Epistasis and entrenchment of drug resistance in HIV-1 subtype B
Epistasis and entrenchment of drug resistance in HIV-1 subtype B
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DOI：
10.7554/elife.50524
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发表时间：
2019-10-08
期刊：
影响因子：
7.7
通讯作者：
Levy, Ronald M.
中科院分区：
文献类型：
--
作者：
Biswas, Avik;Haldane, Allan;Levy, Ronald M.
HIV耐药性的发展是原发性突变的结果，其对病毒适应性的影响取决于整个遗传背景，这种现象称为“上位性”。基于来自斯坦福大学HIV数据库中有药物经验的患者的蛋白质序列，我们使用共同进化（Potts）Hamilton模型来直接确认涉及许多同时突变的上位性。在早期工作的基础上，我们发现导致耐药性的原发性突变可以变得非常有利尽管在野生型背景中不受欢迎，但是通过响应于药物治疗而产生的复杂突变模式来确定（或巩固），并首次证实了所有三种药物靶蛋白的巩固：蛋白酶，逆转录酶和整合酶;比较分析表明，NNRTI诱导的突变与其他突变表现不同。我们进一步表明，耐药突变的可能性在患者人群中差异很大，与特定分子克隆相比，与群体平均值不同。
The development of drug resistance in HIV is the result of primary mutations whose effects on viral fitness depend on the entire genetic background, a phenomenon called 'epistasis'. Based on protein sequences derived from drug-experienced patients in the Stanford HIV database, we use a co-evolutionary (Potts) Hamiltonian model to provide direct confirmation of epistasis involving many simultaneous mutations. Building on earlier work, we show that primary mutations leading to drug resistance can become highly favored (or entrenched) by the complex mutation patterns arising in response to drug therapy despite being disfavored in the wild-type background, and provide the first confirmation of entrenchment for all three drug-target proteins: protease, reverse transcriptase, and integrase; a comparative analysis reveals that NNRTI-induced mutations behave differently from the others. We further show that the likelihood of resistance mutations can vary widely in patient populations, and from the population average compared to specific molecular clones.