Autor(es)Fox Julie M, Long Feng, Edeling Melissa A, Lin Hueylie, van Duijl-Richter Mareike K S, Fong Rachel H, Kahle Kristen M, Smit Jol-a M, Jin Jing, Simmons Graham, Doranz Benjamin J, Crowe James E, Fremont Daved H, Rossmann Michael G, Diamond Michael S

ResumoWe screened a panel of mouse - human monoclonal antibodies (MAbs) against chikungunya virus - identified several with inhibitory activity against multiple alphaviruses. Passive transfer of broadly neutralizing MAbs protected mice against infection by chikungunya, Mayaro, - O'nyong'nyong alphaviruses. Using alanine-scanning mutagenesis, loss-of-function recombinant proteins - viruses, - multiple functional assays, we determined that broadly neutralizing MAbs block multiple steps in the viral lifecycle, including entry - egress, - 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.

ImprentaCell, v. 163, n. 5, p. 1095-1107, 2015

DescritoresChikungunya virus - Cell ; Chikungunya virus - Cytopathology ; Chikungunya virus - Molecular structure ; Chikungunya virus - Proteins ; Chikungunya virus - Antibodies ; Chikungunya Virus - Virus ; Chikungunya virus - Vaccine ; Chikungunya virus - Immunology

Data de Publicação:2015