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Resistance to Influenza Neuraminidase Inhibitors

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Antimicrobial Drug Resistance

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Abstract

Annual epidemics and periodic pandemics caused by influenza viruses are associated with significant disease burden. Three classes of antiviral compounds, M2 ion-channel blockers (Amantadine and Rimantadine), neuraminidase (NA) inhibitors (Zanamivir, Oseltamivir, Peramivir, Laninamivir), and RNA-dependent RNA polymerase inhibitor (Favipiravir) have been approved for clinical use against influenza infections to date. The M2 ion-channel blockers effective in inhibiting proton conductivity of influenza A viruses were no longer recommended for clinical use since 2009 due to high prevalence of resistant variants among seasonal influenza A viruses of H3N2 and H1N1 subtypes. NA inhibitors are the current mainstays for influenza prophylaxis and treatment. Four approved NA inhibitors were structural-based designed to achieve specific interactions with the conserved residues at the NA enzyme site. This Chapter will discuss the resistance mechanisms for the NA inhibitors.

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References

  1. Thompson WW, Shay DK, Weintraub E, Brammer L, Bridges CB, Cox NJ, Fukuda K. Influenza-associated hospitalizations in the United States. JAMA. 2004;292:1333–40.

    Article  CAS  PubMed  Google Scholar 

  2. Centers for Disease C, Prevention. Estimates of deaths associated with seasonal influenza—United States, 1976–2007. MMWR Morb Mortal Wkly Rep. 2010;59:1057–62.

    Google Scholar 

  3. Webster RG, Bean WJ, Gorman OT, Chambers TM, Kawaoka Y. Evolution and ecology of influenza A viruses. Microbiol Rev. 1992;56:152–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Tong S, Li Y, Rivailler P, Conrardy C, Castillo DA, Chen LM, Recuenco S, Ellison JA, Davis CT, York IA, Turmelle AS, Moran D, Rogers S, Shi M, Tao Y, Weil MR, Tang K, Rowe LA, Sammons S, Xu X, Frace M, Lindblade KA, Cox NJ, Anderson LJ, Rupprecht CE, Donis RO. A distinct lineage of influenza A virus from bats. Proc Natl Acad Sci U S A. 2012;109:4269–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tong S, Zhu X, Li Y, Shi M, Zhang J, Bourgeois M, Yang H, Chen X, Recuenco S, Gomez J, Chen LM, Johnson A, Tao Y, Dreyfus C, Yu W, McBride R, Carney PJ, Gilbert AT, Chang J, Guo Z, Davis CT, Paulson JC, Stevens J, Rupprecht CE, Holmes EC, Wilson IA, Donis RO. New world bats harbor diverse influenza A viruses. PLoS Pathog. 2013;9:e1003657.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Osterhaus AD, Rimmelzwaan GF, Martina BE, Bestebroer TM, Fouchier RA. Influenza B virus in seals. Science. 2000;288:1051–3.

    Article  CAS  PubMed  Google Scholar 

  7. Vijaykrishna D, Holmes EC, Joseph U, Fourment M, Su YC, Halpin R, Lee RT, Deng YM, Gunalan V, Lin X, Stockwell TB, Fedorova NB, Zhou B, Spirason N, Kuhnert D, Boskova V, Stadler T, Costa AM, Dwyer DE, Huang QS, Jennings LC, Rawlinson W, Sullivan SG, Hurt AC, Maurer-Stroh S, Wentworth DE, Smith GJ, Barr IG. The contrasting phylodynamics of human influenza B viruses. Elife. 2015;4:e05055.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Gamblin SJ, Skehel JJ. Influenza hemagglutinin and neuraminidase membrane glycoproteins. J Biol Chem. 2010;285:28403–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. van der Vries E, Veldhuis Kroeze EJ, Stittelaar KJ, Linster M, Van der Linden A, Schrauwen EJ, Leijten LM, van Amerongen G, Schutten M, Kuiken T, Osterhaus AD, Fouchier RA, Boucher CA, Herfst S. Multidrug resistant 2009 A/H1N1 influenza clinical isolate with a neuraminidase I223R mutation retains its virulence and transmissibility in ferrets. PLoS Pathog. 2011;7:e1002276.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Skehel JJ, Wiley DC. Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu Rev Biochem. 2000;69:531–69.

    Article  CAS  PubMed  Google Scholar 

  11. Resa-Infante P, Jorba N, Coloma R, Ortin J. The influenza virus RNA synthesis machine: advances in its structure and function. RNA Biol. 2011;8:207–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Nayak DP, Balogun RA, Yamada H, Zhou ZH, Barman S. Influenza virus morphogenesis and budding. Virus Res. 2009;143:147–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Deyde VM, Xu X, Bright RA, Shaw M, Smith CB, Zhang Y, Shu Y, Gubareva LV, Cox NJ, Klimov AI. Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide. J Infect Dis. 2007;196:249–57.

