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

Journal of Virology
Walter BogdanoffRebecca M DuBois

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 c...Continue Reading

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Citations

Aug 7, 2019·Vaccines·Mehdi R M BidokhtiClaudia Baule
Dec 20, 2019·Journal of Virology·Stanislav O FedechkinRebecca M DuBois
Sep 30, 2020·Archives of Microbiology·T G VillaA Sánchez-Pérez
Jul 23, 2020·Cell Reports·Christine R FisherMatthias J Schnell
Jun 3, 2021·Viruses·Matthew Ykema, Yizhi J Tao
Jul 3, 2021·Viruses·Shanley N Roach, Ryan A Langlois

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