Three main mutational pathways in HIV-2 lead to high-level raltegravir and elvitegravir resistance: implications for emerging HIV-2 treatment regimens.
Three main mutational pathways in HIV-2 lead to high-level raltegravir and elvitegravir resistance: implications for emerging HIV-2 treatment regimens.
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DOI：
10.1371/journal.pone.0045372
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
University of Washington-Dakar HIV-2 Study Group
中科院分区：
文献类型：
--
作者：
Smith RA;Raugi DN;Pan C;Coyne M;Hernandez A;Church B;Parker K;Mullins JI;Sow PS;Gottlieb GS;University of Washington-Dakar HIV-2 Study Group
人类免疫缺陷病毒2型（HIV-2）对非核苷类逆转录酶抑制剂具有内在耐药性，对用于HIV-1抗逆转录病毒治疗的几种蛋白酶抑制剂的敏感性降低。因此，迫切需要确定对HIV-2有活性的新型抗逆转录病毒药物。虽然最近的数据表明，整合酶链转移抑制剂雷特格韦和埃替格韦可能是有益的，已知的突变赋予这些药物在HIV-1已报告在HIV-2序列接受雷特格韦含方案的患者。为了检查雷特格韦治疗期间出现的突变的表型效应，我们使用定点诱变构建了一组HIV-2整合酶变体，并测量了突变株对雷特格韦和埃替格韦的敏感性。还评价了单个和多个氨基酸变化对HIV-2复制能力的影响。我们的研究结果表明，在整合酶蛋白的二次置换中发挥关键作用的整合酶抑制剂耐药的HIV-2的发展。总的来说，我们的数据定义了三个主要的突变途径，以高水平的雷特格韦和埃替格韦耐药：i）E92 Q + Y143 C或T97 A + Y143 C，ii）G140 S + Q148 R，和iii）E92 Q + N155 H。这些发现排除了顺序使用雷特格韦和埃替格韦（反之亦然）治疗HIV-2，并为HIV-2感染者整合酶抑制剂耐药性的临床监测提供了重要信息。
Human immunodeficiency virus type 2 (HIV-2) is intrinsically resistant to non-nucleoside reverse transcriptase inhibitors and exhibits reduced susceptibility to several of the protease inhibitors used for antiretroviral therapy of HIV-1. Thus, there is a pressing need to identify new classes of antiretroviral agents that are active against HIV-2. Although recent data suggest that the integrase strand transfer inhibitors raltegravir and elvitegravir may be beneficial, mutations that are known to confer resistance to these drugs in HIV-1 have been reported in HIV-2 sequences from patients receiving raltegravir-containing regimens. To examine the phenotypic effects of mutations that emerge during raltegravir treatment, we constructed a panel of HIV-2 integrase variants using site-directed mutagenesis and measured the susceptibilities of the mutant strains to raltegravir and elvitegravir in culture. The effects of single and multiple amino acid changes on HIV-2 replication capacity were also evaluated. Our results demonstrate that secondary replacements in the integrase protein play key roles in the development of integrase inhibitor resistance in HIV-2. Collectively, our data define three major mutational pathways to high-level raltegravir and elvitegravir resistance: i) E92Q+Y143C or T97A+Y143C, ii) G140S+Q148R, and iii) E92Q+N155H. These findings preclude the sequential use of raltegravir and elvitegravir (or vice versa) for HIV-2 treatment and provide important information for clinical monitoring of integrase inhibitor resistance in HIV-2–infected individuals.
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