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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Characterization of the E138K resistance mutation in HIV-1 reverse transcriptase conferring susceptibility to etravirine in B and non-B HIV-1 subtypes.
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Characterization of the E138K resistance mutation in HIV-1 reverse transcriptase conferring susceptibility to etravirine in B and non-B HIV-1 subtypes.

机译：HIV-1逆转录酶中E138K抗药性突变的特征，赋予B和非B HIV-1亚型对依曲韦林敏感性。

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摘要

We have selected for resistance to etravirine (ETR) and efavirenz (EFV) in tissue culture using three subtype B, three subtype C, and two CRF02_AG clinical isolates, grown in cord blood mononuclear cells. Genotypic analysis was performed at baseline and at various weeks of selection. Phenotypic resistance in regard to ETR, EFV, and nevirapine (NVP) was evaluated at weeks 25 to 30 for all ETR-selected viruses and in viral clones that contained specific resistance mutations that were inserted by site-directed mutagenesis into pNL-4.3 and AG plasmids. The results show that ETR selected mutations at positions V90I, K101Q, E138K, V179D/E/F, Y181C, V189I, G190E, H221H/Y, and M230L and that E138K was the first of these to emerge in most instances. The time to the emergence of resistance was longer in the case of ETR (18 weeks) compared to EFV (11 weeks), and no differences in the patterns of emergent mutations could be documented between the B and non-B subtypes. Viral clones containing E138K displayed low-level phenotypic resistance to ETR (3.8-fold) and modestly impaired replication capacity (2-fold) compared to wild-type virus. ETR-selected virus showed a high degree of cross-resistance to NVP but not to EFV. We identified K101Q, E138K, V179E, V189I, G190E, and H221Y as mutations not included among the 17 currently recognized resistance-associated mutations for ETR.
机译：我们选择了在脐带血单核细胞中生长的三种亚型B，三种亚型C和两种CRF02_AG临床分离株对组织培养中的依曲韦林（ETR）和依非韦伦（EFV）的耐药性。在基线和选择的各个星期进行基因型分析。在25至30周时，针对所有ETR选择的病毒以及包含通过定向诱变插入pNL-4.3和AG的特定抗性突变的病毒克隆，评估了对ETR，EFV和奈韦拉平（NVP）的表型抗性质粒。结果表明，ETR选择了V90I，K101Q，E138K，V179D / E / F，Y181C，V189I，G190E，H221H / Y和M230L位置的突变，而E138K在大多数情况下是第一个出现的突变。与EFV（11周）相比，ETR（18周）产生耐药性的时间更长，并且B和非B亚型之间的突变突变模式没有差异。与野生型病毒相比，包含E138K的病毒克隆对ETR表现出低水平的表型抗性（3.8倍），复制能力受到中等程度的损害（2倍）。 ETR选择的病毒对NVP表现出高度的交叉抗性，而对EFV没有。我们将K101Q，E138K，V179E，V189I，G190E和H221Y确定为目前不包括在17种与ETR相关的耐药相关突变中的突变。

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