title: Broadly Neutralizing Alphavirus Antibodies Bind an Epitope on E2 and Inhibit Entry and Egress.
abstract: We screened a panel of mouse and human monoclonal antibodies (MAbs) against chikungunya virus and identified several with inhibitory activity against multiple alphaviruses. Passive transfer of broadly neutralizing MAbs protected mice against infection by chikungunya, Mayaro, and O'nyong'nyong alphaviruses. Using alanine-scanning mutagenesis, loss-of-function recombinant proteins and viruses, and multiple functional assays, we determined that broadly neutralizing MAbs block multiple steps in the viral lifecycle, including entry and egress, and bind to a conserved epitope on the B domain of the E2 glycoprotein. A 16 Å resolution cryo-electron microscopy structure of a Fab fragment bound to CHIKV E2 B domain provided an explanation for its neutralizing activity. Binding to the B domain was associated with repositioning of the A domain of E2 that enabled cross-linking of neighboring spikes. Our results suggest that B domain antigenic determinants could be targeted for vaccine or antibody therapeutic development against multiple alphaviruses of global concern.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Fox
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Long
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Edeling
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Hueylie
authors.initials: H
authors.lastname: Lin
authors.affiliation: University of Groningen and University Medical Center Groningen, 9713 GZ Groningen, the Netherlands.
authors.forename: Mareike K S
authors.initials: MKS
authors.lastname: van Duijl-Richter
authors.affiliation: Integral Molecular, Inc., Philadelphia, PA 19104, USA.
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Fong
authors.affiliation: Integral Molecular, Inc., Philadelphia, PA 19104, USA.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Kahle
authors.affiliation: University of Groningen and University Medical Center Groningen, 9713 GZ Groningen, the Netherlands.
authors.forename: Jolanda M
authors.initials: JM
authors.lastname: Smit
authors.affiliation: Blood Systems Research Institute, San Francisco, CA 94118, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.affiliation: Blood Systems Research Institute, San Francisco, CA 94118, USA.
authors.forename: Graham
authors.initials: G
authors.lastname: Simmons
authors.affiliation: Integral Molecular, Inc., Philadelphia, PA 19104, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Doranz
authors.affiliation: Departments of Pediatrics, Pathology, Microbiology, and Immunology and the Vanderbilt Vaccine Center, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Crowe
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Daved H
authors.initials: DH
authors.lastname: Fremont
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rossmann
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: diamond@wusm.wustl.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
mesh_terms: D000524:Alphavirus / Q000145:classification / Q000276:immunology* / Q000378:metabolism; D018354:Alphavirus Infections / Q000276:immunology* / Q000517:prevention & control / Q000628:therapy; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D002646:Chikungunya virus / Q000737:chemistry / Q000276:immunology; D020285:Cryoelectron Microscopy; D000939:Epitopes; D006023:Glycoproteins / Q000737:chemistry / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000648:ultrastructure; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology; D053586:Virus Internalization
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; D006023:Glycoproteins; D007140:Immunoglobulin Fab Fragments; D014759:Viral Envelope Proteins; D014765:Viral Vaccines