Neutralizing Monoclonal Antibodies Block Chikungunya Virus Entry and Release by Targeting an Epitope Critical to Viral Pathogenesis

Jing Jin, Nathan M. Liss, Dong Hua Chen, Maofu Liao, Julie M. Fox, Raeann M. Shimak, Rachel H. Fong, Daniel Chafets, Sonia Bakkour, Sheila Keating, Marina E. Fomin, Marcus O. Muench, Michael Sherman, Benjamin J. Doranz, Michael S. Diamond, Graham Simmons

    Research output: Contribution to journalArticle

    27 Citations (Scopus)

    Abstract

    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 and release. Cryo-electron microscopy structures of Fab fragments of two human NAbs and 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.

    Original languageEnglish (US)
    Pages (from-to)2553-2564
    Number of pages12
    JournalCell Reports
    Volume13
    Issue number11
    DOIs
    StatePublished - Dec 22 2015

    Fingerprint

    Chikungunya virus
    Virus Release
    Virus Internalization
    Neutralizing Antibodies
    Viruses
    Epitopes
    Monoclonal Antibodies
    Epitope Mapping
    Cryoelectron Microscopy
    Immunoglobulin Fab Fragments
    Membrane Fusion
    Antibodies
    Infection
    Life Cycle Stages
    Virion
    Amino Acids
    Pressure
    Electron microscopy
    Mutation
    Life cycle

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)

    Cite this

    Neutralizing Monoclonal Antibodies Block Chikungunya Virus Entry and Release by Targeting an Epitope Critical to Viral Pathogenesis. / 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; Doranz, Benjamin J.; Diamond, Michael S.; Simmons, Graham.

    In: Cell Reports, Vol. 13, No. 11, 22.12.2015, p. 2553-2564.

    Research output: Contribution to journalArticle

    Jin, J, Liss, NM, Chen, DH, Liao, M, Fox, JM, Shimak, RM, Fong, RH, Chafets, D, Bakkour, S, Keating, S, Fomin, ME, Muench, MO, Sherman, M, Doranz, BJ, Diamond, MS & Simmons, G 2015, 'Neutralizing Monoclonal Antibodies Block Chikungunya Virus Entry and Release by Targeting an Epitope Critical to Viral Pathogenesis', Cell Reports, vol. 13, no. 11, pp. 2553-2564. https://doi.org/10.1016/j.celrep.2015.11.043
    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 ; Doranz, Benjamin J. ; Diamond, Michael S. ; Simmons, Graham. / Neutralizing Monoclonal Antibodies Block Chikungunya Virus Entry and Release by Targeting an Epitope Critical to Viral Pathogenesis. In: Cell Reports. 2015 ; Vol. 13, No. 11. pp. 2553-2564.
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