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Beneath the surface: Amino acid variation underlying two decades of dengue virus antigenic dynamics in Bangkok, Thailand
Neutralizing 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 prima...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9098070/ https://www.ncbi.nlm.nih.gov/pubmed/35500035 http://dx.doi.org/10.1371/journal.ppat.1010500 |
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author | Huang, Angkana T. Salje, Henrik Escoto, Ana Coello Chowdhury, Nayeem Chávez, Christian Garcia-Carreras, Bernardo Rutvisuttinunt, Wiriya Maljkovic Berry, Irina Gromowski, Gregory D. Wang, Lin Klungthong, Chonticha Thaisomboonsuk, Butsaya Nisalak, Ananda Trimmer-Smith, Luke M. Rodriguez-Barraquer, Isabel Ellison, Damon W. Jones, Anthony R. Fernandez, Stefan Thomas, Stephen J. Smith, Derek J. Jarman, Richard Whitehead, Stephen S. Cummings, Derek A. T. Katzelnick, Leah C. |
author_facet | Huang, Angkana T. Salje, Henrik Escoto, Ana Coello Chowdhury, Nayeem Chávez, Christian Garcia-Carreras, Bernardo Rutvisuttinunt, Wiriya Maljkovic Berry, Irina Gromowski, Gregory D. Wang, Lin Klungthong, Chonticha Thaisomboonsuk, Butsaya Nisalak, Ananda Trimmer-Smith, Luke M. Rodriguez-Barraquer, Isabel Ellison, Damon W. Jones, Anthony R. Fernandez, Stefan Thomas, Stephen J. Smith, Derek J. Jarman, Richard Whitehead, Stephen S. Cummings, Derek A. T. Katzelnick, Leah C. |
author_sort | Huang, Angkana T. |
collection | PubMed |
description | Neutralizing 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. |
format | Online Article Text |
id | pubmed-9098070 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-90980702022-05-13 Beneath the surface: Amino acid variation underlying two decades of dengue virus antigenic dynamics in Bangkok, Thailand Huang, Angkana T. Salje, Henrik Escoto, Ana Coello Chowdhury, Nayeem Chávez, Christian Garcia-Carreras, Bernardo Rutvisuttinunt, Wiriya Maljkovic Berry, Irina Gromowski, Gregory D. Wang, Lin Klungthong, Chonticha Thaisomboonsuk, Butsaya Nisalak, Ananda Trimmer-Smith, Luke M. Rodriguez-Barraquer, Isabel Ellison, Damon W. Jones, Anthony R. Fernandez, Stefan Thomas, Stephen J. Smith, Derek J. Jarman, Richard Whitehead, Stephen S. Cummings, Derek A. T. Katzelnick, Leah C. PLoS Pathog Research Article Neutralizing 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. Public Library of Science 2022-05-02 /pmc/articles/PMC9098070/ /pubmed/35500035 http://dx.doi.org/10.1371/journal.ppat.1010500 Text en https://creativecommons.org/publicdomain/zero/1.0/This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication. |
spellingShingle | Research Article Huang, Angkana T. Salje, Henrik Escoto, Ana Coello Chowdhury, Nayeem Chávez, Christian Garcia-Carreras, Bernardo Rutvisuttinunt, Wiriya Maljkovic Berry, Irina Gromowski, Gregory D. Wang, Lin Klungthong, Chonticha Thaisomboonsuk, Butsaya Nisalak, Ananda Trimmer-Smith, Luke M. Rodriguez-Barraquer, Isabel Ellison, Damon W. Jones, Anthony R. Fernandez, Stefan Thomas, Stephen J. Smith, Derek J. Jarman, Richard Whitehead, Stephen S. Cummings, Derek A. T. Katzelnick, Leah C. Beneath the surface: Amino acid variation underlying two decades of dengue virus antigenic dynamics in Bangkok, Thailand |
title | Beneath the surface: Amino acid variation underlying two decades of dengue virus antigenic dynamics in Bangkok, Thailand |
title_full | Beneath the surface: Amino acid variation underlying two decades of dengue virus antigenic dynamics in Bangkok, Thailand |
title_fullStr | Beneath the surface: Amino acid variation underlying two decades of dengue virus antigenic dynamics in Bangkok, Thailand |
title_full_unstemmed | Beneath the surface: Amino acid variation underlying two decades of dengue virus antigenic dynamics in Bangkok, Thailand |
title_short | Beneath the surface: Amino acid variation underlying two decades of dengue virus antigenic dynamics in Bangkok, Thailand |
title_sort | beneath the surface: amino acid variation underlying two decades of dengue virus antigenic dynamics in bangkok, thailand |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9098070/ https://www.ncbi.nlm.nih.gov/pubmed/35500035 http://dx.doi.org/10.1371/journal.ppat.1010500 |
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