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Title: Structural Basis for Escape of Human Astrovirus from Antibody Neutralization: Broad Implications for Rational Vaccine Design

Abstract

ABSTRACT Human astroviruses are recognized as a leading cause of viral diarrhea worldwide in children, immunocompromised patients, and the elderly. There are currently no vaccines available to prevent astrovirus infection; however, antibodies developed by healthy individuals during previous infection correlate with protection from reinfection, suggesting that an effective vaccine could be developed. In this study, we investigated the molecular mechanism by which several strains of human astrovirus serotype 2 (HAstV-2) are resistant to the potent HAstV-2-neutralizing monoclonal antibody PL-2 (MAb PL-2). Sequencing of the HAstV-2 capsid genes reveals mutations in the PL-2 epitope within the capsid's spike domain. To understand the molecular basis for resistance from MAb PL-2 neutralization, we determined the 1.35-Å-resolution crystal structure of the capsid spike from one of these HAstV-2 strains. Our structure reveals a dramatic conformational change in a loop within the PL-2 epitope due to a serine-to-proline mutation, locking the loop in a conformation that sterically blocks binding and neutralization by MAb PL-2. We show that mutation to serine permits loop flexibility and recovers MAb PL-2 binding. Importantly, we find that HAstV-2 capsid spike containing a serine in this loop is immunogenic and elicits antibodies that neutralize all HAstV-2 strains. Taken together, our resultsmore » have broad implications for rational selection of vaccine strains that do not contain prolines in antigenic loops, so as to elicit antibodies against diverse loop conformations. IMPORTANCEHuman astroviruses (HAstVs) infect nearly every person in the world during childhood and cause diarrhea, vomiting, and fever. In this study, we investigated how several strains of HAstV are resistant to a virus-neutralizing monoclonal antibody. We determined the crystal structure of the capsid protein spike domain from one of these HAstV strains and found that a single amino acid mutation induces a structural change in a loop that is responsible for antibody binding. Our findings reveal how viruses can escape antibody neutralization and provide insight for the rational design of vaccines to elicit diverse antibodies that provide broader protection from infection.« less

Authors:
ORCiD logo; ; ; ORCiD logo; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIHNIAIDOTHER
OSTI Identifier:
1422226
Resource Type:
Journal Article
Journal Name:
Journal of Virology
Additional Journal Information:
Journal Volume: 92; Journal Issue: 1; Journal ID: ISSN 0022-538X
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Bogdanoff, Walter A., Perez, Edmundo I., López, Tomás, Arias, Carlos F., DuBois, Rebecca M., and Schultz-Cherry, Stacey. Structural Basis for Escape of Human Astrovirus from Antibody Neutralization: Broad Implications for Rational Vaccine Design. United States: N. p., 2017. Web. doi:10.1128/JVI.01546-17.
Bogdanoff, Walter A., Perez, Edmundo I., López, Tomás, Arias, Carlos F., DuBois, Rebecca M., & Schultz-Cherry, Stacey. Structural Basis for Escape of Human Astrovirus from Antibody Neutralization: Broad Implications for Rational Vaccine Design. United States. doi:10.1128/JVI.01546-17.
Bogdanoff, Walter A., Perez, Edmundo I., López, Tomás, Arias, Carlos F., DuBois, Rebecca M., and Schultz-Cherry, Stacey. Wed . "Structural Basis for Escape of Human Astrovirus from Antibody Neutralization: Broad Implications for Rational Vaccine Design". United States. doi:10.1128/JVI.01546-17.
@article{osti_1422226,
title = {Structural Basis for Escape of Human Astrovirus from Antibody Neutralization: Broad Implications for Rational Vaccine Design},
author = {Bogdanoff, Walter A. and Perez, Edmundo I. and López, Tomás and Arias, Carlos F. and DuBois, Rebecca M. and Schultz-Cherry, Stacey},
abstractNote = {ABSTRACT Human astroviruses are recognized as a leading cause of viral diarrhea worldwide in children, immunocompromised patients, and the elderly. There are currently no vaccines available to prevent astrovirus infection; however, antibodies developed by healthy individuals during previous infection correlate with protection from reinfection, suggesting that an effective vaccine could be developed. In this study, we investigated the molecular mechanism by which several strains of human astrovirus serotype 2 (HAstV-2) are resistant to the potent HAstV-2-neutralizing monoclonal antibody PL-2 (MAb PL-2). Sequencing of the HAstV-2 capsid genes reveals mutations in the PL-2 epitope within the capsid's spike domain. To understand the molecular basis for resistance from MAb PL-2 neutralization, we determined the 1.35-Å-resolution crystal structure of the capsid spike from one of these HAstV-2 strains. Our structure reveals a dramatic conformational change in a loop within the PL-2 epitope due to a serine-to-proline mutation, locking the loop in a conformation that sterically blocks binding and neutralization by MAb PL-2. We show that mutation to serine permits loop flexibility and recovers MAb PL-2 binding. Importantly, we find that HAstV-2 capsid spike containing a serine in this loop is immunogenic and elicits antibodies that neutralize all HAstV-2 strains. Taken together, our results have broad implications for rational selection of vaccine strains that do not contain prolines in antigenic loops, so as to elicit antibodies against diverse loop conformations. IMPORTANCEHuman astroviruses (HAstVs) infect nearly every person in the world during childhood and cause diarrhea, vomiting, and fever. In this study, we investigated how several strains of HAstV are resistant to a virus-neutralizing monoclonal antibody. We determined the crystal structure of the capsid protein spike domain from one of these HAstV strains and found that a single amino acid mutation induces a structural change in a loop that is responsible for antibody binding. Our findings reveal how viruses can escape antibody neutralization and provide insight for the rational design of vaccines to elicit diverse antibodies that provide broader protection from infection.},
doi = {10.1128/JVI.01546-17},
journal = {Journal of Virology},
issn = {0022-538X},
number = 1,
volume = 92,
place = {United States},
year = {2017},
month = {10}
}