Covalently linked dengue virus envelope glycoprotein dimers reduce exposure of the immunodominant fusion loop epitope

Nat Commun. 2017 May 23:8:15411. doi: 10.1038/ncomms15411.

Abstract

A problem in the search for an efficient vaccine against dengue virus is the immunodominance of the fusion loop epitope (FLE), a segment of the envelope protein E that is buried at the interface of the E dimers coating mature viral particles. Anti-FLE antibodies are broadly cross-reactive but poorly neutralizing, displaying a strong infection enhancing potential. FLE exposure takes place via dynamic 'breathing' of E dimers at the virion surface. In contrast, antibodies targeting the E dimer epitope (EDE), readily exposed at the E dimer interface over the region of the conserved fusion loop, are very potent and broadly neutralizing. We here engineer E dimers locked by inter-subunit disulfide bonds, and show by X-ray crystallography and by binding to a panel of human antibodies that these engineered dimers do not expose the FLE, while retaining the EDE exposure. These locked dimers are strong immunogen candidates for a next-generation vaccine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aedes
  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Viral / immunology
  • Chlorocebus aethiops
  • Crystallography, X-Ray
  • Dengue Virus / immunology*
  • Disulfides
  • Drosophila
  • Enzyme-Linked Immunosorbent Assay
  • Epitope Mapping
  • HEK293 Cells
  • Humans
  • Immunodominant Epitopes / immunology*
  • Liposomes / chemistry
  • Mice
  • Mutation
  • Protein Domains
  • Protein Multimerization
  • Vero Cells
  • Viral Envelope Proteins / immunology*

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Disulfides
  • Immunodominant Epitopes
  • Liposomes
  • Viral Envelope Proteins