title: Neutralizing Monoclonal Antibodies Block Chikungunya Virus Entry and Release by Targeting an Epitope Critical to Viral Pathogenesis.
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.
authors.affiliation: Blood Systems Research Institute, San Francisco, CA 94118, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.affiliation: Blood Systems Research Institute, San Francisco, CA 94118, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Nathan M
authors.initials: NM
authors.lastname: Liss
authors.affiliation: Department of Structural Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Dong-Hua
authors.initials: DH
authors.lastname: Chen
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Maofu
authors.initials: M
authors.lastname: Liao
authors.affiliation: Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Fox
authors.affiliation: Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Raeann M
authors.initials: RM
authors.lastname: Shimak
authors.affiliation: Integral Molecular Inc., Philadelphia, PA 19104, USA.
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Fong
authors.affiliation: Blood Systems Research Institute, San Francisco, CA 94118, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chafets
authors.affiliation: Blood Systems Research Institute, San Francisco, CA 94118, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Bakkour
authors.affiliation: Blood Systems Research Institute, San Francisco, CA 94118, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Sheila
authors.initials: S
authors.lastname: Keating
authors.affiliation: Blood Systems Research Institute, San Francisco, CA 94118, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Marina E
authors.initials: ME
authors.lastname: Fomin
authors.affiliation: Blood Systems Research Institute, San Francisco, CA 94118, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Marcus O
authors.initials: MO
authors.lastname: Muench
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sherman
authors.affiliation: Integral Molecular Inc., Philadelphia, PA 19104, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Doranz
authors.affiliation: Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.affiliation: 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.
authors.forename: Graham
authors.initials: G
authors.lastname: Simmons
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D001168:Arthritis / Q000378:metabolism / Q000473:pathology; D018925:Chemokines / Q000032:analysis; D002646:Chikungunya virus / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology*; D005838:Genotype; D006801:Humans; D008561:Membrane Fusion; D051379:Mice; D008810:Mice, Inbred C57BL; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D020836:Protein Structure, Quaternary; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D018925:Chemokines; D016207:Cytokines; D000939:Epitopes; D014759:Viral Envelope Proteins