title: Functional analysis of antibodies against dengue virus type 4 reveals strain-dependent epitope exposure that impacts neutralization and protection.
abstract: Although prior studies have characterized the neutralizing activities of monoclonal antibodies (MAbs) against dengue virus (DENV) serotypes 1, 2, and 3 (DENV-1, DENV-2, and DENV-3), few reports have assessed the activity of MAbs against DENV-4. Here, we evaluated the inhibitory activity of 81 new mouse anti-DENV-4 MAbs. We observed strain- and genotype-dependent differences in neutralization of DENV-4 by MAbs mapping to epitopes on domain II (DII) and DIII of the envelope (E) protein. Several anti-DENV-4 MAbs inefficiently inhibited at least one strain and/or genotype, suggesting that the exposure or sequence of neutralizing epitopes varies within isolates of this serotype. Remarkably, flavivirus cross-reactive MAbs, which bound to the highly conserved fusion loop in DII and inhibited infection of DENV-1, DENV-2, and DENV-3, more weakly neutralized five different DENV-4 strains encompassing the genetic diversity of the serotype after preincubation at 37°C. However, increasing the time of preincubation at 37°C or raising the temperature to 40°C enhanced the potency of DII fusion loop-specific MAbs and some DIII-specific MAbs against DENV-4 strains. Prophylaxis studies in two new DENV-4 mouse models showed that neutralization titers of MAbs after preincubation at 37°C correlated with activity in vivo. Our studies establish the complexity of MAb recognition against DENV-4 and suggest that differences in epitope exposure relative to other DENV serotypes affect antibody neutralization and protective activity.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Soila
authors.initials: S
authors.lastname: Sukupolvi-Petty
authors.forename: James D
authors.initials: JD
authors.lastname: Brien
authors.forename: S Kyle
authors.initials: SK
authors.lastname: Austin
authors.forename: Bimmi
authors.initials: B
authors.lastname: Shrestha
authors.forename: Sherri
authors.initials: S
authors.lastname: Swayne
authors.forename: Kristen
authors.initials: K
authors.lastname: Kahle
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Doranz
authors.forename: Syd
authors.initials: S
authors.lastname: Johnson
authors.forename: Theodore C
authors.initials: TC
authors.lastname: Pierson
authors.forename: Daved H
authors.initials: DH
authors.lastname: Fremont
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D003429:Cross Reactions; D003715:Dengue / Q000517:prevention & control; D003716:Dengue Virus / Q000276:immunology*; D004195:Disease Models, Animal; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D013696:Temperature; D013997:Time Factors; D014759:Viral Envelope Proteins / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; D014759:Viral Envelope Proteins