Structural insights into the distinct protective mechanisms of human antibodies targeting ZIKV NS1
image: Group I antibodies (3G2 and 4B8) recognize the previously unreported epitopes on the outer surface of the Zika virus (ZIKV) NS1 dimer. Group II antibodies (4F10, 2E11, and 14G5) recognize the common epitopes at the distal end of the ZIKV NS1 β-ladder domain. Group I antibodies have stronger recognition of the cell surface form of NS1, and their IgG and Fab completely inhibit the endothelial permeability caused by ZIKV sNS1 proteins. The blockade efficiency of Group II antibodies is related to their affinity for the ZIKV sNS1 protein and the presence of full length IgG.
Credit: Hongli Hu, the Chinese University of Hong Kong
Zika virus (ZIKV) is a mosquito-borne pathogen that belongs to the flavivirus genus of Flaviviridae, other flavivirus in this family include dengue fever virus (DENV), West Nile virus (WNV), yellow fever virus (YFV), and Japanese encephalitis virus (JEV). During pregnancy, ZIKV infection causes infants to be born with microcephaly and other congenital malformations. In adults, it has been linked to Guillain-Barré syndrome(GBS), neuropathy, and myelitis. Unfortunately, there is no approved vaccine or therapeutic against ZIKV. Non-structural protein 1 (NS1) can facilitate viral RNA replication and virus assembly, inhibit complement, activate platelets and immune cells, and induce vascular endothelial dysfunction in a tissue-specific manner. ZIKV sNS1 may also promote placental dysfunction via modulation of glycosaminoglycans (GAGs) on trophoblasts and chorionic Villi. NS1 is gaining attention as a promising therapeutic target.
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. Here, we determined high-resolution structures of full-length ZIKV NS1 combined with five NS1-targeted human antibodies (tNS1-3G2, tNS1-4B8, tNS1-4F10, dNS1-2E11, and dNS1-14G5). Group I antibodies (3G2 and 4B8) bind to the wing domain and b-ladder domain on the outer surface of the NS1 dimer, whereas Group II antibodies (4F10, 2E11, and 14G5) bind to the distal end of b-ladder domain at different angles. Subsequent biochemical experiments showed that Group I antibodies have stronger recognition of NS1 on the cell membrane surface than Group II antibodies, and their IgG and Fab completely inhibit the endothelial permeability caused by sNS1 proteins. The protective capacity of Group II antibodies may be dependent on their affinity for sNS1 and the presence of full-length IgG. Our study elucidates the correlation between the distinct recognition mode and the protective efficacy of NS1-targeted antibodies and provides significant clues for the rational design of NS1-based vaccines and therapeutics.
See the article:
Pan Q, Xing X, Yu J, et al. Structural insights into the distinct protective mechanisms of human antibodies targeting ZIKV NS1. hLife. https://doi.org/10.1016/j.hlife.2024.05.003.