在病毒中避开抗体中和的热力学机制
Rodrigo A Maillard1, Tong Liu, David W C Beasley
1Department of Biochemistry & Molecular Biology, ‡Department of Microbiology & Immunology, §Department of Pathology, ∥Sealy Center for Vaccine Development, ⊥Institute for Human Infections and Immunity and #Sealy Center for Structural Biology and Molecular Biophysics, The University of Texas Medical Branch , Galveston, Texas 77555, United States.
影响病毒蛋白波动的突变可以改变抗体结合,导致中和抵抗. 了解这些变化是制定有效的抗病毒策略对抗黄病毒病毒的关键.
科学领域:
- 病毒学 病毒学
- 结构生物学 结构生物学
- 免疫学 免疫学 免疫学
背景情况:
- 病毒抗原蛋白表位的突变可以导致抗体耐药性和病毒逃逸.
- 表位残留的基本特性及其对抗体结合的突变效应仍然不太清楚.
研究的目的:
- 描述表位残留物,并了解突变如何影响抗体结合和病毒中和易感性.
- 为了研究热力学扰动,表位位置和抗体逃避之间的关系.
主要方法:
- 利用基于集合的算法来分析突变对蛋白质结构热力学的影响.
- 将该方法应用于西尼罗河和登革热2病毒的包膜蛋白域III (ED3).
- 在表位形状波动与抗体结合亲和力缺陷相关的变化.
主要成果:
- 确定了残留物对热力学变化的敏感性和表位位位置之间的直接关系,使初级表位位的识别成为可能.
- 显示,赋予抗体逃避的突变通过局部或远程效应改变了表位构造的波动.
- 证明遥远的突变通过形状再分配影响中和,而不是连续的途径.
结论:
- 表位构造波动的微妙变化与显著的抗体结合缺陷相关,解释了中和抵抗.
- 病毒逃生突变减少中和可能不会导致重大结构变化,突出显示蛋白质动态的作用.
- 蛋白质的波动和长距离相互作用是基底抗体介导的抗中和性阻力在flaviviruses的关键机制.
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