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

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2023-04, Vol.120 (17), p.e2208718120-e2208718120
Main Authors: Lee, Chung-Young, Raghunathan, Vedhika, Caceres, C Joaquin, Geiger, Ginger, Seibert, Brittany, Cargnin Faccin, Flavio, Gay, L Claire, Ferreri, Lucas M, Kaul, Drishti, Wrammert, Jens, Tan, Gene S, Perez, Daniel R, Lowen, Anice C
Format: Article
Language:English
Subjects:
Antibodies
Antibodies, Neutralizing
Antibodies, Viral
Avidity
Binding
Biological Sciences
Broadly Neutralizing Antibodies - genetics
Constraints
Domains
Epistasis
Epistasis, Genetic
Epitopes
Fitness
Hemagglutinin Glycoproteins, Influenza Virus
Hemagglutinins
Humans
Influenza
Influenza A
Influenza A virus
Influenza Vaccines - genetics
Influenza, Human - genetics
Influenza, Human - prevention & control
Membrane fusion
Mutation
Reproductive fitness
Vaccines
Viruses
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2208718120