Tailored design of protein nanoparticle scaffolds for multivalent presentation of viral glycoprotein antigens
Tailored design of protein nanoparticle scaffolds for multivalent presentation of viral glycoprotein antigens
复制标题
DOI：
10.7554/elife.57659
复制
发表时间：
2020-08-04
期刊：
影响因子：
7.7
通讯作者：
Baker, David
中科院分区：
文献类型：
--
作者：
Ueda, George;Antanasijevic, Aleksandar;Baker, David
病毒糖蛋白的多价呈递可以显著增加抗原特异性抗体的激发。为了实现新一代的抗病毒疫苗，我们设计了自组装蛋白质纳米颗粒，其几何形状定制为呈现流感，HIV和RSV病毒糖蛋白三聚体的胞外域。我们首先从头设计了为抗原融合量身定制的三聚体，其特征在于N-末端螺旋定位成与病毒糖蛋白的C末端相匹配。三聚体，实验采用其设计的配置被纳入作为组件的四面体，八面体，和二十面体的纳米粒子，其特征在于通过冷冻电子显微镜和评估其能力，目前病毒糖蛋白。电子显微镜和抗体结合实验表明，所设计的纳米颗粒呈现抗原性完整的融合前HIV-1 Env，流感血凝素和RSV F三聚体在预测的几何形状。这项工作表明，抗原展示蛋白纳米颗粒可以从头开始设计，并提供了一个系统的方法来研究抗原呈递几何形状对免疫应答的影响。
Multivalent presentation of viral glycoproteins can substantially increase the elicitation of antigen-specific antibodies. To enable a new generation of anti-viral vaccines, we designed selfassembling protein nanoparticles with geometries tailored to present the ectodomains of influenza, HIV, and RSV viral glycoprotein trimers. We first de novo designed trimers tailored for antigen fusion, featuring N-terminal helices positioned to match the C termini of the viral glycoproteins. Trimers that experimentally adopted their designed configurations were incorporated as components of tetrahedral, octahedral, and icosahedral nanoparticles, which were characterized by cryo-electron microscopy and assessed for their ability to present viral glycoproteins. Electron microscopy and antibody binding experiments demonstrated that the designed nanoparticles presented antigenically intact prefusion HIV-1 Env, influenza hemagglutinin, and RSV F trimers in the predicted geometries. This work demonstrates that antigen-displaying protein nanoparticles can be designed from scratch, and provides a systematic way to investigate the influence of antigen presentation geometry on the immune response to vaccination.