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 B. Sherman, Benjamin J. Doranz, Michael S. Diamond, Graham Simmons

    Research output: Contribution to journalArticle

    39 Scopus citations

    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

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)

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    Jin, J., Liss, N. M., Chen, D. H., Liao, M., Fox, J. M., Shimak, R. M., Fong, R. H., Chafets, D., Bakkour, S., Keating, S., Fomin, M. E., Muench, M. O., Sherman, M. B., Doranz, B. J., Diamond, M. S., & Simmons, G. (2015). Neutralizing Monoclonal Antibodies Block Chikungunya Virus Entry and Release by Targeting an Epitope Critical to Viral Pathogenesis. Cell Reports, 13(11), 2553-2564. https://doi.org/10.1016/j.celrep.2015.11.043