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Cell Rep. 2015 Dec 22;13(11):2553-2564. doi: 10.1016/j.celrep.2015.11.043. Epub 2015 Dec 10.

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

Author information

1
Blood Systems Research Institute, San Francisco, CA 94118, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
2
Department of Structural Biology, Stanford University, Stanford, CA 94305, USA.
3
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
4
Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
5
Integral Molecular Inc., Philadelphia, PA 19104, USA.
6
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
7
Blood Systems Research Institute, San Francisco, CA 94118, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: gsimmons@bloodsystems.org.

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.

PMID:
26686638
PMCID:
PMC4720387
DOI:
10.1016/j.celrep.2015.11.043
[Indexed for MEDLINE]
Free PMC Article

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