    Article  CAS  PubMed  Google Scholar 

  14. Gubareva LV, Trujillo AA, Okomo-Adhiambo M, Mishin VP, Deyde VM, Sleeman K, Nguyen HT, Sheu TG, Garten RJ, Shaw MW, Fry AM, Klimov AI. Comprehensive assessment of 2009 pandemic influenza A (H1N1) virus drug susceptibility in vitro. Antivir Ther. 2010;15:1151–9.

    Article  CAS  PubMed  Google Scholar 

  15. Air GM. Influenza neuraminidase. Influenza Other Respi Viruses. 2012;6:245–56.

    Article  CAS  Google Scholar 

  16. Laver WG, Colman PM, Webster RG, Hinshaw VS, Air GM. Influenza virus neuraminidase with hemagglutinin activity. Virology. 1984;137:314–23.

    Article  CAS  PubMed  Google Scholar 

  17. Liu C, Air GM. Selection and characterization of a neuraminidase-minus mutant of influenza virus and its rescue by cloned neuraminidase genes. Virology. 1993;194:403–7.

    Article  CAS  PubMed  Google Scholar 

  18. Ohuchi M, Feldmann A, Ohuchi R, Klenk HD. Neuraminidase is essential for fowl plague virus hemagglutinin to show hemagglutinating activity. Virology. 1995;212:77–83.

    Article  CAS  PubMed  Google Scholar 

  19. Matrosovich MN, Matrosovich TY, Gray T, Roberts NA, Klenk HD. Neuraminidase is important for the initiation of influenza virus infection in human airway epithelium. J Virol. 2004;78:12665–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wagner R, Matrosovich M, Klenk HD. Functional balance between haemagglutinin and neuraminidase in influenza virus infections. Rev Med Virol. 2002;12:159–66.

    Article  PubMed  CAS  Google Scholar 

  21. Burmeister WP, Ruigrok RW, Cusack S. The 2.2 A resolution crystal structure of influenza B neuraminidase and its complex with sialic acid. EMBO J. 1992;11:49–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Russell RJ, Haire LF, Stevens DJ, Collins PJ, Lin YP, Blackburn GM, Hay AJ, Gamblin SJ, Skehel JJ. The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design. Nature. 2006;443:45–9.

    Article  CAS  PubMed  Google Scholar 

  23. Colman PM, Hoyne PA, Lawrence MC. Sequence and structure alignment of paramyxovirus hemagglutinin-neuraminidase with influenza virus neuraminidase. J Virol. 1993;67:2972–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Varghese JN, McKimm-Breschkin JL, Caldwell JB, Kortt AA, Colman PM. The structure of the complex between influenza virus neuraminidase and sialic acid, the viral receptor. Proteins. 1992;14:327–32.

    Article  CAS  PubMed  Google Scholar 

  25. von Itzstein M. The war against influenza: discovery and development of sialidase inhibitors. Nat Rev Drug Discov. 2007;6:967–74.

    Article  CAS  Google Scholar 

  26. Colman PM. Neuraminidase inhibitors as antivirals. Vaccine. 2002;20 Suppl 2:S55–8.

    Article  CAS  PubMed  Google Scholar 

  27. Meindl P, Bodo G, Palese P, Schulman J, Tuppy H. Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid. Virology. 1974;58:457–63.

    Article  CAS  PubMed  Google Scholar 

  28. Palese P, Compans RW. Inhibition of influenza virus replication in tissue culture by 2-deoxy-2,3-dehydro-N-trifluoroacetylneuraminic acid (FANA): mechanism of action. J Gen Virol. 1976;33:159–63.

    Article  CAS  PubMed  Google Scholar 

  29. Colman PM. Influenza virus neuraminidase: structure, antibodies, and inhibitors. Protein Sci. 1994;3:1687–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Colman PM, Varghese JN, Laver WG. Structure of the catalytic and antigenic sites in influenza virus neuraminidase. Nature. 1983;303:41–4.

    Article  CAS  PubMed  Google Scholar 

  31. Varghese JN, Laver WG, Colman PM. Structure of the influenza virus glycoprotein antigen neuraminidase at 2.9 A resolution. Nature. 1983;303:35–40.

    Article  CAS  PubMed  Google Scholar 

  32. von Itzstein M, Wu WY, Kok GB, Pegg MS, Dyason JC, ** B, Van Phan T, Smythe ML, White HF, Oliver SW, et al. Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature. 1993;363:418–23.

    Article  Google Scholar 

  33. Varghese JN, Epa VC, Colman PM. Three-dimensional structure of the complex of 4-guanidino-Neu5Ac2en and influenza virus neuraminidase. Protein Sci. 1995;4:1081–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Woods JM, Bethell RC, Coates JA, Healy N, Hiscox SA, Pearson BA, Ryan DM, Ticehurst J, Tilling J, Walcott SM, et al. 4-Guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid is a highly effective inhibitor both of the sialidase (neuraminidase) and of growth of a wide range of influenza A and B viruses in vitro. Antimicrob Agents Chemother. 1993;37:1473–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gubareva LV, Penn CR, Webster RG. Inhibition of replication of avian influenza viruses by the neuraminidase inhibitor 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid. Virology. 1995;212:323–30.

