1887

Abstract

The polymerase acidic (PA) I38T substitution is a dominant marker of resistance to baloxavir. We evaluated the impact of I38T on the fitness of a contemporary influenza A(H3N2) virus. Influenza A/Switzerland/9715293/2013 (H3N2) wild-type (WT) virus and its I38T mutant were rescued by reverse genetics. Replication kinetics were compared using ST6GalI-MDCK and A549 cells and infectivity/contact transmissibility were evaluated in guinea pigs. Nasal wash (NW) viral titres were determined by TCID50 ml in ST6GalI-MDCK cells. Competition experiments were performed and the evolution of viral population was assessed by droplet digital RT-PCR. I38T did not alter replication. I38T induced comparable titres vs the WT in guinea pigs NWs and the two viruses transmitted equally by direct contact. However, a 50 %:50 % mixture inoculum evolved to mean WT/I38T ratios of 71 %:29 % and 66.4 %:33.6 % on days 4 and 6 p.i., respectively. Contemporary influenza A(H3N2)-I38T PA variants may conserve a significant level of viral fitness.

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/content/journal/jgv/10.1099/jgv.0.001659
2021-10-18
2024-04-25
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References

  1. Jester BJ, Uyeki TM, Jernigan DB. Fifty years of influenza A(H3N2) following the pandemic of 1968. Am J Public Health 2020; 110:669–676 [View Article] [PubMed]
    [Google Scholar]
  2. Chambers BS, Parkhouse K, Ross TM, Alby K, Hensley SE. Identification of hemagglutinin residues responsible for H3N2 antigenic drift during the 2014-2015 influenza season. Cell Rep 2015; 12:1–6 [View Article] [PubMed]
    [Google Scholar]
  3. Yang J, Huang Y, Liu S. Investigational antiviral therapies for the treatment of influenza. Expert Opin Investig Drugs 2019; 28:481–488 [View Article] [PubMed]
    [Google Scholar]
  4. Beard KR, Brendish NJ, Clark TW. Treatment of influenza with neuraminidase inhibitors. Curr Opin Infect Dis 2018; 31:514–519 [View Article] [PubMed]
    [Google Scholar]
  5. Stevaert A, Naesens L. The influenza virus polymerase complex: an update on its structure, functions, and significance for antiviral drug design. Med Res Rev 2016; 36:1127–1173 [View Article] [PubMed]
    [Google Scholar]
  6. Hayden FG, Shindo N. Influenza virus polymerase inhibitors in clinical development. Curr Opin Infect Dis 2019; 32:176–186 [View Article] [PubMed]
    [Google Scholar]
  7. Lee LYY, Zhou J, Frise R, Goldhill DH, Koszalka P et al. Baloxavir treatment of ferrets infected with influenza A(H1N1)pdm09 virus reduces onward transmission. PLoS Pathog 2020; 16:e1008395
    [Google Scholar]
  8. Noshi T, Kitano M, Taniguchi K, Yamamoto A, Omoto S. In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit. Antiviral Res 2018; 160:109–117 [View Article] [PubMed]
    [Google Scholar]
  9. Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med 2018; 379:913–923 [View Article] [PubMed]
    [Google Scholar]
  10. Ison MG, Portsmouth S, Yoshida Y, Shishido T, Mitchener M. Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial. Lancet Infect Dis 2020; 20:1204–1214 [View Article] [PubMed]
    [Google Scholar]
  11. Hirotsu N, Sakaguchi H, Sato C, Ishibashi T, Baba K. Baloxavir marboxil in Japanese pediatric patients with influenza: safety and clinical and virologic outcomes. Clin Infect Dis 2020; 71:971–981 [View Article] [PubMed]
    [Google Scholar]
  12. Chesnokov A, Patel MC, Mishin VP, De La Cruz JA, Lollis L. Replicative fitness of seasonal influenza A viruses with decreased susceptibility to baloxavir. J Infect Dis 2020; 221:367–371 [View Article] [PubMed]
    [Google Scholar]
  13. Uehara T, Hayden FG, Kawaguchi K, Omoto S, Hurt AC. Treatment-emergent influenza variant viruses with reduced baloxavir susceptibility: impact on clinical and virologic outcomes in uncomplicated influenza. J Infect Dis 2020; 221:346–355 [View Article] [PubMed]
    [Google Scholar]
  14. Gubareva LV, Mishin VP, Patel MC, Chesnokov A, Nguyen HT. Assessing baloxavir susceptibility of influenza viruses circulating in the United States during the 2016/17 and 2017/18 seasons. Euro Surveill 2019; 24: [View Article] [PubMed]
