tetano
Editor, Senior Moderator
J Infect Dis. 2015 May 17. pii: jiv288. [Epub ahead of print]
[h=1]The E119D Neuraminidase Mutation Confers Pan-Resistance to Neuraminidase Inhibitors in an A(H1N1)pdm09 Isolate From a Stem-Cell Transplant Recipient.[/h] L'Huillier AG[SUP]1[/SUP], Abed Y[SUP]2[/SUP], Petty TJ[SUP]3[/SUP], Cordey S[SUP]1[/SUP], Thomas Y[SUP]1[/SUP], Bouhy X[SUP]2[/SUP], Schibler M[SUP]1[/SUP], Simon A[SUP]4[/SUP], Chalandon Y[SUP]4[/SUP], van Delden C[SUP]5[/SUP], Zdobnov E[SUP]3[/SUP], Boquete-Suter P[SUP]1[/SUP], Boivin G[SUP]2[/SUP], Kaiser L[SUP]6[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] [h=4]BACKGROUND:[/h] An influenza A(H1N1)pdm09 infection was diagnosed in a hematopoietic stem cell transplant recipient during conditioning regimen. He was treated by oral oseltamivir, latter combined to intravenous zanamivir.The H275Y neuraminidase mutation was first detected and while on zanamivir therapy, an E119D neuraminidase mutation was identified.
[h=4]METHODS:[/h] Recombinant wild-type E119D and E119D/H275Y A(H1N1)pdm09 neuraminidase variants were generated by reverse genetics. Susceptibility to neuraminidase inhibitors (NAI) was evaluated by a fluorometric assay using the MUNANA substrate. Susceptibility to favipiravir (T-705) was assessed by plaque reduction assays. The Km and Vmax values were determined by neuraminidase enzymatic studies.
[h=4]RESULTS:[/h] We identified an influenza A(H1N1)pdm09 E119D mutant that exhibited a marked increase in the 50% inhibitory concentration (IC50) values against all tested NAI (827-, 25-, 286- and 702-fold for zanamivir, oseltamivir, peramivir and laninamivir, respectively). The double E119D/H275Y mutation further increased oseltamivir and peramivir IC50s by 790- and >5000-fold, respectively, versus the wild-type. The mutant viruses remained susceptible to favipiravir. Km and Vmax values of the E119D variant increased by 8.1-fold and decreased by 4.5-fold, respectively, versus the wild-type.
[h=4]CONCLUSION:[/h] The actual emergence of a single neuraminidase mutation conferring pan-NAI resistance in the clinical setting reinforces the pressing need to develop new anti-influenza strategies.
? The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
PMID: 25985905 [PubMed - as supplied by publisher]
[h=1]The E119D Neuraminidase Mutation Confers Pan-Resistance to Neuraminidase Inhibitors in an A(H1N1)pdm09 Isolate From a Stem-Cell Transplant Recipient.[/h] L'Huillier AG[SUP]1[/SUP], Abed Y[SUP]2[/SUP], Petty TJ[SUP]3[/SUP], Cordey S[SUP]1[/SUP], Thomas Y[SUP]1[/SUP], Bouhy X[SUP]2[/SUP], Schibler M[SUP]1[/SUP], Simon A[SUP]4[/SUP], Chalandon Y[SUP]4[/SUP], van Delden C[SUP]5[/SUP], Zdobnov E[SUP]3[/SUP], Boquete-Suter P[SUP]1[/SUP], Boivin G[SUP]2[/SUP], Kaiser L[SUP]6[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] [h=4]BACKGROUND:[/h] An influenza A(H1N1)pdm09 infection was diagnosed in a hematopoietic stem cell transplant recipient during conditioning regimen. He was treated by oral oseltamivir, latter combined to intravenous zanamivir.The H275Y neuraminidase mutation was first detected and while on zanamivir therapy, an E119D neuraminidase mutation was identified.
[h=4]METHODS:[/h] Recombinant wild-type E119D and E119D/H275Y A(H1N1)pdm09 neuraminidase variants were generated by reverse genetics. Susceptibility to neuraminidase inhibitors (NAI) was evaluated by a fluorometric assay using the MUNANA substrate. Susceptibility to favipiravir (T-705) was assessed by plaque reduction assays. The Km and Vmax values were determined by neuraminidase enzymatic studies.
[h=4]RESULTS:[/h] We identified an influenza A(H1N1)pdm09 E119D mutant that exhibited a marked increase in the 50% inhibitory concentration (IC50) values against all tested NAI (827-, 25-, 286- and 702-fold for zanamivir, oseltamivir, peramivir and laninamivir, respectively). The double E119D/H275Y mutation further increased oseltamivir and peramivir IC50s by 790- and >5000-fold, respectively, versus the wild-type. The mutant viruses remained susceptible to favipiravir. Km and Vmax values of the E119D variant increased by 8.1-fold and decreased by 4.5-fold, respectively, versus the wild-type.
[h=4]CONCLUSION:[/h] The actual emergence of a single neuraminidase mutation conferring pan-NAI resistance in the clinical setting reinforces the pressing need to develop new anti-influenza strategies.
? The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
PMID: 25985905 [PubMed - as supplied by publisher]