An I436N substitution confers resistance of influenza A(H1N1)pdm09 viruses to multiple neuraminidase inhibitors without affecting viral fitness

The Journal of General Virology
Jin Jung KwonMin-Suk Song

Abstract

The resistance of influenza viruses to neuraminidase (NA) inhibitors (NAIs; i.e. oseltamivir, zanamivir, peramivir and laninamivir) can be associated with several NA substitutions, with differing effects on viral fitness. To identify novel molecular markers conferring multi-NAI resistance, the NA gene of oseltamivir-resistant (H275Y, N1 numbering) 2009 pandemic influenza [A(H1N1)pdm09] virus was enriched with random mutations. This randomly mutated viral library was propagated in Madin-Darby canine kidney (MDCK) cells under zanamivir pressure and gave rise to additional changes within NA, including an I436N substitution located outside the NA enzyme active site. We generated four recombinant A(H1N1)pdm09 viruses containing either wild-type NA or NA with single (I436N or H275Y) or double (H275Y-I436N) substitutions. The double H275Y-I436N mutation significantly reduced inhibition by oseltamivir and peramivir and reduced inhibition by zanamivir and laninamivir. I436N alone reduced inhibition by all NAIs, suggesting that it is a multi-NAI resistance marker. I436N did not affect viral fitness in vitro or in a murine model; however, H275Y and I436N together had a negative impact on viral fitness. Further, I436N alone did not have an...Continue Reading

References

Dec 22, 1999·Current Opinion in Chemical Biology·B Imperiali, S E O'Connor
Dec 24, 2005·The New England Journal of Medicine·Menno D de JongJeremy Farrar
Dec 7, 2007·Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology·Olivier Ferraris, Bruno Lina
Sep 12, 2009·The New England Journal of Medicine·Kathy HancockJacqueline M Katz
Jan 8, 2010·The New England Journal of Medicine·Sanford Dennis Guttler
Oct 1, 2010·The New England Journal of Medicine·Erhard van der VriesCharles A B Boucher
Dec 22, 2011·The Lancet Infectious Diseases·Aeron C HurtUNKNOWN WHO Consultation on Pandemic Influenza A (H1N1) 2009 Virus Resistance to Antivirals
Feb 9, 2012·Antiviral Therapy·Ha T NguyenLarisa V Gubareva
Mar 24, 2012·Current Opinion in Virology·Tatiana BaranovichElena A Govorkova
Mar 26, 2013·Antiviral Research·Mélanie SamsonGuy Boivin
Jul 3, 2013·Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology·A PirallaF Baldanti
Nov 27, 2015·Euro Surveillance : Bulletin Européen Sur Les Maladies Transmissibles = European Communicable Disease Bulletin·Karen LittleAeron C Hurt
Mar 16, 2016·Proceedings of the National Academy of Sciences of the United States of America·Min-Suk SongStephen W White

❮ Previous
Next ❯

Citations

Aug 5, 2018·The Journal of Biological Chemistry·Alex B KleinpeterChad M Petit
Sep 16, 2018·Viruses·Ahmed MostafaStephan Pleschka
Mar 11, 2020·Cold Spring Harbor Perspectives in Medicine·Larisa Gubareva, Teena Mohan

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antimicrobial Resistance

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Antimicrobial Resistance (ASM)

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.