ArticleNature ecology & evolution2026
Pleiotropic mutational effects on function and stability constrain the antigenic evolution of influenza haemagglutinin.
Article in Nature ecology & evolution, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed.
- In silico analysis of pH stabilising mutations of hemagglutinin of influenza A virus H5N1 clade 2.3.4.4b.Npj viruses · 2026Review
- Article
- From sites to structure to serology: a roadmap for structure-aware molecular evolution of antigenically evolving viruses.Journal of virology · 2026Review
- Concepts of RNA virus evolution for the design of better antiviral countermeasures.Nature reviews. Microbiology · 2026Review
- Epistasis facilitates the long-term antigenic evolution of the influenza B virus hemagglutinin.bioRxiv : the preprint server for biology · 2026Article
- Scanning the horizon: deep mutational scanning approaches in virology.Journal of virology · 2026Review
- New determinant of influenza hemagglutinin cleavability identified through random mutagenesis for acid-stabilizing mutations.Microbiology spectrum · 2026Article
- Deep mutational scanning of recent SARS-CoV-2 variants highlights changing amino acid preferences within epistatic hotspot residues.PLoS pathogens · 2026Article
- Influenza hemagglutinin subtypes have different sequence constraints despite sharing extremely similar structures.bioRxiv : the preprint server for biology · 2026Article
- Learning a viral protein's vocabulary.Nature ecology & evolution · 2026Article
- Functional and antigenic constraints on the Nipah virus fusion protein.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Interim 2025/26 influenza vaccine effectiveness estimates with immuno-epidemiological considerations for A(H3N2) subclade K protection, Canada, January 2026.Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin · 2026Article
- Functional and antigenic constraints on the Nipah virus fusion protein.bioRxiv : the preprint server for biology · 2026Article
- Influenza hemagglutinin subtypes have different sequence constraints despite sharing extremely similar structures.Virus evolution · 2026Article
- First detection and transatlantic introduction of Influenza A(H3N2) subclade K (J.2.4.1) into Ecuador: insights from genomic sentinel surveillance.Frontiers in public health · 2026Article
- Resistance Mutations to Broadly Neutralizing Antibodies Destabilize Hemagglutinin and Attenuate H1N1 Influenza Virus.Viruses · 2025Article
- Article
- Immune pressure is key to understanding observed patterns of respiratory virus evolution in prolonged infections.Virus evolution · 2025Article
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Abstract
The evolution of human influenza virus haemagglutinin (HA) involves simultaneous selection to acquire antigenic mutations that escape population immunity while preserving protein function and stability. Epistasis shapes this evolution, as an antigenic mutation that is deleterious in one genetic background may become tolerated in another. However, the extent to which epistasis can alleviate pleiotropic conflicts between immune escape and protein function/stability is unclear. Here we measure how all amino acid mutations in the HA of a recent human H3N2 influenza strain affect its cell entry function, acid stability and neutralization by human serum antibodies. We find that epistasis has entrenched certain mutations so that reverting to the ancestral amino acid identity in earlier strains is no longer tolerated. Epistasis has also enabled the emergence of antigenic mutations that were detrimental to the cell entry function of HA in earlier strains. However, epistasis appears insufficient to overcome the pleiotropic costs of antigenic mutations that impair the stability of HA, explaining why some mutations that strongly escape human antibodies never fix in nature. Our results refine our understanding of the mutational constraints that shape recent H3N2 influenza evolution: epistasis can enable antigenic change, but pleiotropic effects can restrict its trajectory.
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