James Crowe
Faculty Member
Last active: 3/31/2019

Broadly Neutralizing Alphavirus Antibodies Bind an Epitope on E2 and Inhibit Entry and Egress.

Fox JM, Long F, Edeling MA, Lin H, van Duijl-Richter MKS, Fong RH, Kahle KM, Smit JM, Jin J, Simmons G, Doranz BJ, Crowe JE, Fremont DH, Rossmann MG, Diamond MS
Cell. 2015 163 (5): 1095-1107

PMID: 26553503 · PMCID: PMC4659373 · DOI:10.1016/j.cell.2015.10.050

We screened a panel of mouse and human monoclonal antibodies (MAbs) against chikungunya virus and identified several with inhibitory activity against multiple alphaviruses. Passive transfer of broadly neutralizing MAbs protected mice against infection by chikungunya, Mayaro, and O'nyong'nyong alphaviruses. Using alanine-scanning mutagenesis, loss-of-function recombinant proteins and viruses, and multiple functional assays, we determined that broadly neutralizing MAbs block multiple steps in the viral lifecycle, including entry and egress, and bind to a conserved epitope on the B domain of the E2 glycoprotein. A 16 Å resolution cryo-electron microscopy structure of a Fab fragment bound to CHIKV E2 B domain provided an explanation for its neutralizing activity. Binding to the B domain was associated with repositioning of the A domain of E2 that enabled cross-linking of neighboring spikes. Our results suggest that B domain antigenic determinants could be targeted for vaccine or antibody therapeutic development against multiple alphaviruses of global concern.

Copyright © 2015 Elsevier Inc. All rights reserved.

MeSH Terms (21)

Alphavirus Alphavirus Infections Amino Acid Sequence Animals Antibodies, Monoclonal Antibodies, Neutralizing Antibodies, Viral Chikungunya virus Cryoelectron Microscopy Epitopes Glycoproteins Humans Immunoglobulin Fab Fragments Mice Models, Molecular Molecular Sequence Data Protein Structure, Tertiary Sequence Alignment Viral Envelope Proteins Viral Vaccines Virus Internalization

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