A human antibody against Zika virus crosslinks the E protein to prevent infection

S Saif Hasan,Michael G Rossmann,Feng Long,Gopal Sapparapu,James E Crowe,Thomas Klose,Wen Jiang,Michael S Diamond,Andrew Miller,Andrei Fokine,Richard J Kuhn,Jason C Porta,Estefania Fernandez

doi:10.1038/ncomms14722

Abstract

The recent Zika virus (ZIKV) epidemic has been linked to unusual and severe clinical manifestations including microcephaly in fetuses of infected pregnant women and Guillian-Barré syndrome in adults. Neutralizing antibodies present a possible therapeutic approach to prevent and control ZIKV infection. Here we present a 6.2 Å resolution three-dimensional cryo-electron microscopy (cryoEM) structure of an infectious ZIKV (strain H/PF/2013, French Polynesia) in complex with the Fab fragment of a highly therapeutic and neutralizing human monoclonal antibody, ZIKV-117. The antibody had been shown to prevent fetal infection and demise in mice. The structure shows that ZIKV-117 Fabs cross-link the monomers within the surface E glycoprotein dimers as well as between neighbouring dimers, thus preventing the reorganization of E protein monomers into fusogenic trimers in the acidic environment of endosomes.

Highlights

The recent Zika virus (ZIKV) epidemic has been linked to unusual and severe clinical manifestations including microcephaly in fetuses of infected pregnant women and Guillian-Barresyndrome in adults
MAb ZIKV-117 was isolated from a B cell in a peripheral blood sample, obtained from an otherwise healthy human subject with previous history of symptomatic ZIKV infection[20]
The ZIKV particles were incubated with Fab fragments of ZIKV-117, flash-frozen on lacey carbon EM grids and imaged using a Gatan K2 direct electron detector attached to a Titan-Krios microscope

Summary

Introduction

The recent Zika virus (ZIKV) epidemic has been linked to unusual and severe clinical manifestations including microcephaly in fetuses of infected pregnant women and Guillian-Barresyndrome in adults. We present a 6.2 Å resolution three-dimensional cryo-electron microscopy (cryoEM) structure of an infectious ZIKV (strain H/PF/2013, French Polynesia) in complex with the Fab fragment of a highly therapeutic and neutralizing human monoclonal antibody, ZIKV-117. The structure shows that ZIKV-117 Fabs cross-link the monomers within the surface E glycoprotein dimers as well as between neighbouring dimers, preventing the reorganization of E protein monomers into fusogenic trimers in the acidic environment of endosomes. A recent study identified a human monoclonal antibody (mAb), ZIKV-117, that was demonstrated to possess therapeutic potential, with no cross-reactivity to other flaviviruses[20]. This is significant as ZIKV antibodies that cross-react with DENV have been shown to promote DENV infection by antibody dependent enhancement[21]. Saturation is achieved by binding of only 60 Fabs to the 180 chemically equivalent sites on the virus, greatly reducing the concentration of the antibody needed for neutralization

Methods

Results

Conclusion