Potent Dengue Virus Neutralization by a Therapeutic Antibody with Low Monovalent Affinity Requires Bivalent Engagement

Melissa A. Edeling, S. Kyle Austin, Bimmi Shrestha, Kimberly A. Dowd, Swati Mukherjee, Christopher A. Nelson, Syd Johnson, Manu N. Mabila, Elizabeth A. Christian, Joseph Rucker, Theodore C. Pierson, Michael S. Diamond, Daved H. Fremont

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

We recently described our most potently neutralizing monoclonal antibody, E106, which protected against lethal Dengue virus type 1 (DENV-1) infection in mice. To further understand its functional properties, we determined the crystal structure of E106 Fab in complex with domain III (DIII) of DENV-1 envelope (E) protein to 2.45 Å resolution. Analysis of the complex revealed a small antibody-antigen interface with the epitope on DIII composed of nine residues along the lateral ridge and A-strand regions. Despite strong virus neutralizing activity of E106 IgG at picomolar concentrations, E106 Fab exhibited a ∼20,000-fold decrease in virus neutralization and bound isolated DIII, E, or viral particles with only a micromolar monovalent affinity. In comparison, E106 IgG bound DENV-1 virions with nanomolar avidity. The E106 epitope appears readily accessible on virions, as neutralization was largely temperature-independent. Collectively, our data suggest that E106 neutralizes DENV-1 infection through bivalent engagement of adjacent DIII subunits on a single virion. The isolation of anti-flavivirus antibodies that require bivalent binding to inhibit infection efficiently may be a rare event due to the unique icosahedral arrangement of envelope proteins on the virion surface.

Original languageEnglish
Article numbere1004072
JournalPLoS pathogens
Volume10
Issue number4
DOIs
StatePublished - Apr 2014

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