title: Dengue virus envelope protein domain I/II hinge determines long-lived serotype-specific dengue immunity.
abstract: The four dengue virus (DENV) serotypes, DENV-1, -2, -3, and -4, are endemic throughout tropical and subtropical regions of the world, with an estimated 390 million acute infections annually. Infection confers long-term protective immunity against the infecting serotype, but secondary infection with a different serotype carries a greater risk of potentially fatal severe dengue disease, including dengue hemorrhagic fever and dengue shock syndrome. The single most effective measure to control this threat to global health is a tetravalent DENV vaccine. To date, attempts to develop a protective vaccine have progressed slowly, partly because the targets of type-specific human neutralizing antibodies (NAbs), which are critical for long-term protection, remain poorly defined, impeding our understanding of natural immunity and hindering effective vaccine development. Here, we show that the envelope glycoprotein domain I/II hinge of DENV-3 and DENV-4 is the primary target of the long-term type-specific NAb response in humans. Transplantation of a DENV-4 hinge into a recombinant DENV-3 virus showed that the hinge determines the serotype-specific neutralizing potency of primary human and nonhuman primate DENV immune sera and that the hinge region both induces NAbs and is targeted by protective NAbs in rhesus macaques. These results suggest that the success of live dengue vaccines may depend on their ability to stimulate NAbs that target the envelope glycoprotein domain I/II hinge region. More broadly, this study shows that complex conformational antibody epitopes can be transplanted between live viruses, opening up similar possibilities for improving the breadth and specificity of vaccines for influenza, HIV, hepatitis C virus, and other clinically important viral pathogens.
authors.affiliation: Department of Molecular Microbiology and Immunology and Division of Infectious Diseases, Department of Medicine, Oregon Health and Sciences University, Portland, OR 97239.
authors.forename: William B
authors.initials: WB
authors.lastname: Messer
authors.forename: Ruklanthi
authors.initials: R
authors.lastname: de Alwis
authors.forename: Boyd L
authors.initials: BL
authors.lastname: Yount
authors.forename: Scott R
authors.initials: SR
authors.lastname: Royal
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Huynh
authors.forename: Scott A
authors.initials: SA
authors.lastname: Smith
authors.forename: James E
authors.initials: JE
authors.lastname: Crowe
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Doranz
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Kahle
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Pfaff
authors.forename: Laura J
authors.initials: LJ
authors.lastname: White
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Sariol
authors.forename: Aravinda M
authors.initials: AM
authors.lastname: de Silva
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Baric
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral / Q000276:immunology; D003715:Dengue / Q000276:immunology* / Q000821:virology*; D003716:Dengue Virus / Q000145:classification* / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007109:Immunity / Q000276:immunology*; D020014:K562 Cells; D008253:Macaca mulatta / Q000276:immunology / Q000821:virology; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins; D012703:Serotyping; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013997:Time Factors; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D014766:Viremia / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D011994:Recombinant Proteins; D014759:Viral Envelope Proteins
keywords: infectious clone; neutralizing antibody