    Article  CAS  PubMed  Google Scholar 

  36. Kim CU, Lew W, Williams MA, Liu H, Zhang L, Swaminathan S, Bischofberger N, Chen MS, Mendel DB, Tai CY, Laver WG, Stevens RC. Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J Am Chem Soc. 1997;119:681–90.

    Article  CAS  PubMed  Google Scholar 

  37. Babu YS, Chand P, Bantia S, Kotian P, Dehghani A, El-Kattan Y, Lin TH, Hutchison TL, Elliott AJ, Parker CD, Ananth SL, Horn LL, Laver GW, Montgomery JA. BCX-1812 (RWJ-270201): discovery of a novel, highly potent, orally active, and selective influenza neuraminidase inhibitor through structure-based drug design. J Med Chem. 2000;43:3482–6.

    Article  CAS  PubMed  Google Scholar 

  38. Varghese JN, Smith PW, Sollis SL, Blick TJ, Sahasrabudhe A, McKimm-Breschkin JL, Colman PM. Drug design against a shifting target: a structural basis for resistance to inhibitors in a variant of influenza virus neuraminidase. Structure. 1998;6:735–46.

    Article  CAS  PubMed  Google Scholar 

  39. Samson M, Pizzorno A, Abed Y, Boivin G. Influenza virus resistance to neuraminidase inhibitors. Antiviral Res. 2013;98:174–85.

    Article  CAS  PubMed  Google Scholar 

  40. Vavricka CJ, Li Q, Wu Y, Qi J, Wang M, Liu Y, Gao F, Liu J, Feng E, He J, Wang J, Liu H, Jiang H, Gao GF. Structural and functional analysis of laninamivir and its octanoate prodrug reveals group specific mechanisms for influenza NA inhibition. PLoS Pathog. 2011;7:e1002249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. McKimm-Breschkin JL. Influenza neuraminidase inhibitors: antiviral action and mechanisms of resistance. Influenza Other Respi Viruses. 2013;7 Suppl 1:25–36.

    Article  CAS  Google Scholar 

  42. Bantia S, Parker CD, Ananth SL, Horn LL, Andries K, Chand P, Kotian PL, Dehghani A, El-Kattan Y, Lin T, Hutchison TL, Montgomery JA, Kellog DL, Babu YS. Comparison of the anti-influenza virus activity of RWJ-270201 with those of oseltamivir and zanamivir. Antimicrob Agents Chemother. 2001;45:1162–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Govorkova EA, Leneva IA, Goloubeva OG, Bush K, Webster RG. Comparison of efficacies of RWJ-270201, zanamivir, and oseltamivir against H5N1, H9N2, and other avian influenza viruses. Antimicrob Agents Chemother. 2001;45:2723–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bantia S, Arnold CS, Parker CD, Upshaw R, Chand P. Anti-influenza virus activity of peramivir in mice with single intramuscular injection. Antiviral Res. 2006;69:39–45.

    Article  CAS  PubMed  Google Scholar 

  45. Boltz DA, Ilyushina NA, Arnold CS, Babu YS, Webster RG, Govorkova EA. Intramuscularly administered neuraminidase inhibitor peramivir is effective against lethal H5N1 influenza virus in mice. Antiviral Res. 2008;80:150–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sidwell RW, Smee DF, Huffman JH, Barnard DL, Bailey KW, Morrey JD, Babu YS. In vivo influenza virus-inhibitory effects of the cyclopentane neuraminidase inhibitor RJW-270201. Antimicrob Agents Chemother. 2001;45:749–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. McLaughlin MM, Skoglund EW, Ison MG. Peramivir: an intravenous neuraminidase inhibitor. Expert Opin Pharmacother. 2015;16:1889–900.

    Article  CAS  PubMed  Google Scholar 

  48. Kubo S, Tomozawa T, Kakuta M, Tokumitsu A, Yamashita M. Laninamivir prodrug CS-8958, a long-acting neuraminidase inhibitor, shows superior anti-influenza virus activity after a single administration. Antimicrob Agents Chemother. 2010;54:1256–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Yamashita M, Tomozawa T, Kakuta M, Tokumitsu A, Nasu H, Kubo S. CS-8958, a prodrug of the new neuraminidase inhibitor R-125489, shows long-acting anti-influenza virus activity. Antimicrob Agents Chemother. 2009;53:186–92.

    Article  CAS  PubMed  Google Scholar 

  50. Barnett JM, Cadman A, Burrell FM, Madar SH, Lewis AP, Tisdale M, Bethell R. In vitro selection and characterisation of influenza B/Bei**g/1/87 isolates with altered susceptibility to zanamivir. Virology. 1999;265:286–95.

    Article  CAS  PubMed  Google Scholar 

  51. Blick TJ, Tiong T, Sahasrabudhe A, Varghese JN, Colman PM, Hart GJ, Bethell RC, McKimm-Breschkin JL. Generation and characterization of an influenza virus neuraminidase variant with decreased sensitivity to the neuraminidase-specific inhibitor 4-guanidino-Neu5Ac2en. Virology. 1995;214:475–84.

