埃替拉韦克服整合酶突变 Y143 引起的对拉替拉韦的耐药性。
Elvitegravir overcomes resistance to raltegravir induced by integrase mutation Y143.
机构信息
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
出版信息
AIDS. 2011 Jun 1;25(9):1175-8. doi: 10.1097/QAD.0b013e3283473599.
Abstract
OBJECTIVE
In this study, we characterized elvitegravir activity in the context of raltegravir resistance mutations.
DESIGN
Using site-directed mutagenesis, we generated recombinant integrase proteins and viruses harboring raltegravir resistance mutation to assess the biochemical and cellular activity of elvitegravir in the presence of such mutants.
METHODS
Recombinant proteins were used in gel-based assays. Antiviral data were obtained with reporter viruses in a single-round infection using a luciferase-based assay.
RESULTS
Although main raltegravir resistance pathways involving mutations at integrase position 148 and 155 confer cross-resistance to elvitegravir, elvitegravir remains fully active against the Y143R mutant integrase and virus particles.
CONCLUSION
In addition to favorable pharmacokinetics compared to raltegravir, our findings provide the rationale for using elvitegravir in patients failing raltegravir because of the integrase mutation Y143.
摘要
目的
本研究旨在探讨依曲韦林在整合酶耐药突变背景下的活性。
设计
通过定点突变，我们构建了携带整合酶耐药突变的重组整合酶蛋白和病毒，以评估依曲韦林在存在这些突变体时的生化和细胞活性。
方法
使用凝胶基检测法检测重组蛋白。采用基于荧光素酶的检测法，利用单轮感染中的报告病毒获得抗病毒数据。
结果
尽管涉及整合酶位置 148 和 155 突变的主要耐药途径导致与依曲韦林交叉耐药，但依曲韦林对 Y143R 突变整合酶和病毒颗粒仍保持完全活性。
结论
与依曲韦林相比，除了良好的药代动力学特性外，我们的研究结果为因整合酶突变 Y143 而对依曲韦林耐药的患者使用依曲韦林提供了依据。
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