Structural Considerations in the Fitness Landscape of a Virus
Structural Considerations in the Fitness Landscape of a Virus
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DOI：
10.1093/molbev/msq056
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发表时间：
2010-08-01
影响因子：
10.7
通讯作者：
Kishino, Hirohisa
中科院分区：
文献类型：
--
作者：
Watabe, Teruaki;Kishino, Hirohisa
病毒适应性由宿主内的复制和宿主间的传播决定。我们研究了具有拮抗作用的多效性突变（即，抗体逃避与受体结合）对宿主内病毒复制的影响可以影响宿主群体中的病毒免疫逃避。当宿主群体接种疫苗时，病毒通过靶蛋白表面上的抗体结合区的突变逃避被动免疫。然而，抗体结合病毒的能力降低通常伴随着病毒结合细胞受体的能力降低，因为抗体结合区与受体结合结构域（RBD）重叠。允许的突变类型是有限的。为了研究病毒基因组中的突变与病毒群体的适应性进化之间的因果关系，我们开发了一个数学模型，该模型描述了宿主内病毒、抗体和正常/感染细胞的群体动态。该系数描述了病毒与诱导抗体之间以及病毒与其受体之间的结合亲和力。我们的基于知识的索引使我们能够估计结合区域中的突变对结合亲和力的影响。利用群体遗传学理论，我们评估了突变体在宿主群体中被固定的概率。可以以高概率固定的突变可能决定疫苗保持有效的时间。我们模拟了严重急性呼吸综合征的病原体冠状病毒的适应性进化，并表明RBD中的一些突变可能在接种疫苗的宿主群体中具有较高的固定概率。
Viral fitness is determined by replication within hosts and transmission between them. We examine how pleiotropic mutations that have antagonistic effects (i.e., antibody evasion vs. receptor binding) on viral replication within hosts can impact viral immune escape in the host population. When the host population is vaccinated, the virus escapes from passive immunity by mutations in the antibody-binding region on the surface of the target protein. However, the reduced ability of the antibody to bind the virus is often accompanied by a reduced ability of the virus to bind the cell receptor because the antibody-binding region overlaps with the receptor-binding domain (RBD). The types of permitted mutations are limited. To investigate the causal relation between a mutation in a viral genome and adaptive evolution of a viral population, we developed a mathematical model that describes the population dynamics of viruses, antibodies, and normal/infected cells within a host. The coefficients describe the binding affinity between the virus and the induced antibody and that between the virus and its receptor. Our knowledge-based index enables us to estimate the effect of a mutation in a binding region on the binding affinity. Using population genetic theory, we evaluated the probability that a mutant is fixed in a host population. The mutations that can be fixed with high probabilities may determine how long a vaccine remains effective. We simulate the adaptive evolution of coronavirus, the etiological agent of severe acute respiratory syndrome, and show that some of mutations in the RBD may have high fixation probabilities in the vaccinated host population.