    Article  CAS  PubMed  Google Scholar 

  52. Gubareva LV, Bethell R, Hart GJ, Murti KG, Penn CR, Webster RG. Characterization of mutants of influenza A virus selected with the neuraminidase inhibitor 4-guanidino-Neu5Ac2en. J Virol. 1996;70:1818–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Gubareva LV, Robinson MJ, Bethell RC, Webster RG. Catalytic and framework mutations in the neuraminidase active site of influenza viruses that are resistant to 4-guanidino-Neu5Ac2en. J Virol. 1997;71:3385–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. McKimm-Breschkin JL. Resistance of influenza viruses to neuraminidase inhibitors—a review. Antiviral Res. 2000;47:1–17.

    Article  CAS  PubMed  Google Scholar 

  55. McKimm-Breschkin JL, Blick TJ, Sahasrabudhe A, Tiong T, Marshall D, Hart GJ, Bethell RC, Penn CR. Generation and characterization of variants of NWS/G70C influenza virus after in vitro passage in 4-amino-Neu5Ac2en and 4-guanidino-Neu5Ac2en. Antimicrob Agents Chemother. 1996;40:40–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Staschke KA, Colacino JM, Baxter AJ, Air GM, Bansal A, Hornback WJ, Munroe JE, Laver WG. Molecular basis for the resistance of influenza viruses to 4-guanidino-Neu5Ac2en. Virology. 1995;214:642–6.

    Article  CAS  PubMed  Google Scholar 

  57. Tai CY, Escarpe PA, Sidwell RW, Williams MA, Lew W, Wu H, Kim CU, Mendel DB. Characterization of human influenza virus variants selected in vitro in the presence of the neuraminidase inhibitor GS 4071. Antimicrob Agents Chemother. 1998;42:3234–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. McKimm-Breschkin JL, Sahasrabudhe A, Blick TJ, McDonald M, Colman PM, Hart GJ, Bethell RC, Varghese JN. Mutations in a conserved residue in the influenza virus neuraminidase active site decreases sensitivity to Neu5Ac2en-derived inhibitors. J Virol. 1998;72:2456–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Herlocher ML, Truscon R, Fenton R, Klimov A, Elias S, Ohmit SE, Monto AS. Assessment of development of resistance to antivirals in the ferret model of influenza virus infection. J Infect Dis. 2003;188:1355–61.

    Article  CAS  PubMed  Google Scholar 

  60. Blick TJ, Sahasrabudhe A, McDonald M, Owens IJ, Morley PJ, Fenton RJ, McKimm-Breschkin JL. The interaction of neuraminidase and hemagglutinin mutations in influenza virus in resistance to 4-guanidino-Neu5Ac2en. Virology. 1998;246:95–103.

    Article  CAS  PubMed  Google Scholar 

  61. Ginting TE, Shinya K, Kyan Y, Makino A, Matsumoto N, Kaneda S, Kawaoka Y. Amino acid changes in hemagglutinin contribute to the replication of oseltamivir-resistant H1N1 influenza viruses. J Virol. 2012;86:121–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gubareva LV. Molecular mechanisms of influenza virus resistance to neuraminidase inhibitors. Virus Res. 2004;103:199–203.

    Article  CAS  PubMed  Google Scholar 

  63. Hayden F. Develo** new antiviral agents for influenza treatment: what does the future hold? Clin Infect Dis. 2009;48 Suppl 1:S3–13.

    Article  CAS  PubMed  Google Scholar 

  64. McKimm-Breschkin J, Trivedi T, Hampson A, Hay A, Klimov A, Tashiro M, Hayden F, Zambon M. Neuraminidase sequence analysis and susceptibilities of influenza virus clinical isolates to zanamivir and oseltamivir. Antimicrob Agents Chemother. 2003;47:2264–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Meijer A, Rebelo-de-Andrade H, Correia V, Besselaar T, Drager-Dayal R, Fry A, Gregory V, Gubareva L, Kageyama T, Lackenby A, Lo J, Odagiri T, Pereyaslov D, Siqueira MM, Takashita E, Tashiro M, Wang D, Wong S, Zhang W, Daniels RS, Hurt AC. Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2012–2013. Antiviral Res. 2014;110:31–41.

    Article  CAS  PubMed  Google Scholar 

  66. Sheu TG, Deyde VM, Okomo-Adhiambo M, Garten RJ, Xu X, Bright RA, Butler EN, Wallis TR, Klimov AI, Gubareva LV. Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide from 2004 to 2008. Antimicrob Agents Chemother. 2008;52:3284–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Okomo-Adhiambo M, Sheu TG, Gubareva LV. Assays for monitoring susceptibility of influenza viruses to neuraminidase inhibitors. Influenza Other Respi Viruses. 2013;7 Suppl 1:44–9.

    Article  CAS  Google Scholar 

  68. WHO. Meetings of the WHo working group on surveillance of influenza antiviral susceptibility—Geneva, November 2011 and June 2012. MMWR Morb Mortal Wkly Rep. 2012;39:369–80.

