Structural basis of a potent human monoclonal antibody against Zika virus targeting a quaternary epitope

Feng Long, Michael Doyle, Estefania Fernandez, Andrew S. Miller, Thomas Klose, Madhumati Sevvana, Aubrey Bryan, Edgar Davidson, Benjamin J. Doranz, Richard J. Kuhn, Michael S. Diamond, James E. Crowe, Michael G. Rossmann

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Zika virus (ZIKV) is a major human pathogen and member of the Flavivirus genus in the Flaviviridae family. In contrast to most other insect-transmitted flaviviruses, ZIKV also can be transmitted sexually and from mother to fetus in humans. During recent outbreaks, ZIKV infections have been linked to microcephaly, congenital disease, and Guillain-Barré syndrome. Neutralizing antibodies have potential as therapeutic agents. We report here a 4-Å-reso-lution cryo-electron microscopy structure of the ZIKV virion in complex with Fab fragments of the potently neutralizing human monoclonal antibody ZIKV-195. The footprint of the ZIKV-195 Fab fragment expands across two adjacent envelope (E) protein protomers. ZIKV neutralization by this antibody is presumably accomplished by cross-linking the E proteins, which likely prevents formation of E protein trimers required for fusion of the viral and cellular membranes. A single dose of ZIKV-195 administered 5 days after virus inoculation showed marked protection against lethality in a stringent mouse model of infection.

Original languageEnglish
Pages (from-to)1591-1596
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number5
DOIs
StatePublished - Jan 29 2019

Keywords

  • Cryo-EM structure
  • Membrane-fusion inhibition
  • Monoclonal antibody
  • Neutralization mechanism
  • Zika virus

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    Long, F., Doyle, M., Fernandez, E., Miller, A. S., Klose, T., Sevvana, M., Bryan, A., Davidson, E., Doranz, B. J., Kuhn, R. J., Diamond, M. S., Crowe, J. E., & Rossmann, M. G. (2019). Structural basis of a potent human monoclonal antibody against Zika virus targeting a quaternary epitope. Proceedings of the National Academy of Sciences of the United States of America, 116(5), 1591-1596. https://doi.org/10.1073/pnas.1815432116