Long-term evolution of human seasonal influenza virus A(H3N2) is associated with an increase in polymerase complex activity

René M Vigeveno, Alvin X Han, Robert P de Vries, Edyth Parker, Karen de Haan, Sarah van Leeuwen, Katina D Hulme, Adam S Lauring, Aartjan J W Te Velthuis, Geert-Jan Boons, Ron A M Fouchier, Colin A Russell, Menno D de Jong, Dirk Eggink*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Since the influenza pandemic in 1968, influenza A(H3N2) viruses have become endemic. In this state, H3N2 viruses continuously evolve to overcome immune pressure as a result of prior infection or vaccination, as is evident from the accumulation of mutations in the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA). However, phylogenetic studies have also demonstrated ongoing evolution in the influenza A(H3N2) virus RNA polymerase complex genes. The RNA polymerase complex of seasonal influenza A(H3N2) viruses produces mRNA for viral protein synthesis and replicates the negative sense viral RNA genome (vRNA) through a positive sense complementary RNA intermediate (cRNA). Presently, the consequences and selection pressures driving the evolution of the polymerase complex remain largely unknown. Here, we characterize the RNA polymerase complex of seasonal influenza A(H3N2) viruses representative of nearly 50 years of influenza A(H3N2) virus evolution. The H3N2 polymerase complex is a reassortment of human and avian influenza virus genes. We show that since 1968, influenza A(H3N2) viruses have increased the transcriptional activity of the polymerase complex while retaining a close balance between mRNA, vRNA, and cRNA levels. Interestingly, the increased polymerase complex activity did not result in increased replicative ability on differentiated human airway epithelial (HAE) cells. We hypothesize that the evolutionary increase in polymerase complex activity of influenza A(H3N2) viruses may compensate for the reduced HA receptor binding and avidity that is the result of the antigenic evolution of influenza A(H3N2) viruses.

Original languageEnglish
Article numberveae030
Number of pages14
JournalVirus Evolution
Volume10
Issue number1
DOIs
Publication statusPublished - 24 May 2024

Keywords

  • H3N2
  • Infuenza virus
  • antigenic drif
  • evolution
  • polymerase complex activity
  • receptor specifcity

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