    Google Scholar 

  69. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, Kimura K, Hayden FG, Sugaya N, Kawaoka Y. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet. 2004;364:759–65.

    Article  CAS  PubMed  Google Scholar 

  70. Roberts NA. Treatment of influenza with neuraminidase inhibitors: virological implications. Philos Trans R Soc Lond B Biol Sci. 2001;356:1895–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Whitley RJ, Boucher CA, Lina B, Nguyen-Van-Tam JS, Osterhaus A, Schutten M, Monto AS. Global assessment of resistance to neuraminidase inhibitors, 2008–2011: the Influenza Resistance Information Study (IRIS). Clin Infect Dis. 2013;56:1197–205.

    Article  CAS  PubMed  Google Scholar 

  72. Whitley RJ, Hayden FG, Reisinger KS, Young N, Dutkowski R, Ipe D, Mills RG, Ward P. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J. 2001;20:127–33.

    Article  CAS  PubMed  Google Scholar 

  73. Baz M, Abed Y, McDonald J, Boivin G. Characterization of multidrug-resistant influenza A/H3N2 viruses shed during 1 year by an immunocompromised child. Clin Infect Dis. 2006;43:1555–61.

    Article  CAS  PubMed  Google Scholar 

  74. Escuret V, Collins PJ, Casalegno JS, Vachieri SG, Cattle N, Ferraris O, Sabatier M, Frobert E, Caro V, Skehel JJ, Gamblin S, Valla F, Valette M, Ottmann M, McCauley JW, Daniels RS, Lina B. A novel I221L substitution in neuraminidase confers high-level resistance to oseltamivir in influenza B viruses. J Infect Dis. 2014;210:1260–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Eshaghi A, Shalhoub S, Rosenfeld P, Li A, Higgins RR, Stogios PJ, Savchenko A, Bastien N, Li Y, Rotstein C, Gubbay JB. Multiple influenza A (H3N2) mutations conferring resistance to neuraminidase inhibitors in a bone marrow transplant recipient. Antimicrob Agents Chemother. 2014;58:7188–97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Gubareva LV, Matrosovich MN, Brenner MK, Bethell RC, Webster RG. Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis. 1998;178:1257–62.

    Article  CAS  PubMed  Google Scholar 

  77. Memoli MJ, Athota R, Reed S, Czajkowski L, Bristol T, Proudfoot K, Hagey R, Voell J, Fiorentino C, Ademposi A, Shoham S, Taubenberger JK. The natural history of influenza infection in the severely immunocompromised vs nonimmunocompromised hosts. Clin Infect Dis. 2014;58:214–24.

    Article  PubMed  Google Scholar 

  78. Piralla A, Gozalo-Marguello M, Fiorina L, Rovida F, Muzzi A, Colombo AA, Alessandrino PE, Baldanti F. Different drug-resistant influenza A(H3N2) variants in two immunocompromised patients treated with oseltamivir during the 2011–2012 influenza season in Italy. J Clin Virol. 2013;58:132–7.

    Article  CAS  PubMed  Google Scholar 

  79. Weinstock DM, Gubareva LV, Zuccotti G. Prolonged shedding of multidrug-resistant influenza A virus in an immunocompromised patient. N Engl J Med. 2003;348:867–8.

    Article  PubMed  Google Scholar 

  80. Ison MG, Gubareva LV, Atmar RL, Treanor J, Hayden FG. Recovery of drug-resistant influenza virus from immunocompromised patients: a case series. J Infect Dis. 2006;193:760–4.

    Article  CAS  PubMed  Google Scholar 

  81. Tamura D, DeBiasi RL, Okomo-Adhiambo M, Mishin VP, Campbell AP, Loechelt B, Wiedermann BL, Fry AM, Gubareva LV. Emergence of multidrug-resistant influenza A(H1N1)pdm09 virus variants in an immunocompromised child treated with oseltamivir and zanamivir. J. Infect. Dis. 2015;212:1209–13.

    Google Scholar 

  82. Wang MZ, Tai CY, Mendel DB. Mechanism by which mutations at his274 alter sensitivity of influenza a virus n1 neuraminidase to oseltamivir carboxylate and zanamivir. Antimicrob Agents Chemother. 2002;46:3809–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Gubareva LV, Kaiser L, Matrosovich MN, Soo-Hoo Y, Hayden FG. Selection of influenza virus mutants in experimentally infected volunteers treated with oseltamivir. J Infect Dis. 2001;183:523–31.

    Article  CAS  PubMed  Google Scholar 

  84. de Jong MD, Tran TT, Truong HK, Vo MH, Smith GJ, Nguyen VC, Bach VC, Phan TQ, Do QH, Guan Y, Peiris JS, Tran TH, Farrar J. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med. 2005;353:2667–72.

    Article  PubMed  Google Scholar 

  85. Le QM, Kiso M, Someya K, Sakai YT, Nguyen TH, Nguyen KH, Pham ND, Ngyen HH, Yamada S, Muramoto Y, Horimoto T, Takada A, Goto H, Suzuki T, Suzuki Y, Kawaoka Y. Avian flu: isolation of drug-resistant H5N1 virus. Nature. 2005;437:1108.

