近日，美国La Jolla免疫学研究所的Erica Ollmann Saphire研究组通过解析拉沙（LASV）病毒抗体的晶体结构，进一步研发了泛拉沙病毒抗体。该项研究成果发表在2019年8月9日出版的《细胞》上。
研究人员比较了LASV表面糖蛋白（GPC）与不同中和效力的GPC-B抗体形成复合体的三种晶体结构。每种GPC-B抗体识别参与两个相邻GPC单体结合的重叠表位并保持融合前三聚体构象。 GPC与抗体相互作用之间的差异凸显了增强中和作用的特定氨基酸残基。使用结构指导的氨基酸置换，研究人员增加了这些抗体针对所有主要的LASV谱系的中和效力和范围。对于开发有效的疗法以及对于疫苗设计和评估而言，寻找可以增加中和活力的氨基酸残基并分析前体抗体信息是至关重要的。
据介绍，拉沙病毒能够引起出血热并且在西非流行。保护性抗体应答主要针对LASV表面糖蛋白，而GPC-B竞争抗体在人类中通常显示出有效的中和活性。然而，哪些特征能够产生有效且广泛中和抗体反应尚不清楚。
附：英文原文
Title: Convergent Structures Illuminate Features for Germline Antibody Binding and Pan-Lassa Virus Neutralization
Author: Kathryn M. Hastie, Robert W. Cross, Stephanie S. Harkins, Michelle A. Zandonatti, Anatoliy P. Koval, Megan L. Heinrich, Megan M. Rowland, James E. Robinson, Thomas W. Geisbert, Robert F. Garry, Luis M. Branco, Erica Ollmann Saphire
Issue&Volume: Volume 178 Issue 4
Abstract: Lassa virus (LASV) causes hemorrhagic fever and is endemic in West Africa. Protective antibody responses primarily target the LASV surface glycoprotein (GPC), and GPC-B competition group antibodies often show potent neutralizing activity in humans. However, which features confer potent and broadly neutralizing antibody responses is unclear. Here, we compared three crystal structures of LASV GPC complexed with GPC-B antibodies of varying neutralization potency. Each GPC-B antibody recognized an overlapping epitope involved in binding of two adjacent GPC monomers and preserved the prefusion trimeric conformation. Differences among GPC-antibody interactions highlighted specific residues that enhance neutralization. Using structure-guided amino acid substitutions, we increased the neutralization potency and breadth of these antibodies to include all major LASV lineages. The ability to define antibody residues that allow potent and broad neutralizing activity, together with findings from analyses of inferred germline precursors, is critical to develop potent therapeutics and for vaccine design and assessment.
DOI: https://doi.org/10.1016/j.cell.2019.07.020
Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30785-8