Miller Nathaniel L, Clark Thomas, Raman Rahul, Sasisekharan Ram
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
bioRxiv. 2022 Mar 2:2022.02.25.481957. doi: 10.1101/2022.02.25.481957.
The SARS-CoV-2 Omicron sub-variants BA.1 and BA.2 have become the dominant variants worldwide due to enhanced transmissibility and immune evasion. In response to the rise of BA.1 and BA.2, two recent studies by Liu et al. and Iketani et al. provide a detailed analysis of loss of therapeutic antibody potency through evaluation of escape by pseudotyped viruses harboring BA.1 and BA.2 receptor binding domain (RBD) point mutations. Surprisingly, Liu et al. and Iketani et al. observed a profoundly broad escape effect for the individual mutations S371L and S371F. This result cannot be explained by known escape mechanisms of the SARS-CoV-2 RBD, and conflicts with existing computational and experimental escape measurements for S371 mutations performed on monomeric RBD. Through an examination of these conflicting datasets and a structural analysis of the antibodies assayed by Liu et al. and Iketani et al., we propose a mechanism to explain S371L/F escape according to a perturbation of spike trimer conformational dynamics that has not yet been described for any SARS-CoV-2 escape mutation. The proposed mechanism is relevant to Omicron and future variant surveillance as well as therapeutic antibody design.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的奥密克戎亚变体BA.1和BA.2由于传播性增强和免疫逃逸，已成为全球主要变体。为应对BA.1和BA.2的出现，刘等人和池谷等人最近的两项研究通过评估携带BA.1和BA.2受体结合域（RBD）点突变的假型病毒的逃逸情况，对治疗性抗体效力的丧失进行了详细分析。令人惊讶的是，刘等人和池谷等人观察到单个突变S371L和S371F具有广泛的逃逸效应。这一结果无法用SARS-CoV-2 RBD已知的逃逸机制来解释，并且与对单体RBD进行的S371突变的现有计算和实验逃逸测量结果相矛盾。通过检查这些相互矛盾的数据集，并对刘等人和池谷等人检测的抗体进行结构分析，我们提出了一种机制，根据刺突三聚体构象动力学的扰动来解释S371L/F逃逸，这种扰动尚未在任何SARS-CoV-2逃逸突变中被描述过。所提出的机制与奥密克戎及未来变体监测以及治疗性抗体设计相关。
