title: The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1.
abstract: Antibody protection against flaviviruses is associated with the development of neutralizing antibodies against the viral envelope (E) protein. Prior studies with West Nile virus (WNV) identified therapeutic mouse and human monoclonal antibodies (MAbs) that recognized epitopes on domain III (DIII) of the E protein. To identify an analogous panel of neutralizing antibodies against DENV type-1 (DENV-1), we immunized mice with a genotype 2 strain of DENV-1 virus and generated 79 new MAbs, 16 of which strongly inhibited infection by the homologous virus and localized to DIII. Surprisingly, only two MAbs, DENV1-E105 and DENV1-E106, retained strong binding and neutralizing activity against all five DENV-1 genotypes. In an immunocompromised mouse model of infection, DENV1-E105 and DENV1-E106 exhibited therapeutic activity even when administered as a single dose four days after inoculation with a heterologous genotype 4 strain of DENV-1. Using epitope mapping and X-ray crystallographic analyses, we localized the neutralizing determinants for the strongly inhibitory MAbs to distinct regions on DIII. Interestingly, sequence variation in DIII alone failed to explain disparities in neutralizing potential of MAbs among different genotypes. Overall, our experiments define a complex structural epitope on DIII of DENV-1 that can be recognized by protective antibodies with therapeutic potential.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Bimmi
authors.initials: B
authors.lastname: Shrestha
authors.forename: James D
authors.initials: JD
authors.lastname: Brien
authors.forename: Soila
authors.initials: S
authors.lastname: Sukupolvi-Petty
authors.forename: S Kyle
authors.initials: SK
authors.lastname: Austin
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Edeling
authors.forename: Taekyung
authors.initials: T
authors.lastname: Kim
authors.forename: Katie M
authors.initials: KM
authors.lastname: O'Brien
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Nelson
authors.forename: Syd
authors.initials: S
authors.lastname: Johnson
authors.forename: Daved H
authors.initials: DH
authors.lastname: Fremont
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing / Q000276:immunology*; D003716:Dengue Virus / Q000235:genetics* / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D005838:Genotype; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D017434:Protein Structure, Tertiary; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D018985:Epitopes, B-Lymphocyte; D014759:Viral Envelope Proteins; C072281:E protein TH Sman, Dengue virus