Structural insights into the distinct protective mechanisms of human antibodies targeting ZIKV NS1
Qi Pan,
Xiaomin Xing,
Jianhai Yu,
Qiang Chen,
Haizhan Jiao,
Wanqin Zhang,
Yingfen Wen,
Ming Gao,
Wei Zhao,
Lei Yu,
Hongli Hu
Affiliations
Qi Pan
Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
Xiaomin Xing
Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangdong, China
Jianhai Yu
BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangdong, China
Qiang Chen
Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
Haizhan Jiao
Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
Wanqin Zhang
Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
Yingfen Wen
Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangdong, China
Ming Gao
Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangdong, China
Wei Zhao
BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangdong, China; Correspondence:
Lei Yu
Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangdong, China; Correspondence:
Hongli Hu
Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China; Correspondence:
Antibodies targeting non-structural protein 1 (NS1) confer protection against Zika virus (ZIKV). Although monoclonal antibodies (MAbs) 3G2 and 4B8 are more potent than MAb 4F10 in suppressing ZIKV infection in neonatal mice models, the epitopes are unclear. Herein, we determined the Cryo-electron microscopy (Cryo-EM) structures of ZIKV NS1 in complex with five human antibodies at 2.6–2.9 Å resolution. Group I antibodies (3G2 and 4B8) recognize the previously unreported epitopes on the outer surface of the NS1 dimer. The unique binding mode of Group I antibodies led to a stronger recognition of the cell surface form of NS1 and completely inhibited secreted form non-structural protein 1 (sNS1)-induced endothelial permeability via their immunoglobulin G (IgG) and Fab. Group II antibodies (4F10, 2E11, and 14G5) recognize common epitopes in the distal end of the β-ladder domain, with a blockade efficiency that may be related to their affinity for the sNS1 protein and the presence of full-length IgG. These findings elucidate the correlation between epitope recognition and protective efficacy of anti-NS1 antibodies and highlight the diagnostic and therapeutic potential of 3G2 and 4B8.
