Structural basis of Zika virus NS1 multimerization and human antibody recognition

Abstract

The Zika virus (ZIKV) is a mosquito-transmitted flavivirus related to the dengue virus that has emerged in recent global outbreaks, with previously unreported neurological or birth abnormalities. There remains a large, unmet need for efficacious vaccines and antiviral agents against ZIKV. Flavivirus non-structural protein 1 (NS1) is the only secreted viral protein that has proven useful in diagnostics. However, its physiologically relevant structural forms and pathogenesis mechanisms remain unclear. While many antibodies targeting NS1 with mapped immunodomain epitopes have been reported, antibody-NS1 structures are starting to emerge, which may guide vaccine and therapeutic design. Here, we present high-resolution cryoEM structures of ZIKV recombinant secreted NS1 (rsNS1) and its complexes with three human monoclonal antibodies, as well as evidence of ZIKV infection-derived secreted NS1 (isNS1) binding to HDL. We showed that ZIKV rsNS1 forms tetramers and filamentous repeats of tetramers. The studied antibodies (AA12, EB9, GB5) did not disrupt the ZIKV NS1 tetramers as they bound to the wing and connector subdomain to the β-ladder. Our study reveals new insights into NS1 multimerization, highlights the need to distinguish the polymorphic nature of rsNS1 and isNS1, and expands the mechanistic basis of the protection conferred by antibodies targeting NS1.

The step-by-step assembly mechanism of secreted flavivirus NS1 tetramer and hexamer captured at atomic resolution

“…This discrepancy could be attributed to differences among these flavivirus species or variations in the expression and purification conditions. Another study by Luo et al (28) observed filaments of NS1 tetramers in the cryo-EM micrographs. We did not observe similar long filaments in our collected micrographs.…”