The evolutionary potential of influenza A virus hemagglutinin is highly constrained by epistatic interactions with neuraminidase

Liu, Tongyu; Wang, Yiquan; Tan, Timothy J.C.; Wu, Nicholas C.; Brooke, Christopher B.

doi:10.1016/j.chom.2022.09.003

Cited by 19 publications

(21 citation statements)

References 60 publications

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“…2 ). In contrast with our previous results obtained using PR8 31 , the fitness score distributions were similar across the different NA backgrounds and the CA09+NAI control, suggesting that the range of NA activities tested here had little effect on the overall mutational robustness of HA1 in the pdm2009 lineage. The means of the average fitness scores from the different NA backgrounds were statistically significant (p < 0.001 by the Wilcoxon matched-pairs signed rank test); however, so were the differences between technical replicates for the individual groups, suggesting that these differences primarily reflect technical noise.…”

Section: Resultscontrasting

confidence: 99%

Natural variation in neuraminidase activity influences the evolutionary potential of the seasonal H1N1 lineage hemagglutinin

Liu,

Reiser,

Tan

et al. 2024

Preprint

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The antigenic evolution of the influenza A virus hemagglutinin (HA) gene poses a major challenge for the development of vaccines capable of eliciting long-term protection. Prior efforts to understand the mechanisms that govern viral antigenic evolution mainly focus on HA in isolation, ignoring the fact that HA must act in concert with the viral neuraminidase (NA) during replication and spread. Numerous studies have demonstrated that the degree to which the receptor binding avidity of HA and receptor cleaving activity of NA are balanced with each other influences overall viral fitness. We recently showed that changes in NA activity can significantly alter the mutational fitness landscape of HA in the context of a lab-adapted virus strain. Here, we test whether natural variation in relative NA activity can influence the evolutionary potential of HA in the context of the seasonal H1N1 lineage (pdmH1N1) that has circulated in humans since the 2009 pandemic. We observed substantial variation in the relative activities of NA proteins encoded by a panel of H1N1 vaccine strains isolated between 2009 and 2019. We comprehensively assessed the effect of NA background on the HA mutational fitness landscape in the circulating pdmH1N1 lineage using deep mutational scanning and observed pronounced epistasis between NA and residues in or near the receptor binding site of HA. To determine whether NA variation could influence the antigenic evolution of HA, we performed neutralizing antibody selection experiments using a panel of monoclonal antibodies targeting different HA epitopes. We found that the specific antibody escape profiles of HA were highly contingent upon NA background. Overall, our results indicate that natural variation in NA activity plays a significant role in governing the evolutionary potential of HA in the currently circulating pdmH1N1 lineage.

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Section: Resultscontrasting

confidence: 99%

Natural variation in neuraminidase activity influences the evolutionary potential of the seasonal H1N1 lineage hemagglutinin

Liu,

Reiser,

Tan

et al. 2024

Preprint

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“… 46 – 48 Consistently, our recent study has shown that the mutational fitness landscape of HA can be influenced by NA. 49 As a result, we acknowledge that our deep mutational scanning experiment may be slightly different if both HA and NA from Mos99 are used.…”

Section: Discussionmentioning

confidence: 99%

Mutational fitness landscape of human influenza H3N2 neuraminidase

et al. 2023

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“…Therefore, it may be possible that further affinity maturation additionally restricts potential escape mutations in SI06. In addition to epistasis within HA, intergenic epistasis between HA and NA also influences the accessible escape mutations in HA 44,45 . For each virus library, we used the matched NA from that strain.…”

Section: Limitations Of Studymentioning

confidence: 99%

Antigenic drift expands viral escape pathways from imprinted host humoral immunity

Maurer,

Vu,

Schmidt

2024

Preprint

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An initial virus exposure can imprint antibodies such that future responses to antigenically drifted strains are dependent on the identity of the imprinting strain. Subsequent exposure to antigenically distinct strains followed by affinity maturation can guide immune responses toward generation of cross-reactive antibodies. How viruses evolve in turn to escape these imprinted broad antibody responses is unclear. Here, we used clonal antibody lineages from two human donors recognizing conserved influenza virus hemagglutinin (HA) epitopes to assess viral escape potential using deep mutational scanning. We show that even though antibody affinity maturation does restrict the number of potential escape routes in the imprinting strain through repositioning the antibody variable domains, escape is still readily observed in drifted strains and attributed to epistatic networks within HA. These data explain how influenza virus continues to evolve in the human population by escaping even broad antibody responses.

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The evolutionary potential of influenza A virus hemagglutinin is highly constrained by epistatic interactions with neuraminidase

Cited by 19 publications

References 60 publications

Natural variation in neuraminidase activity influences the evolutionary potential of the seasonal H1N1 lineage hemagglutinin

Natural variation in neuraminidase activity influences the evolutionary potential of the seasonal H1N1 lineage hemagglutinin

Mutational fitness landscape of human influenza H3N2 neuraminidase

Antigenic drift expands viral escape pathways from imprinted host humoral immunity

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