Center for Biophysics and Computational Biology, Temple University, Philadelphia, United States.
Department of Physics, Temple University, Philadelphia, United States.
Elife. 2019 Oct 8;8:e50524. doi: 10.7554/eLife.50524.
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.
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，这一现象被称为“上位性”。基于来自斯坦福 HIV 数据库中药物经验丰富的患者的蛋白质序列，我们使用共进化（Potts）哈密顿模型，直接证实了涉及许多同时突变的上位性。在早期工作的基础上，我们表明，尽管在野生型背景下不占优势，但导致耐药性的原发性突变可能会因药物治疗引起的复杂突变模式而变得非常有利（或根深蒂固），并首次证实所有三种药物靶点蛋白（蛋白酶、逆转录酶和整合酶）的根深蒂固现象；比较分析表明，NNRTI 诱导的突变与其他突变不同。我们还表明，耐药突变的可能性在患者群体中差异很大，与特定分子克隆相比，与人群平均值相比差异很大。
