tetano
Editor, Senior Moderator
Antiviral Res
. 2024 Jul 8:105959.
doi: 10.1016/j.antiviral.2024.105959. Online ahead of print. Genotypic and phenotypic susceptibility of emerging avian influenza A viruses to neuraminidase and cap-dependent endonuclease inhibitors
Konstantin Andreev[SUP] 1 [/SUP], Jeremy C Jones[SUP] 1 [/SUP], Patrick Seiler[SUP] 1 [/SUP], Ahmed Kandeil[SUP] 2 [/SUP], Richard J Webby[SUP] 1 [/SUP], Elena A Govorkova[SUP] 3 [/SUP]
Affiliations
Avian influenza outbreaks, including ones caused by highly pathogenic A(H5N1) clade 2.3.4.4b viruses, have devastated animal populations and remain a threat to humans. Risk elements assessed for emerging influenza viruses include their susceptibility to approved antivirals. Here, we screened >20,000 neuraminidase (NA) or polymerase acidic (PA) protein sequences of potentially pandemic A(H5Nx), A(H7Nx), and A(H9N2) viruses that circulated globally in 2010-2023. The frequencies of NA or PA substitutions associated with reduced inhibition (RI) or highly reduced inhibition (HRI) by NA inhibitors (NAIs) (oseltamivir, zanamivir) or a cap-dependent endonuclease inhibitor, baloxavir, were low: 0.60% (137/22,713) and 0.62% (126/20,347), respectively. All tested subtypes were susceptible to NAIs and baloxavir at sub-nanomolar concentrations. A(H9N2) viruses were the most susceptible to oseltamivir, with IC[SUB]50[/SUB]s 3- to 4-fold lower than for other subtypes (median IC[SUB]50[/SUB]: 0.18 nM; n = 22). NA-I222M conferred RI of A(H5N1) viruses by oseltamivir (with a 26-fold IC[SUB]50[/SUB] increase), but NA-S246N did not reduce inhibition. PA-E23G, PA-K34R, PA-I38M/T, and the previously unreported PA-A36T caused RI by baloxavir in all subtypes tested. Avian A(H9N2) viruses endemic in Egyptian poultry predominantly acquired PA-I38V, which causes only a <3-fold decrease in the baloxavir EC[SUB]50[/SUB] and fails to meet the RI criteria. PA-E199A/D in A(H7Nx) and A(H9N2) viruses caused a 2- to 4-fold decrease in EC[SUB]50[/SUB] (close to the borderline for RI) and should be closely monitored. Our data indicate antiviral susceptibility is high among avian influenza A viruses with pandemic potential and present novel markers of resistance to existing antiviral interventions.
Keywords: antiviral susceptibility; avian influenza viruses; baloxavir; neuraminidase inhibitors;
. 2024 Jul 8:105959.
doi: 10.1016/j.antiviral.2024.105959. Online ahead of print. Genotypic and phenotypic susceptibility of emerging avian influenza A viruses to neuraminidase and cap-dependent endonuclease inhibitors
Konstantin Andreev[SUP] 1 [/SUP], Jeremy C Jones[SUP] 1 [/SUP], Patrick Seiler[SUP] 1 [/SUP], Ahmed Kandeil[SUP] 2 [/SUP], Richard J Webby[SUP] 1 [/SUP], Elena A Govorkova[SUP] 3 [/SUP]
Affiliations
- PMID: 38986873
- DOI: 10.1016/j.antiviral.2024.105959
Avian influenza outbreaks, including ones caused by highly pathogenic A(H5N1) clade 2.3.4.4b viruses, have devastated animal populations and remain a threat to humans. Risk elements assessed for emerging influenza viruses include their susceptibility to approved antivirals. Here, we screened >20,000 neuraminidase (NA) or polymerase acidic (PA) protein sequences of potentially pandemic A(H5Nx), A(H7Nx), and A(H9N2) viruses that circulated globally in 2010-2023. The frequencies of NA or PA substitutions associated with reduced inhibition (RI) or highly reduced inhibition (HRI) by NA inhibitors (NAIs) (oseltamivir, zanamivir) or a cap-dependent endonuclease inhibitor, baloxavir, were low: 0.60% (137/22,713) and 0.62% (126/20,347), respectively. All tested subtypes were susceptible to NAIs and baloxavir at sub-nanomolar concentrations. A(H9N2) viruses were the most susceptible to oseltamivir, with IC[SUB]50[/SUB]s 3- to 4-fold lower than for other subtypes (median IC[SUB]50[/SUB]: 0.18 nM; n = 22). NA-I222M conferred RI of A(H5N1) viruses by oseltamivir (with a 26-fold IC[SUB]50[/SUB] increase), but NA-S246N did not reduce inhibition. PA-E23G, PA-K34R, PA-I38M/T, and the previously unreported PA-A36T caused RI by baloxavir in all subtypes tested. Avian A(H9N2) viruses endemic in Egyptian poultry predominantly acquired PA-I38V, which causes only a <3-fold decrease in the baloxavir EC[SUB]50[/SUB] and fails to meet the RI criteria. PA-E199A/D in A(H7Nx) and A(H9N2) viruses caused a 2- to 4-fold decrease in EC[SUB]50[/SUB] (close to the borderline for RI) and should be closely monitored. Our data indicate antiviral susceptibility is high among avian influenza A viruses with pandemic potential and present novel markers of resistance to existing antiviral interventions.
Keywords: antiviral susceptibility; avian influenza viruses; baloxavir; neuraminidase inhibitors;