Advertisement

Virus Genes

pp 1–8 | Cite as

Characterization of viral genomic mutations in novel influenza A (H7N9)-infected patients: the association between oseltamivir-resistant variants and viral shedding duration

  • Renke Chen
  • Qianda Zou
  • Guoliang Xie
  • Fei Yu
  • Xianzhi Yang
  • Lingyong Cao
  • Zhaoxia HuoEmail author
  • Shufa ZhengEmail author
Original Paper

Abstract

Since February 2013, human infections with the novel influenza A H7N9 virus have occurred in eastern China. It is important to detect mutations in viral genes and analyze the clinical features of patients and viral shedding duration related to neuraminidase inhibitor (NAI) resistance. We collected clinical specimens from 31 hospitalized H7N9 patients and sequenced NA, PB2, HA, and M gene fragments. Of the 31 identified patients, 7 (22.6%) carried the R292K substitution in NA, 30 (96.8%), 3 (9.7%), and 5 (16.1%) carried E627K, Q591K, and D701N mutations in PB2, respectively, and 2 (6.5%) carried both E627K and D701N mutations in PB2. All 26 identified patients harbored Q226L mutations and possessed only a single arginine (R) at cleavage sites in the HA and a S31N mutation in M2. Among 7 NA-R292K mutated patients, 3 died and 4 were discharged. There was no significant difference in the days that patients started oseltamivir treatment after symptom onset between NA-R292K mutant and NA-R292 wild-type patients (median days, 7 vs 6, P = 0.374). NA-R292K mutant patients had a significantly longer duration of viral shedding than NA-R292 wild-type patients after oseltamivir treatment (median days, 10 vs 5, P = 0.022). The mutation of R292K in NA conferring the potential ability of oseltamivir resistance resulted in prolonged viral duration and poor outcome and should be taken into consideration in the clinical management of infected patients.

Keywords

Influenza A (H7N9) Mutation Neuraminidase (NA) Oseltamivir resistance Viral duration 

Notes

Acknowledgements

We thank Prof. Kwok-Yung Yuen and Prof. Hong-Lin Chen in the State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, University of Hong Kong for their advice in study design, and Dr. Weifeng Liang (State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China) for help with the clinical data collection.

Funding

This work was supported by the China National Mega-Projects for Infectious Diseases (Grant Number 2017ZX10103008), the National Natural Science Foundation of China (Grant Numbers 81672014, 81600300 and 81702079), the Natural Science Foundation of Zhejiang Province (Grant Number LQ 15H100001), the Fundamental Research Funds for the Central Universities (Grant Number 2017QNA7016), and the General research projects of zhejiang education department (Y201738209).

Compliance with ethical standards

Conflict of interest

We declare that all authors have no conflict of interest.

Ethical approval

This study conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Institutional Review Board of the First Affiliated Hospital of Zhejiang University.

Supplementary material

11262_2019_1678_MOESM1_ESM.docx (2.5 mb)
Supplementary material 1 (DOCX 2556 kb)

