Cryo-EM structures elucidate neutralizing mechanisms of anti-chikungunya human monoclonal antibodies with therapeutic activity
Autor(es): Long Feng, Fong Rachel H, Austin Stephen K, Chen Zhenguo, Klose Thomas, Fokine Andrei, Liu Yue, Porta Jason, Sapparapu Gopal, Akahata Wataru, Doranz Benjamin J, Crowe James E, Diamond Michael S, Rossmann Michael G
Resumo: Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes severe acute - chronic disease in humans. Although highly inhibitory murine - human monoclonal antibodies (mAbs) have been generated, the structural basis of their neutralizing activity remains poorly characterized. Here, we determined the cryo-EM structures of chikungunya virus-like particles complexed with antibody fragments (Fab) of two highly protective human mAbs, 4J21 - 5M16, that block virus fusion with host membranes. Both mAbs bind primarily to sites within the A - B domains, as well as to the B domain's ?-ribbon connector of the viral glycoprotein E2. The footprints of these antibodies on the viral surface were consistent with results from loss-of-binding studies using an alanine scanning mutagenesis-based epitope mapping approach. The Fab fragments stabilized the position of the B domain relative to the virus, particularly for the complex with 5M16. This finding is consistent with a mechanism of neutralization in which anti-CHIKV mAbs that bridge the A - B domains impede movement of the B domain away from the underlying fusion loop on the E1 glycoprotein - therefore block the requisite pH-dependent fusion of viral - host membranes.
Palavras-Chave: Chikungunya virus-antibody complexes; Cryo-electron microscopy structure; Neutralizing mechanism; Viral fusion inhibition
Imprenta: Proceedings of the National Academy of Sciences of the United States of America, v. 112, n. 45, p. 13898-13903, 2015
Identificador do objeto digital: 10.1073/pnas.1515558112
Descritores: Chikungunya virus - Cytopathology ; Chikungunya virus - Molecular structure ; Chikungunya virus - Pathogenesis ; Chikungunya virus - Proteins ; Chikungunya virus - Antibodies ; Chikungunya virus - Viral infections ; Chikungunya virus - Molecular methods ; Chikungunya Virus - Virus ; Chikungunya virus - Vaccine ; Chikungunya virus - Chikungunya fever ; Chikungunya virus - Immunology
Data de publicação: 2015
