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VanBlargan LA, Milutinovic PS, Goo L, et al. Dengue Virus Serotype 1 Conformational Dynamics Confers Virus Strain-Dependent Patterns of Neutralization by Polyclonal Sera. J Virol. 2021;95(23):e0095621doi: 10.1128/JVI.00956-21.
VanBlargan, L. A., Milutinovic, P. S., Goo, L., DeMaso, C. R., Durbin, A. P., Whitehead, S. S., Pierson, T. C., & Dowd, K. A. (2021). Dengue Virus Serotype 1 Conformational Dynamics Confers Virus Strain-Dependent Patterns of Neutralization by Polyclonal Sera. Journal of virology, 95(23), e0095621. https://doi.org/10.1128/JVI.00956-21
VanBlargan, Laura A, et al. "Dengue Virus Serotype 1 Conformational Dynamics Confers Virus Strain-Dependent Patterns of Neutralization by Polyclonal Sera." Journal of virology vol. 95,23 (2021): e0095621. doi: https://doi.org/10.1128/JVI.00956-21
VanBlargan LA, Milutinovic PS, Goo L, DeMaso CR, Durbin AP, Whitehead SS, Pierson TC, Dowd KA. Dengue Virus Serotype 1 Conformational Dynamics Confers Virus Strain-Dependent Patterns of Neutralization by Polyclonal Sera. J Virol. 2021 Nov 09;95(23):e0095621. doi: 10.1128/JVI.00956-21. Epub 2021 Sep 22. PMID: 34549976; PMCID: PMC8577358.
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J Virol. 2021 Nov 09;95(23):e0095621. doi: 10.1128/JVI.00956-21. Epub 2021 Sep 22.

Dengue Virus Serotype 1 Conformational Dynamics Confers Virus Strain-Dependent Patterns of Neutralization by Polyclonal Sera.

Journal of virology

Laura A VanBlargan, Pavle S Milutinovic, Leslie Goo, Christina R DeMaso, Anna P Durbin, Stephen S Whitehead, Theodore C Pierson, Kimberly A Dowd

Affiliations

  1. Viral Pathogenesis Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Healthgrid.94365.3d, Bethesda, Maryland, USA.
  2. Biological Sciences Graduate Program, University of Maryland, College Park, Maryland, USA.
  3. Center for Immunization Research, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
  4. Arbovirus Vaccine Research Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Healthgrid.94365.3d, Bethesda, Maryland, USA.

PMID: 34549976 PMCID: PMC8577358 DOI: 10.1128/JVI.00956-21

Abstract

Dengue virus cocirculates globally as four serotypes (DENV1 to -4) that vary up to 40% at the amino acid level. Viral strains within a serotype further cluster into multiple genotypes. Eliciting a protective tetravalent neutralizing antibody response is a major goal of vaccine design, and efforts to characterize epitopes targeted by polyclonal mixtures of antibodies are ongoing. Previously, we identified two E protein residues (126 and 157) that defined the serotype-specific antibody response to DENV1 genotype 4 strain West Pac-74. DENV1 and DENV2 human vaccine sera neutralized DENV1 viruses incorporating these substitutions equivalently. In this study, we explored the contribution of these residues to the neutralization of DENV1 strains representing distinct genotypes. While neutralization of the genotype 1 strain TVP2130 was similarly impacted by mutation at E residues 126 and 157, mutation of these residues in the genotype 2 strain 16007 did not markedly change neutralization sensitivity, indicating the existence of additional DENV1 type-specific antibody targets. The accessibility of antibody epitopes can be strongly influenced by the conformational dynamics of virions and modified allosterically by amino acid variation. We found that changes at E domain II residue 204, shown previously to impact access to a poorly accessible E domain III epitope, impacted sensitivity of DENV1 16007 to neutralization by vaccine immune sera. Our data identify a role for minor sequence variation in changes to the antigenic structure that impacts antibody recognition by polyclonal immune sera. Understanding how the many structures sampled by flaviviruses influence antibody recognition will inform the design and evaluation of DENV immunogens.

Keywords: dengue virus; humoral immunity; neutralizing antibody; polyclonal antibody; structural dynamics; vaccines

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