    Article  CAS  PubMed  Google Scholar 

  86. Earhart KC, Elsayed NM, Saad MD, Gubareva LV, Nayel A, Deyde VM, Abdelsattar A, Abdelghani AS, Boynton BR, Mansour MM, Essmat HM, Klimov A, Shuck-Lee D, Monteville MR, Tjaden JA. Oseltamivir resistance mutation N294S in human influenza A(H5N1) virus in Egypt. J Infect Public Health. 2009;2:74–80.

    Article  PubMed  Google Scholar 

  87. Bloom JD, Gong LI, Baltimore D. Permissive secondary mutations enable the evolution of influenza oseltamivir resistance. Science. 2010;328:1272–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Duan S, Govorkova EA, Bahl J, Zaraket H, Baranovich T, Seiler P, Prevost K, Webster RG, Webby RJ. Epistatic interactions between neuraminidase mutations facilitated the emergence of the oseltamivir-resistant H1N1 influenza viruses. Nat Commun. 2014;5:5029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Abed Y, Pizzorno A, Bouhy X, Boivin G. Role of permissive neuraminidase mutations in influenza A/Brisbane/59/2007-like (H1N1) viruses. PLoS Pathog. 2011;7:e1002431.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Rameix-Welti MA, Munier S, Le Gal S, Cuvelier F, Agou F, Enouf V, Naffakh N, van der Werf S. Neuraminidase of 2007–2008 influenza A(H1N1) viruses shows increased affinity for sialic acids due to the D344N substitution. Antivir Ther. 2011;16:597–603.

    Article  CAS  PubMed  Google Scholar 

  91. Baz M, Abed Y, Papenburg J, Bouhy X, Hamelin ME, Boivin G. Emergence of oseltamivir-resistant pandemic H1N1 virus during prophylaxis. N Engl J Med. 2009;361:2296–7.

    Article  CAS  PubMed  Google Scholar 

  92. Memoli MJ, Hrabal RJ, Hassantoufighi A, Eichelberger MC, Taubenberger JK. Rapid selection of oseltamivir- and peramivir-resistant pandemic H1N1 virus during therapy in 2 immunocompromised hosts. Clin Infect Dis. 2010;50:1252–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Hurt AC, Hardie K, Wilson NJ, Deng YM, Osbourn M, Leang SK, Lee RT, Iannello P, Gehrig N, Shaw R, Wark P, Caldwell N, Givney RC, Xue L, Maurer-Stroh S, Dwyer DE, Wang B, Smith DW, Levy A, Booy R, Dixit R, Merritt T, Kelso A, Dalton C, Durrheim D, Barr IG. Characteristics of a widespread community cluster of H275Y oseltamivir-resistant A(H1N1)pdm09 influenza in Australia. J Infect Dis. 2012;206:148–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Takashita E, Kiso M, Fujisaki S, Yokoyama M, Nakamura K, Shirakura M, Sato H, Odagiri T, Kawaoka Y, Tashiro M. Characterization of a large cluster of influenza A(H1N1)pdm09 viruses cross-resistant to oseltamivir and peramivir during the 2013–2014 influenza season in Japan. Antimicrob Agents Chemother. 2015;59:2607–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Okomo-Adhiambo M, Fry AM, Su S, Nguyen HT, Elal AA, Negron E, Hand J, Garten RJ, Barnes J, **yan X, Villanueva JM, Gubareva LV, Group USIAW. Oseltamivir-resistant influenza A(H1N1)pdm09 viruses, United States, 2013–14. Emerg Infect Dis. 2015;21:136–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Butler J, Hooper KA, Petrie S, Lee R, Maurer-Stroh S, Reh L, Guarnaccia T, Baas C, Xue L, Vitesnik S, Leang SK, McVernon J, Kelso A, Barr IG, McCaw JM, Bloom JD, Hurt AC. Estimating the fitness advantage conferred by permissive neuraminidase mutations in recent oseltamivir-resistant A(H1N1)pdm09 influenza viruses. PLoS Pathog. 2014;10:e1004065.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Hurt AC, Lee RT, Leang SK, Cui L, Deng YM, Phuah SP, Caldwell N, Freeman K, Komadina N, Smith D, Speers D, Kelso A, Lin RT, Maurer-Stroh S, Barr IG. Increased detection in Australia and Singapore of a novel influenza A(H1N1)2009 variant with reduced oseltamivir and zanamivir sensitivity due to a S247N neuraminidase mutation. Euro. Surveill. 2011;16(23). pii: 19884.

    Google Scholar 

  98. Nguyen HT, Fry AM, Loveless PA, Klimov AI, Gubareva LV. Recovery of a multidrug-resistant strain of pandemic influenza A 2009 (H1N1) virus carrying a dual H275Y/I223R mutation from a child after prolonged treatment with oseltamivir. Clin Infect Dis. 2010;51:983–4.

