动力共进化模型预测在药物选择压力下,HIV-1耐药性突变的时间出现
Avik Biswas1,2,3, Indrani Choudhuri1,4, Eddy Arnold5
1Center for Biophysics and Computational Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122.
概括
了解HIV-1药物耐药性的演变至关重要. 突变相互作用驱动着随着时间的推移产生耐药突变 (DRM),影响治疗的有效性.
科学领域:
- 病毒学 病毒学
- 计算生物学 计算生物学
- 进化生物学 进化生物学
背景情况:
- 人类免疫缺陷病毒1型 (HIV-1) 的耐药性构成了全球卫生挑战.
- 现有的数据库广泛记录了耐药突变 (DRM),但它们的进化动态和共同进化不明.
- 突变之间的相互作用 (epistasis) 对HIV-1耐药性的时间发展至关重要.
研究的目的:
- 研究HIV-1中耐药突变 (DRM) 的进化动力学.
- 了解表观症如何影响DRM在药物选择压力下的出现和共同演变.
- 通过使用计算建模,探索DRM获取途径在药物原始患者序列中.
主要方法:
- 利用波特的序列-共变统计-能量模型来捕捉HIV-1蛋白质中的表皮性相互作用.
- 采用动力蒙特卡洛模拟来建模HIV-1序列的进化轨迹.
- 在模拟药物压力下跟踪了52个DRM在蛋白酶,逆转录酶 (RT) 和整合酶的出现.
主要成果:
- DRM 的出现率与在药物压力下观察到的获取率有很强的相关性.
- 快速获得的DRMs在药物施加压力后立即积累.
- 缓慢获得的DRM需要先前积累辅助突变,表明随机进化.
结论:
- 在确定HIV-1中DRM出现的动力学方面,表观作用起着核心作用.
- 像波茨模型这样的计算方法可以阐明药物耐药性的时间演变.
- 这种方法提供了对HIV-1药物耐药性途径的机制性见解,可以应用于其他传染病原体.
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