Structural Basis for Neutralization and Protection by a Zika Virus-Specific Human Antibody

Abstract

Highlights d A potent and protective human ZIKV-specific antibody was characterized d Crystal structure defined the epitope at a resolution of 2.32 Å d Cryo-EM analyses revealed the unique coverage on the mature virion d The antibody interferes with postattachment steps of ZIKV infection

Development of a Potent and Protective Germline-Like Antibody Lineage Against Zika Virus in a Convalescent Human

“…Multiple sequence alignment (MSA) was calculated using BioEdit ClustalW. The crystal structure of ZIKV E DIII-ZK2B10 Fab complex has been determined and analyzed here to identify the 'hotspot' residues critical to ZK2B10 lineage development (31). For the intermolecular interactions shown in Figure 5, 4 Å was used as the maximal cut-off distance for hydrogen bonds.…”

“…A mong the 11 mAbs, 8 (2H-1, −4, −5, −6, −9, −10, −15, and −16) demonstrated strong binding affinities for E and E DIII at a similar level to ZK2B10, with the half-maximal effective concentrations (EC 50 ) ranging from 3.4 to 11.2 ng/ml, while the remaining 3 mAbs (2H-2, −3, and −14) showed low affinities (Figure 4A). ZIKV E protein and E DIII were expressed in bacterial cells following the same procedure as previously described for the crystallographic analysis (31,39). It must be noted that the affinity of a mAb may vary depending on the expression system used to produce the antigen.…”

“…The loss of function observed for most λ chain somatic variants, in which V L was reverted to IGLV1-47, suggested that light chain maturation is crucial for the ZK2B10 lineage to acquire its potency and specificity, reminiscent of the HIV-1 bNAb, VRC01 (36). (31). The identified hotspot residues that potentially critical for ZK2B10 maturation are marked in red.…”

“…This result suggested that the ZK2B10 lineage has a restricted V H gene usage to achieve high affinity and potency against ZIKV. Based on the crystal structure of ZK2B10 in complex with ZIKV E DIII, four residues within the HCDR3 loop (Y111, Y114, Y116, and Y118) are directly involved in the contact interface (31). Although D39 is within the HCDR1 loop, it forms hydrogen bonds with Y115 and Y117 on the opposite side of the HCDR3 loop, thus stabilizing the HCDR3 conformation (Figure 5C).…”

“…ZK2B10 also demonstrated remarkable prophylactic and therapeutic activities against lethal challenge in the mouse models of ZIKV infection and microcephaly (30). Crystal structure and cryo-EM analysis revealed that ZK2B10 recognizes the lateral ridge of E DIII and blocks infection by inhibiting membrane fusion after cellular attachment (31). Since ZK2B10 may serve as a promising candidate for antibody-based interventions, the ontogeny of ZK2B10 could provide insight into the protective antibody response during ZIKV infection in humans and inform rational vaccine design.…”