References

  1. 1.
    Gao R, Cao B, Hu Y, Feng Z, Wang D, Hu W et al (2013) Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med 368:1888–1897CrossRefGoogle Scholar
  2. 2.
    Wang X, Jiang H, Wu P, Uyeki T, Feng L, Lai S et al (2017) Epidemiology of avian influenza A H7N9 virus in human beings across five epidemics in mainland China, 2013–17: an epidemiological study of laboratory-confirmed case series. Lancet Infect Dis 17(8):822–832CrossRefGoogle Scholar
  3. 3.
    Arzey GG, Kirkland PD, Arzey KE, Frost M, Maywood P, Conaty S et al (2012) Influenza virus A (H10N7) in chickens and poultry abattoir workers, Australia. Emerg Infect Dis 18(5):814–816CrossRefGoogle Scholar
  4. 4.
    Lai S, Qin Y, Cowling BJ, Ren X, Wardrop NA, Gilbert M (2016) Global epidemiology of avian influenza A H5N1 virus infection in humans, 1997–2015: a systematic review of individual case data. Lancet Infect Dis 6(7):e108–e118CrossRefGoogle Scholar
  5. 5.
    Fouchier RA, Schneeberger PM, Rozendaal FW, Broekman JM, Kemink SA, Munster V et al (2004) Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc Natl Acad Sci USA 101(5):1356–1361CrossRefGoogle Scholar
  6. 6.
    Chen Y, Liang W, Yang S, Wu N, Gao H, Sheng J et al (2013) Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: clinical analysis and characterisation of viral genome. Lancet 381(9881):1916–1925CrossRefGoogle Scholar
  7. 7.
    Chen LM, Blixt O, Stevens J, Lipatov AS, Davis CT, Collins BE et al (2012) In vitro evolution of H5N1 avian influenza virus toward human-type receptor specificity. Virology 422(1):105–113CrossRefGoogle Scholar
  8. 8.
    Herfst S, Schrauwen EJ, Linster M, Chutinimitkul S, de Wit E, Munster VJ et al (2012) Airborne transmission of influenza A/H5N1 virus between ferrets. Science 336(6088):1534–1541CrossRefGoogle Scholar
  9. 9.
    Imai M, Watanabe T, Hatta M, Das SC, Ozawa M, Shinya K et al (2012) Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature 486(7403):420–428CrossRefGoogle Scholar
  10. 10.
    Hatta M, Gao P, Halfmann P, Kawaoka Y (2001) Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 293(5536):1840–1842CrossRefGoogle Scholar
  11. 11.
    Li Z, Chen H, Jiao P, Deng G, Tian G, Li Y et al (2005) Molecular basis of replication of duck H5N1 influenza viruses in a mammalian mouse model. J Virol 79(18):12058–12064CrossRefGoogle Scholar
  12. 12.
    Subbarao EK, London W, Murphy BR (1993) A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J Virol 67(4):1761–1764Google Scholar
  13. 13.
    Yamada S, Hatta M, Staker BL, Watanabe S, Imai M, Shinya K et al (2010) Biological and structural characterization of a host-adapting amino acid in influenza virus. PLoS Pathog 6(8):e1001034CrossRefGoogle Scholar
  14. 14.
    Ling LM, Chow AL, Lye DC, Tan AS, Krishnan P, Cui L et al (2010) Effects of early oseltamivir therapy on viral shedding in 2009 pandemic influenza A (H1N1) virus infection. Clin Infect Dis 50(7):963–969CrossRefGoogle Scholar
  15. 15.
    Sugaya N, Tamura D, Yamazaki M, Ichikawa M, Kawakami C, Kawaoka A et al (2008) Comparison of the clinical effectiveness of oseltamivir and zanamivir against influenza virus infection in children. Clin Infect Dis 47(3):339–345CrossRefGoogle Scholar
  16. 16.
    Yen HL, Ilyushina NA, Salomon R, Hoffmann E, Webster RG, Govorkova EA (2007) Neuraminidase inhibitor-resistant recombinant A/Vietnam/1203/04 (H5N1) influenza viruses retain their replication efficiency and pathogenicity in vitro and in vivo. J Virol 81(22):12418–12426CrossRefGoogle Scholar
  17. 17.
    Hayden FG (2006) Antiviral resistance in influenza viruses—implications for management and pandemic response. N Engl J Med 354(8):785–788CrossRefGoogle Scholar
  18. 18.
    Hayden FG, Belshe RB, Clover RD, Hay AJ, Oakes MG, Soo W (1989) Emergence and apparent transmission of rimantadine-resistant influenza A virus in families. N Engl J Med 321(25):1696–1702CrossRefGoogle Scholar
  19. 19.
    Chen H, Wen X, To KK, Wang P, Tse H, Chan JF et al (2010) Quasispecies of the D225G substitution in the hemagglutinin of pandemic influenza A(H1N1) 2009 virus from patients with severe disease in Hong Kong China. J Infect Dis 201(10):1517–1521CrossRefGoogle Scholar
  20. 20.
    Steel J, Lowen AC, Mubareka S, Palese P (2009) Transmission of influenza virus in a mammalian host is increased by PB2 amino acids 627K or 627E/701N. PLoS Pathog 5(1):e1000252CrossRefGoogle Scholar
  21. 21.
    Garten RJ, Davis CT, Russell CA, Shu B, Lindstrom S, Balish A et al (2009) Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science 325(5937):197–201CrossRefGoogle Scholar
  22. 22.
    Hu Y, Lu S, Song Z, Wang W, Hao P, Li J et al (2013) 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 381(9885):2273–2279CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Renke Chen
    • 1
  • Qianda Zou
    • 2
    • 3
  • Guoliang Xie
    • 2
    • 3
  • Fei Yu
    • 2
    • 3
  • Xianzhi Yang
    • 2
    • 3
  • Lingyong Cao
    • 1
  • Zhaoxia Huo
    • 4
    Email author
  • Shufa Zheng
    • 2
    • 3
    Email author
  1. 1.Zhejiang Chinese Medical UniversityHangzhouPeople’s Republic of China
  2. 2.Center of Clinical Laboratory, First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouPeople’s Republic of China
  3. 3.Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang ProvinceHangzhouPeople’s Republic of China
  4. 4.Experimental Teaching Center, School of Basic Medical SciencesZhejiang UniversityHangzhouPeople’s Republic of China

Personalised recommendations