Abstract：
Lassa virus is estimated to cause thousands of human deaths per year, primarily due to spillovers from its natural host, Mastomys rodents. Efforts to create vaccines and antibody therapeutics must account for the evolutionary variability of the Lassa virus\'s glycoprotein complex (GPC), which mediates viral entry into cells and is the target of neutralizing antibodies. To map the evolutionary space accessible to GPC, we used pseudovirus deep mutational scanning to measure how nearly all GPC amino-acid mutations affected cell entry and antibody neutralization. Our experiments defined functional constraints throughout GPC. We quantified how GPC mutations affected neutralization with a panel of monoclonal antibodies. All antibodies tested were escaped by mutations that existed among natural Lassa virus lineages. Overall, our work describes a biosafety-level-2 method to elucidate the mutational space accessible to GPC and shows how prospective characterization of antigenic variation could aid the design of therapeutics and vaccines.
摘要：
拉沙病毒估计每年导致数千人死亡，主要是由于其自然宿主的溢出效应，Mastomys啮齿动物。创建疫苗和抗体疗法的努力必须考虑到拉沙病毒糖蛋白复合物（GPC）的进化变异性，介导病毒进入细胞，是中和抗体的靶标。要绘制GPC可访问的进化空间，我们使用假病毒深度突变扫描来测量几乎所有GPC氨基酸突变如何影响细胞进入和抗体中和.我们的实验在整个GPC中定义了功能约束。我们用一组单克隆抗体定量GPC突变如何影响中和。所有测试的抗体都通过天然拉沙病毒谱系中存在的突变而逃脱。总的来说,我们的工作描述了一种生物安全2级方法来阐明GPC可进入的突变空间,并展示了抗原变异的前瞻性表征如何有助于治疗和疫苗的设计.
