inhibitory concentration of nevirapine 100-fold. Substitution of cysteine for tyrosine at residue 181 into the wild-type viral genome conferred a similar reduction in susceptibility to nevirapine. Mutants were also resistant to a tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione derivative and two 6-phenylthiouracil derivatives but retained their sensitivity to the other reverse transcriptase inhibitors, 3'-azido-3'-deoxythymidine and foscarnet.