Neutralizing monoclonal antibodies block Chikungunya virus entry and release by targeting an epitope critical to viral pathogenesis
Autor(es): Jin Jing, Liss Nathan M, Chen Dong-Hua, Liao Maofu, Fox Julie M, Shimak Raeann M, Fong Rachel H, Chafets Daniel, Bakkour Sonia, Keating Sheila, Fomin Marina E, Muench Marcus O, Sherman Michael B, Doranz Benjamin J, Diamond Michael S, Simmons Graham
Resumo: We evaluated the mechanism by which neutralizing human monoclonal antibodies inhibit chikungunya virus (CHIKV) infection. Potently neutralizing antibodies (NAbs) blocked infection at multiple steps of the virus life cycle, including entry - release. Cryo-electron microscopy structures of Fab fragments of two human NAbs - chikungunya virus-like particles showed a binding footprint that spanned independent domains on neighboring E2 subunits within one viral spike, suggesting a mechanism for inhibiting low-pH-dependent membrane fusion. Detailed epitope mapping identified amino acid E2-W64 as a critical interaction residue. An escape mutation (E2-W64G) at this residue rendered CHIKV attenuated in mice. Consistent with these data, CHIKV-E2-W64G failed to emerge in vivo under the selection pressure of one of the NAbs, IM-CKV063. As our study suggests that antibodies engaging the residue E2-W64 can potently inhibit CHIKV at multiple stages of infection, antibody-based therapies or immunogens that target this region might have protective value.
Imprenta: Cell Reports, v. 13, n. 11, p. 2553-2564, 2015
Identificador do objeto digital: 10.1016/j.celrep.2015.11.043
Descritores: Chikungunya virus - Biochemistry ; Chikungunya virus - Cell ; Chikungunya virus - Cytopathology ; Chikungunya virus - Pathogenesis ; Chikungunya virus - Antibodies ; Chikungunya Virus - Virus ; Chikungunya virus - Immunology
Data de publicação: 2015