    [Google Scholar]
  15. Omoto S, Speranzini V, Hashimoto T, Noshi T, Yamaguchi H. Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil. Sci Rep 2018; 8:9633 [View Article] [PubMed]
    [Google Scholar]
  16. Takashita E, Kawakami C, Ogawa R, Morita H, Fujisaki S. Influenza A(H3N2) virus exhibiting reduced susceptibility to baloxavir due to a polymerase acidic subunit I38T substitution detected from a hospitalised child without prior baloxavir treatment, Japan, January 2019. Euro Surveill 2019; 24: [View Article] [PubMed]
    [Google Scholar]
  17. Takashita E, Ichikawa M, Morita H, Ogawa R, Fujisaki S. Human-to-Human transmission of influenza A(H3N2) virus with reduced susceptibility to baloxavir, Japan, February 2019. Emerg Infect Dis 2019; 25:2108–2111 [View Article] [PubMed]
    [Google Scholar]
  18. Checkmahomed L, Carbonneau J, Venable MC, Baz M. Impact of the baloxavir-resistant polymerase acid I38T substitution on the fitness of contemporary influenza A(H1N1)pdm09 and A(H3N2) strains. J Infect Dis 2020; 221:63–70 [View Article] [PubMed]
    [Google Scholar]
  19. Imai M, Yamashita M, Sakai-Tagawa Y, Iwatsuki-Horimoto K, Kiso M. Influenza A variants with reduced susceptibility to baloxavir isolated from Japanese patients are fit and transmit through respiratory droplets. Nat Microbiol 2020; 5:27–33 [View Article] [PubMed]
    [Google Scholar]
  20. Jones JC, Pascua PNQ, Fabrizio TP, Marathe BM, Seiler P. Influenza A and B viruses with reduced baloxavir susceptibility display attenuated in vitro fitness but retain ferret transmissibility. Proc Natl Acad Sci U S A 2020; 117:8593–8601 [View Article] [PubMed]
    [Google Scholar]
  21. Bouvier NM, Lowen AC. Animal models for influenza virus pathogenesis and transmission. Viruses 2010; 2:1530–1563 [View Article] [PubMed]
    [Google Scholar]
  22. Baz M, Carbonneau J, Lavigne S, Couture C. Synergistic PA and HA mutations confer mouse adaptation of a contemporary A/H3N2 influenza virus. Sci Rep 2019; 9:16616 [View Article] [PubMed]
    [Google Scholar]
  23. Hatakeyama S, Sakai-Tagawa Y, Kiso M, Goto H, Kawakami C et al. Enhanced expression of an alpha2,6-linked sialic acid on MDCK cells improves isolation of human influenza viruses and evaluation of their sensitivity to a neuraminidase inhibitor. J Clin Microbiol 2005; 43:4139–4146
    [Google Scholar]
  24. Ann J, Abed Y, Beaulieu E, Bouhy X, Joly MH. Impact of a large deletion in the neuraminidase protein identified in a laninamivir-selected influenza A/Brisbane/10/2007 (H3N2) variant on viral fitness in vitro and in ferrets. Influenza Other Respir Viruses 2016; 10:122–126 [View Article] [PubMed]
    [Google Scholar]
  25. Palmer DF DW, Coleman MT, Schild GC. Advanced Laboratory Techniques for Influenza Diagnosis Atlanta: Centers for Disease Control, US Department of Health, Education and Welfare; 1975
    [Google Scholar]
  26. Taylor SC, Carbonneau J, Shelton DN, Boivin G. Optimization of Droplet Digital PCR from RNA and DNA extracts with direct comparison to RT-qPCR: Clinical implications for quantification of Oseltamivir-resistant subpopulations. Journal of virological methods, Comparative Study Evaluation Study 2015; 224:58–66
    [Google Scholar]
  27. Lee LY, Zhou J, Koszalka P, Frise R, Farrukee R. Evaluating the fitness of PA/I38T-substituted influenza A viruses with reduced baloxavir susceptibility in a competitive mixtures ferret model. PLoS Pathog 2021; 17:e1009527 [View Article] [PubMed]
    [Google Scholar]
  28. Takada K, Kawakami C, Fan S, Chiba S, Zhong G. A humanized MDCK cell line for the efficient isolation and propagation of human influenza viruses. Nat Microbiol 2019; 4:1268–1273 [View Article] [PubMed]
    [Google Scholar]
  29. Lowen AC, Mubareka S, Tumpey TM, Garcia-Sastre A, Palese P. The guinea pig as a transmission model for human influenza viruses. Proc Natl Acad Sci U S A 2006; 103:9988–9992 [View Article] [PubMed]
    [Google Scholar]
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