    Article  PubMed  Google Scholar 

  99. Nguyen HT, Trujillo AA, Sheu TG, Levine M, Mishin VP, Shaw M, Ades EW, Klimov AI, Fry AM, Gubareva LV. Analysis of influenza viruses from patients clinically suspected of infection with an oseltamivir resistant virus during the 2009 pandemic in the United States. Antiviral Res. 2012;93:381–6.

    Article  CAS  PubMed  Google Scholar 

  100. Centers for Disease C, Prevention. Oseltamivir-resistant novel influenza A (H1N1) virus infection in two immunosuppressed patients—Seattle, Washington, 2009. MMWR Morb Mortal Wkly Rep. 2009;58:893–6.

    Google Scholar 

  101. Eshaghi A, Patel SN, Sarabia A, Higgins RR, Savchenko A, Stojios PJ, Li Y, Bastien N, Alexander DC, Low DE, Gubbay JB. Multidrug-resistant pandemic (H1N1) 2009 infection in immunocompetent child. Emerg Infect Dis. 2011;17:1472–4.

    PubMed  PubMed Central  Google Scholar 

  102. van der Vries E, Stelma FF, Boucher CA. Emergence of a multidrug-resistant pandemic influenza A (H1N1) virus. N Engl J Med. 2010;363:1381–2.

    Article  PubMed  Google Scholar 

  103. Takashita E, Meijer A, Lackenby A, Gubareva L, Rebelo-de-Andrade H, Besselaar T, Fry A, Gregory V, Leang SK, Huang W, Lo J, Pereyaslov D, Siqueira MM, Wang D, Mak GC, Zhang W, Daniels RS, Hurt AC, Tashiro M. Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2013–2014. Antiviral Res. 2015;117:27–38.

    Article  CAS  PubMed  Google Scholar 

  104. Hurt AC, Holien JK, Parker M, Kelso A, Barr IG. Zanamivir-resistant influenza viruses with a novel neuraminidase mutation. J Virol. 2009;83:10366–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Yates PJ, Mehta N, Horton J, Tisdale M. Virus susceptibility analyses from a phase IV clinical trial of inhaled zanamivir treatment in children infected with influenza. Antimicrob Agents Chemother. 2013;57:1677–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kaminski MM, Ohnemus A, Staeheli P, Rubbenstroth D. Pandemic 2009 H1N1 influenza A virus carrying a Q136K mutation in the neuraminidase gene is resistant to zanamivir but exhibits reduced fitness in the guinea pig transmission model. J Virol. 2013;87:1912–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Yen HL, Herlocher LM, Hoffmann E, Matrosovich MN, Monto AS, Webster RG, Govorkova EA. Neuraminidase inhibitor-resistant influenza viruses may differ substantially in fitness and transmissibility. Antimicrob Agents Chemother. 2005;49:4075–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Mishin VP, Hayden FG, Gubareva LV. Susceptibilities of antiviral-resistant influenza viruses to novel neuraminidase inhibitors. Antimicrob Agents Chemother. 2005;49:4515–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Hurt AC, Leang SK, Tiedemann K, Butler J, Mechinaud F, Kelso A, Downie P, Barr IG. Progressive emergence of an oseltamivir-resistant A(H3N2) virus over two courses of oseltamivir treatment in an immunocompromised paediatric patient. Influenza Other Respi Viruses. 2013;7:904–8.

    Article  CAS  Google Scholar 

  110. Abed Y, Baz M, Boivin G. A novel neuraminidase deletion mutation conferring resistance to oseltamivir in clinical influenza A/H3N2 virus. J Infect Dis. 2009;199:180–3.

    Article  CAS  PubMed  Google Scholar 

  111. Dapat C, Suzuki Y, Saito R, Kyaw Y, Myint YY, Lin N, Oo HN, Oo KY, Win N, Naito M, Hasegawa G, Dapat IC, Zaraket H, Baranovich T, Nishikawa M, Saito T, Suzuki H. Rare influenza A (H3N2) variants with reduced sensitivity to antiviral drugs. Emerg Infect Dis. 2010;16:493–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Lin YP, Gregory V, Collins P, Kloess J, Wharton S, Cattle N, Lackenby A, Daniels R, Hay A. Neuraminidase receptor binding variants of human influenza A(H3N2) viruses resulting from substitution of aspartic acid 151 in the catalytic site: a role in virus attachment? J Virol. 2010;84:6769–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Zhu X, McBride R, Nycholat CM, Yu W, Paulson JC, Wilson IA. Influenza virus neuraminidases with reduced enzymatic activity that avidly bind sialic acid receptors. J Virol. 2012;86:13371–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Tamura D, Nguyen HT, Sleeman K, Levine M, Mishin VP, Yang H, Guo Z, Okomo-Adhiambo M, Xu X, Stevens J, Gubareva LV. Cell culture-selected substitutions in influenza A(H3N2) neuraminidase affect drug susceptibility assessment. Antimicrob Agents Chemother. 2013;57:6141–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Hu Y, Lu S, Song Z, Wang W, Hao P, Li J, Zhang X, Yen HL, Shi B, Li T, Guan W, Xu L, Liu Y, Wang S, Zhang X, Tian D, Zhu Z, He J, Huang K, Chen H, Zheng L, Li X, ** J, Kang B, ** X, Zha L, Li Y, Zhang Z, Peiris M, Yuan Z. Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance. Lancet. 2013;381:2273–9.

