tetano
Editor, Senior Moderator
J Infect Dis. 2017 Sep 15;216(suppl_4):S566-S574. doi: 10.1093/infdis/jiw625.
[h=1]Drug Susceptibility Evaluation of an Influenza A(H7N9) Virus by Analyzing Recombinant Neuraminidase Proteins.[/h] Gubareva LV[SUP]1[/SUP], Sleeman K[SUP]1[/SUP], Guo Z[SUP]1[/SUP], Yang H[SUP]1[/SUP], Hodges E[SUP]1,[/SUP][SUP]2[/SUP], Davis CT[SUP]1[/SUP], Baranovich T[SUP]1,[/SUP][SUP]2[/SUP], Stevens J[SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] [h=4]Background:[/h] Neuraminidase (NA) inhibitors are the recommended antiviral medications for influenza treatment. However, their therapeutic efficacy can be compromised by NA changes that emerge naturally and/or following antiviral treatment. Knowledge of which molecular changes confer drug resistance of influenza A(H7N9) viruses (group 2NA) remains sparse.
[h=4]Methods:[/h] Fourteen amino acid substitutions were introduced into the NA of A/Shanghai/2/2013(H7N9). Recombinant N9 (recN9) proteins were expressed in a baculovirus system in insect cells and tested using the Centers for Disease Control and Prevention standardized NA inhibition (NI) assay with oseltamivir, zanamivir, peramivir, and laninamivir. The wild-type N9 crystal structure was determined in complex with oseltamivir, zanamivir, or sialic acid, and structural analysis was performed.
[h=4]Results:[/h] All substitutions conferred either reduced or highly reduced inhibition by at least 1 NA inhibitor; half of them caused reduced inhibition or highly reduced inhibition by all NA inhibitors. R292K conferred the highest increase in oseltamivir half-maximal inhibitory concentration (IC50), and E119D conferred the highest zanamivir IC50. Unlike N2 (another group 2NA), H274Y conferred highly reduced inhibition by oseltamivir. Additionally, R152K, a naturally occurring variation at the NA catalytic residue of A(H7N9) viruses, conferred reduced inhibition by laninamivir.
[h=4]Conclusions:[/h] The recNA method is a valuable tool for assessing the effect of NA changes on drug susceptibility of emerging influenza viruses.
[h=4]KEYWORDS:[/h] A(H7N9); Neuraminidase; bird flu; drug resistance; recombinant protein
PMID: 28934455 DOI: 10.1093/infdis/jiw625
[h=1]Drug Susceptibility Evaluation of an Influenza A(H7N9) Virus by Analyzing Recombinant Neuraminidase Proteins.[/h] Gubareva LV[SUP]1[/SUP], Sleeman K[SUP]1[/SUP], Guo Z[SUP]1[/SUP], Yang H[SUP]1[/SUP], Hodges E[SUP]1,[/SUP][SUP]2[/SUP], Davis CT[SUP]1[/SUP], Baranovich T[SUP]1,[/SUP][SUP]2[/SUP], Stevens J[SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] [h=4]Background:[/h] Neuraminidase (NA) inhibitors are the recommended antiviral medications for influenza treatment. However, their therapeutic efficacy can be compromised by NA changes that emerge naturally and/or following antiviral treatment. Knowledge of which molecular changes confer drug resistance of influenza A(H7N9) viruses (group 2NA) remains sparse.
[h=4]Methods:[/h] Fourteen amino acid substitutions were introduced into the NA of A/Shanghai/2/2013(H7N9). Recombinant N9 (recN9) proteins were expressed in a baculovirus system in insect cells and tested using the Centers for Disease Control and Prevention standardized NA inhibition (NI) assay with oseltamivir, zanamivir, peramivir, and laninamivir. The wild-type N9 crystal structure was determined in complex with oseltamivir, zanamivir, or sialic acid, and structural analysis was performed.
[h=4]Results:[/h] All substitutions conferred either reduced or highly reduced inhibition by at least 1 NA inhibitor; half of them caused reduced inhibition or highly reduced inhibition by all NA inhibitors. R292K conferred the highest increase in oseltamivir half-maximal inhibitory concentration (IC50), and E119D conferred the highest zanamivir IC50. Unlike N2 (another group 2NA), H274Y conferred highly reduced inhibition by oseltamivir. Additionally, R152K, a naturally occurring variation at the NA catalytic residue of A(H7N9) viruses, conferred reduced inhibition by laninamivir.
[h=4]Conclusions:[/h] The recNA method is a valuable tool for assessing the effect of NA changes on drug susceptibility of emerging influenza viruses.
[h=4]KEYWORDS:[/h] A(H7N9); Neuraminidase; bird flu; drug resistance; recombinant protein
PMID: 28934455 DOI: 10.1093/infdis/jiw625