title: A human PrM antibody that recognizes a novel cryptic epitope on dengue E glycoprotein.
abstract: Dengue virus (DENV) is a major mosquito-borne pathogen infecting up to 100 million people each year; so far no effective treatment or vaccines are available. Recently, highly cross-reactive and infection-enhancing pre-membrane (prM)-specific antibodies were found to dominate the anti-DENV immune response in humans, raising concern over vaccine candidates that contain native dengue prM sequences. In this study, we have isolated a broadly cross-reactive prM-specific antibody, D29, during a screen with a non-immunized human Fab-phage library against the four serotypes of DENV. The antibody is capable of restoring the infectivity of virtually non-infectious immature DENV (imDENV) in FcγR-bearing K562 cells. Remarkably, D29 also cross-reacted with a cryptic epitope on the envelope (E) protein located to the DI/DII junction as evidenced by site-directed mutagenesis. This cryptic epitope, while inaccessible to antibody binding in a native virus particle, may become exposed if E is not properly folded. These findings suggest that generation of anti-prM antibodies that enhance DENV infection may not be completely avoided even with immunization strategies employing E protein alone or subunits of E proteins.
authors.affiliation: Bio-Defence Programme, DMERI, DSO National Laboratories, Singapore, Singapore.
authors.forename: Annie Hoi Yi
authors.initials: AH
authors.lastname: Chan
authors.forename: Hwee Cheng
authors.initials: HC
authors.lastname: Tan
authors.forename: Angelia Yee
authors.initials: AY
authors.lastname: Chow
authors.forename: Angeline Pei Chiew
authors.initials: AP
authors.lastname: Lim
authors.forename: Shee Mei
authors.initials: SM
authors.lastname: Lok
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Moreland
authors.forename: Subhash G
authors.initials: SG
authors.lastname: Vasudevan
authors.forename: Paul A
authors.initials: PA
authors.lastname: MacAry
authors.forename: Eng Eong
authors.initials: EE
authors.lastname: Ooi
authors.forename: Brendon J
authors.initials: BJ
authors.lastname: Hanson
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology*; D000915:Antibody Affinity; D000918:Antibody Specificity; D002460:Cell Line; D003716:Dengue Virus / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D019151:Peptide Library; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; D006023:Glycoproteins; D007074:Immunoglobulin G; D019151:Peptide Library; D014759:Viral Envelope Proteins