Potent dengue virus neutralization by a therapeutic antibody with low monovalent affinity requires bivalent engagement.
| Autor: | 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: | |
| Zdroj: | PLoS Pathogens, Vol 10, Iss 4, p e1004072 (2014) |
| Druh dokumentu: | article |
| ISSN: | 1553-7366 1553-7374 |
| DOI: | 10.1371/journal.ppat.1004072 |
| Popis: | 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. |
| Databáze: | Directory of Open Access Journals |
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