A highly potent human antibody neutralizes dengue virus serotype 3 by binding across three surface proteins

Nat Commun. 2015 Feb 20;6:6341. doi: 10.1038/ncomms7341.

Abstract

Dengue virus (DENV) infects ~400 million people annually. There is no licensed vaccine or therapeutic drug. Only a small fraction of the total DENV-specific antibodies in a naturally occurring dengue infection consists of highly neutralizing antibodies. Here we show that the DENV-specific human monoclonal antibody 5J7 is exceptionally potent, neutralizing 50% of virus at nanogram-range antibody concentration. The 9 Å resolution cryo-electron microscopy structure of the Fab 5J7-DENV complex shows that a single Fab molecule binds across three envelope proteins and engages three functionally important domains, each from a different envelope protein. These domains are critical for receptor binding and fusion to the endosomal membrane. The ability to bind to multiple domains allows the antibody to fully coat the virus surface with only 60 copies of Fab, that is, half the amount compared with other potent antibodies. Our study reveals a highly efficient and unusual mechanism of molecular recognition by an antibody.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Neutralizing / chemistry*
  • Antibodies, Viral / chemistry*
  • Cell Membrane / chemistry
  • Chlorocebus aethiops
  • Cryoelectron Microscopy
  • Dengue / immunology*
  • Dengue Virus / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes / chemistry
  • Genotype
  • Humans
  • Immunoglobulin Fab Fragments / chemistry*
  • Membrane Proteins / chemistry*
  • Mice
  • Molecular Sequence Data
  • Neutralization Tests
  • Protein Binding
  • Protein Structure, Quaternary
  • Sequence Homology, Amino Acid
  • Serogroup
  • Vero Cells

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Epitopes
  • Immunoglobulin Fab Fragments
  • Membrane Proteins