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dc.contributor.authorHuang, Angkana T
dc.contributor.authorSalje, Henrik
dc.contributor.authorEscoto, Ana Coello
dc.contributor.authorChowdhury, Nayeem
dc.contributor.authorChávez, Christian
dc.contributor.authorGarcia-Carreras, Bernardo
dc.contributor.authorRutvisuttinunt, Wiriya
dc.contributor.authorMaljkovic Berry, Irina
dc.contributor.authorGromowski, Gregory D
dc.contributor.authorWang, Lin
dc.contributor.authorKlungthong, Chonticha
dc.contributor.authorThaisomboonsuk, Butsaya
dc.contributor.authorNisalak, Ananda
dc.contributor.authorTrimmer-Smith, Luke M
dc.contributor.authorRodriguez-Barraquer, Isabel
dc.contributor.authorEllison, Damon W
dc.contributor.authorJones, Anthony R
dc.contributor.authorFernandez, Stefan
dc.contributor.authorThomas, Stephen J
dc.contributor.authorSmith, Derek J
dc.contributor.authorJarman, Richard
dc.contributor.authorWhitehead, Stephen S
dc.contributor.authorCummings, Derek AT
dc.contributor.authorKatzelnick, Leah C
dc.date.accessioned2022-06-07T08:13:52Z
dc.date.available2022-06-07T08:13:52Z
dc.date.issued2022-05
dc.identifier.issn1553-7366
dc.identifier.other35500035
dc.identifier.otherPMC9098070
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/337802
dc.descriptionFunder: Division of Intramural Research, National Institute of Allergy and Infectious Diseases
dc.descriptionFunder: Military Infectious Disease Research Program
dc.descriptionFunder: Armed Forces Health Surveillance Branch
dc.description.abstractNeutralizing antibodies are important correlates of protection against dengue. Yet, determinants of variation in neutralization across strains within the four dengue virus serotypes (DENV1-4) is imperfectly understood. Studies focus on structural DENV proteins, especially the envelope (E), the primary target of anti-DENV antibodies. Although changes in immune recognition (antigenicity) are often attributed to variation in epitope residues, viral processes influencing conformation and epitope accessibility also affect neutralizability, suggesting possible modulating roles of nonstructural proteins. We estimated effects of residue changes in all 10 DENV proteins on antigenic distances between 348 DENV collected from individuals living in Bangkok, Thailand (1994-2014). Antigenic distances were derived from response of each virus to a panel of twenty non-human primate antisera. Across 100 estimations, excluding 10% of virus pairs each time, 77 of 295 positions with residue variability in E consistently conferred antigenic effects; 52 were within ±3 sites of known binding sites of neutralizing human monoclonal antibodies, exceeding expectations from random assignments of effects to sites (p = 0.037). Effects were also identified for 16 sites on the stem/anchor of E which were only recently shown to become exposed under physiological conditions. For all proteins, except nonstructural protein 2A (NS2A), root-mean-squared-error (RMSE) in predicting distances between pairs held out in each estimation did not outperform sequences of equal length derived from all proteins or E, suggesting that antigenic signals present were likely through linkage with E. Adjusted for E, we identified 62/219 sites embedding the excess signals in NS2A. Concatenating these sites to E additionally explained 3.4% to 4.0% of observed variance in antigenic distances compared to E alone (50.5% to 50.8%); RMSE outperformed concatenating E with sites from any protein of the virus (ΔRMSE, 95%IQR: 0.01, 0.05). Our results support examining antigenic determinants beyond the DENV surface.
dc.languageeng
dc.publisherPublic Library of Science (PLoS)
dc.sourcenlmid: 101238921
dc.sourceessn: 1553-7374
dc.subjectAnimals
dc.subjectDengue Virus
dc.subjectDengue
dc.subjectAmino Acids
dc.subjectViral Envelope Proteins
dc.subjectAntibodies, Monoclonal
dc.subjectAntibodies, Viral
dc.subjectEpitopes
dc.subjectThailand
dc.subjectAntibodies, Neutralizing
dc.titleBeneath the surface: Amino acid variation underlying two decades of dengue virus antigenic dynamics in Bangkok, Thailand.
dc.typeArticle
dc.date.updated2022-06-07T08:13:52Z
prism.issueIdentifier5
prism.publicationNamePLoS Pathog
prism.volume18
dc.identifier.doi10.17863/CAM.85211
dcterms.dateAccepted2022-04-05
rioxxterms.versionofrecord10.1371/journal.ppat.1010500
rioxxterms.versionVoR
dc.contributor.orcidHuang, Angkana T [0000-0002-9857-3506]
dc.contributor.orcidKatzelnick, Leah C [0000-0003-1033-6758]
dc.identifier.eissn1553-7374
pubs.funder-project-idEuropean Commission Horizon 2020 (H2020) ERC (804744)
cam.issuedOnline2022-05-02


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