Primary mutations selected in vitro with raltegravir confer large fold changes in susceptibility to first-generation integrase inhibitors, but minor fold changes to inhibitors with second-generation resistance profiles
Primary mutations selected in vitro with raltegravir confer large fold changes in susceptibility to first-generation integrase inhibitors, but minor fold changes to inhibitors with second-generation resistance profiles
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DOI：
10.1016/j.virol.2010.03.034
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发表时间：
2010-07-05
期刊：
影响因子：
3.7
通讯作者：
Clayton, Reginald
中科院分区：
文献类型：
--
作者：
Goethals, Olivia;Vos, Ann;Clayton, Reginald
对雷特格韦耐药性的出现降低了其在HIV-1感染患者中的治疗效果。为了描述耐药突变对病毒对整合酶抑制剂敏感性的影响，使用雷特格韦和MK-2048（一种具有第二代样耐药特征的整合酶抑制剂）进行了体外耐药选择。突变Q148 R出现在6个雷特格韦选择耐药病毒中的4个。此外，选择突变Q148 K和N155 H。在相同的时间范围内，MK-2048未选择突变。Q148 H/K/R和N155 H赋予了对雷特格韦的耐药性，但对MK-2048的敏感性仅有微小变化。V54 I是一种以前未报告的突变，用雷特格韦选择，被确定为可能的补偿突变。基于整合酶的结构模型，提出了N155 H、Q148 H/K/R、Y143 R和E92 Q赋予抗性的机制。这些数据提高了对雷特格韦耐药性和对MK-2048和其他整合酶抑制剂交叉耐药性的理解，这将有助于发现第二代整合酶抑制剂。(C)2010年爱思唯尔公司All rights reserved.
Emergence of resistance to raltegravir reduces its treatment efficacy in HIV-1-infected patients. To delineate the effect of resistance mutations on viral susceptibility to integrase inhibitors, in vitro resistance selections with raltegravir and with MK-2048, an integrase inhibitor with a second-generation-like resistance profile, were performed. Mutation Q148R arose in four out of six raltegravir-selected resistant viruses. In addition, mutations Q148K and N155H were selected. In the same time frame, no mutations were selected with MK-2048. Q148H/K/R and N155H conferred resistance to raltegravir, but only minor changes in susceptibility to MK-2048. V54I, a previously unreported mutation, selected with raltegravir, was identified as a possible compensation mutation. Mechanisms by which N155H, Q148H/K/R, Y143R and E92Q confer resistance are proposed based on a structural model of integrase. These data improve the understanding of resistance against raltegravir and cross-resistance to MK-2048 and other integrase inhibitors, which will aid in the discovery of second-generation integrase inhibitors. (C) 2010 Elsevier Inc. All rights reserved.