    Article  PubMed  Google Scholar 

  116. Yen HL, McKimm-Breschkin JL, Choy KT, Wong DD, Cheung PP, Zhou J, Ng IH, Zhu H, Webby RJ, Guan Y, Webster RG, Peiris JS. Resistance to neuraminidase inhibitors conferred by an R292K mutation in a human influenza virus H7N9 isolate can be masked by a mixed R/K viral population. mBio. 2013;4:e00396–13.

    Google Scholar 

  117. Marjuki H, Mishin VP, Chesnokov AP, Jones J, De La Cruz JA, Sleeman K, Tamura D, Nguyen HT, Wu HS, Chang FY, Liu MT, Fry AM, Cox NJ, Villanueva JM, Davis CT, Gubareva LV. Characterization of drug-resistant influenza A(H7N9) variants isolated from an oseltamivir-treated patient in Taiwan. J Infect Dis. 2015;211:249–57.

    Article  PubMed  Google Scholar 

  118. Hatakeyama S, Sugaya N, Ito M, Yamazaki M, Ichikawa M, Kimura K, Kiso M, Shimizu H, Kawakami C, Koike K, Mitamura K, Kawaoka Y. Emergence of influenza B viruses with reduced sensitivity to neuraminidase inhibitors. JAMA. 2007;297:1435–42.

    Article  CAS  PubMed  Google Scholar 

  119. Hurt AC, Iannello P, Jachno K, Komadina N, Hampson AW, Barr IG, McKimm-Breschkin JL. Neuraminidase inhibitor-resistant and -sensitive influenza B viruses isolated from an untreated human patient. Antimicrob Agents Chemother. 2006;50:1872–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Okomo-Adhiambo M, Sleeman K, Ballenger K, Nguyen HT, Mishin VP, Sheu TG, Smagala J, Li Y, Klimov AI, Gubareva LV. Neuraminidase inhibitor susceptibility testing in human influenza viruses: a laboratory surveillance perspective. Viruses. 2010;2:2269–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Sheu TG, Deyde VM, Garten RJ, Klimov AI, Gubareva LV. Detection of antiviral resistance and genetic lineage markers in influenza B virus neuraminidase using pyrosequencing. Antiviral Res. 2010;85:354–60.

    Article  CAS  PubMed  Google Scholar 

  122. Escuret V, Frobert E, Bouscambert-Duchamp M, Sabatier M, Grog I, Valette M, Lina B, Morfin F, Ferraris O. Detection of human influenza A (H1N1) and B strains with reduced sensitivity to neuraminidase inhibitors. J Clin Virol. 2008;41:25–8.

    Article  CAS  PubMed  Google Scholar 

  123. Carr S, Ilyushina NA, Franks J, Adderson EE, Caniza M, Govorkova EA, Webster RG. Oseltamivir-resistant influenza A and B viruses pre- and postantiviral therapy in children and young adults with cancer. Pediatr Infect Dis J. 2011;30:284–8.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Higgins RR, Beniprashad M, Chong-King E, Li Y, Bastien N, Low DE, Gubbay JB. Recovery of influenza B virus with the H273Y point mutation in the neuraminidase active site from a human patient. J Clin Microbiol. 2012;50:2500–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Fujisaki S, Takashita E, Yokoyama M, Taniwaki T, Xu H, Kishida N, Sato H, Tashiro M, Imai M, Odagiri T. A single E105K mutation far from the active site of influenza B virus neuraminidase contributes to reduced susceptibility to multiple neuraminidase-inhibitor drugs. Biochem Biophys Res Commun. 2012;429:51–6.

    Article  CAS  PubMed  Google Scholar 

  126. Kim JH, Resende R, Wennekes T, Chen HM, Bance N, Buchini S, Watts AG, Pilling P, Streltsov VA, Petric M, Liggins R, Barrett S, McKimm-Breschkin JL, Niikura M, Withers SG. Mechanism-based covalent neuraminidase inhibitors with broad-spectrum influenza antiviral activity. Science. 2013;340:71–5.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong

    Hui-Ling Yen

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  1. Treiber Therapeutics, Cambridge, Massachusetts, USA

    Douglas L. Mayers

  2. Wayne State University School of Medicine, Detroit Medical Center, Detroit, Michigan, USA

    Jack D. Sobel

  3. Centre de recherche en Infectiologie, University of Laval, Quebec City, Canada

    Marc Ouellette

  4. Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA

    Keith S. Kaye

  5. Infection Control and Prevention Unit of Infectious Diseases, Assaf Harofeh Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel

    Dror Marchaim

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Yen, HL. (2017). Resistance to Influenza Neuraminidase Inhibitors. In: Mayers, D., Sobel, J., Ouellette, M., Kaye, K., Marchaim, D. (eds) Antimicrobial Drug Resistance. Springer, Cham. https://doi.org/10.1007/978-3-319-46718-4_32

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