Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Science. 2021 Jan 8;371(6525):190-194. doi: 10.1126/science.abb9425.
There are no approved flaviviral therapies and the development of vaccines against flaviruses has the potential of being undermined by antibody-dependent enhancement (ADE). The flavivirus nonstructural protein 1 (NS1) is a promising vaccine antigen with low ADE risk but has yet to be explored as a broad-spectrum therapeutic antibody target. Here, we provide the structural basis of NS1 antibody cross-reactivity through cocrystallization of the antibody 1G5.3 with NS1 proteins from dengue and Zika viruses. The 1G5.3 antibody blocks multi-flavivirus NS1-mediated cell permeability in disease-relevant cell lines, and therapeutic application of 1G5.3 reduces viremia and improves survival in dengue, Zika, and West Nile virus murine models. Finally, we demonstrate that 1G5.3 protection is independent of effector function, identifying the 1G5.3 epitope as a key site for broad-spectrum antiviral development.
目前尚无批准的黄病毒治疗方法，而疫苗的开发有可能因抗体依赖性增强（ADE）而受到影响。黄病毒非结构蛋白 1（NS1）是一种很有前途的疫苗抗原，其 ADE 风险较低，但尚未被探索作为广谱治疗性抗体靶标。在这里，我们通过与登革热和寨卡病毒的 NS1 蛋白共结晶，提供了 NS1 抗体交叉反应性的结构基础。抗体 1G5.3 可阻断多种黄病毒 NS1 介导的疾病相关细胞系中的细胞通透性，并且 1G5.3 的治疗应用可降低登革热、寨卡病毒和西尼罗河病毒小鼠模型中的病毒血症并提高存活率。最后，我们证明 1G5.3 的保护作用不依赖于效应功能，确定了 1G5.3 表位是广谱抗病毒药物开发的关键部位。
