Epistasis reduces fitness costs of influenza A virus escape from stem-binding antibodies

• Type of Material: Article
• Authors: Chung-Young Lee, Emory University; Vedhika Raghunathan, Emory University; Joauin C Caceres, University of Georgia; Ginger Geiger, University of Georgia; Brittany Seibert, University of Georgia; Flavio Cargnin Faccin, University of Georgia; Claire L Gay, University of Georgia; Lucas Ferreri, Emory University; Drishti Kaul, J. Craig Venter Institute; Jens Wrammert, Emory University; Gene S Tan, J. Craig Venter Institute; Daniel R Perez, University of Georgia; Anice Lowen, Emory University
• Language: English
• Date: 2023-04-25
• Publisher: NATL ACAD SCIENCES
• Publication Version: Final Published Version
• Copyright Statement: © 2023 the Author(s). Published by PNAS.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.2208718120
• Title of Journal or Parent Work: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• Volume: 120
• Issue: 17
• Start Page: e2208718120
• End Page: e2208718120
• Grant/Funding Information: The research was funded by the NIH/NIAID Centers of Excellence in Influenza Research and Surveillance, contract number HHSN272201400004C and R01 AI165644 to A.C.L.
• Keywords: EVOLUTION; influenza A virus; NEUTRALIZING EPITOPE; Science & Technology - Other Topics; SPECIFICITY; epistasis; HEMAGGLUTININ; HUMANS; ANTIGENIC DRIFT; MONOCLONAL-ANTIBODY; antigenic escape; PERSPECTIVE; RECEPTOR; MUTATIONS; Multidisciplinary Sciences; evolution; Science & Technology; HA stem

Abstract

The hemagglutinin (HA) stem region is a major target of universal influenza vaccine efforts owing to the presence of highly conserved epitopes across multiple influenza A virus (IAV) strains and subtypes. To explore the potential impact of vaccine-induced immunity targeting the HA stem, we examined the fitness effects of viral escape from stem-binding broadly neutralizing antibodies (stem-bnAbs). Recombinant viruses containing each individual antibody escape substitution showed diminished replication compared to wild-type virus, indicating that stem-bnAb escape incurred fitness costs. A second-site mutation in the HA head domain (N129D; H1 numbering) reduced the fitness effects observed in primary cell cultures and likely enabled the selection of escape mutations. Functionally, this putative permissive mutation increased HA avidity for its receptor. These results suggest a mechanism of epistasis in IAV, wherein modulating the efficiency of attachment eases evolutionary constraints imposed by the requirement for membrane fusion. Taken together, the data indicate that viral escape from stem-bnAbs is costly but highlights the potential for epistatic interactions to enable evolution within the functionally constrained HA stem domain.