Implications of HIV-1 M Group Polymorphisms on Integrase Inhibitor Efficacy and Resistance: Genetic and Structural in Silico Analyses
Implications of HIV-1 M Group Polymorphisms on Integrase Inhibitor Efficacy and Resistance: Genetic and Structural in Silico Analyses
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DOI：
10.1021/bi8019349
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发表时间：
2009-01-13
期刊：
影响因子：
2.9
通讯作者：
Kostrikis, Leondios G.
中科院分区：
文献类型：
--
作者：
Loizidou, Eriketi Z.;Kousiappa, Ioanna;Kostrikis, Leondios G.
HIV-1亚型之间广泛的多态性与耐药性的发展有关。整合酶抑制剂是HIV-1治疗的最新补充，目前正在研究其在M组菌株中的疗效和耐药模式。本研究分析了来自7个亚型的108个整合酶序列的亚型间变异。所有菌株中与催化活性和对雷特格韦的原发性耐药相关的残基高度保守。在与次生抗性相关的残留物中观察到变异。分子模拟研究表明，雷特格韦的双向结合模式解释了耐药途径和整合酶-雷特格韦相互作用中非保守突变的含义。
The extensive polymorphisms among HIV-1 subtypes have been implicated in drug resistance development. Integrase inhibitors represent the latest addition to the treatment of HIV-1, and their efficacy and resistance patterns among M group strains are currently under investigation. This study analyzed the intersubtype variation within 108 integrase sequences from seven subtypes. The residues associated with catalytic activity and primary resistance to raltegravir were highly conserved among all strains. Variations were observed in residues associated with secondary resistance. Molecular modeling studies indicated a two-way binding mode of raltegravir that explains the resistance pathways and the implication of nonconservative mutations in integrase-raltegravir interactions.