tetano
Editor, Senior Moderator
Antiviral Res
. 2023 Jul 24;105679.
doi: 10.1016/j.antiviral.2023.105679. Online ahead of print. Antiviral susceptibility of clade 2.3.4.4b highly pathogenic avian influenza A(H5N1) viruses isolated from birds and mammals in the United States, 2022
Ha T Nguyen[SUP] 1 [/SUP], Anton Chesnokov[SUP] 1 [/SUP], Juan De La Cruz[SUP] 1 [/SUP], Philippe Noriel Q Pascua[SUP] 1 [/SUP], Vasiliy P Mishin[SUP] 1 [/SUP], Yunho Jang[SUP] 1 [/SUP], Joyce Jones[SUP] 1 [/SUP], Han Di[SUP] 1 [/SUP], Andrei A Ivashchenko[SUP] 2 [/SUP], Mary Lea Killian[SUP] 3 [/SUP], Mia K Torchetti[SUP] 3 [/SUP], Kristina Lantz[SUP] 3 [/SUP], David E Wentworth[SUP] 1 [/SUP], Charles T Davis[SUP] 1 [/SUP], Alexandre V Ivachtchenko[SUP] 4 [/SUP], Larisa V Gubareva[SUP] 5 [/SUP]
Affiliations
Clade 2.3.4.4 b highly pathogenic avian influenza (HPAI) A (H5N1) viruses that are responsible for devastating outbreaks in birds and mammals pose a potential threat to public health. Here, we evaluated their susceptibility to influenza antivirals. Of 1015 sequences of HPAI A (H5N1) viruses collected in the United States during 2022, eight viruses (∼0.8%) had a molecular marker of drug resistance to an FDA-approved antiviral: three adamantane-resistant (M2-V27A), four oseltamivir-resistant (NA-H275Y), and one baloxavir-resistant (PA-I38T). Additionally, 31 viruses contained mutations that may reduce susceptibility to inhibitors of neuraminidase (NA) (n = 20) or cap-dependent endonuclease (CEN) (n = 11). A panel of 22 representative viruses was tested phenotypically. Overall, clade 2.3.4.4 b A (H5N1) viruses lacking recognized resistance mutations were susceptible to FDA-approved antivirals. Oseltamivir was least potent at inhibiting NA activity, while the investigational NA inhibitor AV5080 was most potent, including against NA mutants. A novel NA substitution T438N conferred 12-fold reduced inhibition by zanamivir, and in combination with the known marker N295S, synergistically affected susceptibility to all five NA inhibitors. In cell culture-based assays HINT and IRINA, the PA-I38T virus displayed 75- to 108-fold and 37- to 78-fold reduced susceptibility to CEN inhibitors baloxavir and investigational AV5116, respectively. Viruses with PA-I38M or PA-A37T showed 5- to 10-fold reduced susceptibilities. As HPAI A (H5N1) viruses continue to circulate and evolve, close monitoring of drug susceptibility is needed for risk assessment and to inform decisions regarding antiviral stockpiling.
Keywords: AV5080; Antiviral resistance; Baloxavir; CEN inhibitor; Neuraminidase inhibitors.
. 2023 Jul 24;105679.
doi: 10.1016/j.antiviral.2023.105679. Online ahead of print. Antiviral susceptibility of clade 2.3.4.4b highly pathogenic avian influenza A(H5N1) viruses isolated from birds and mammals in the United States, 2022
Ha T Nguyen[SUP] 1 [/SUP], Anton Chesnokov[SUP] 1 [/SUP], Juan De La Cruz[SUP] 1 [/SUP], Philippe Noriel Q Pascua[SUP] 1 [/SUP], Vasiliy P Mishin[SUP] 1 [/SUP], Yunho Jang[SUP] 1 [/SUP], Joyce Jones[SUP] 1 [/SUP], Han Di[SUP] 1 [/SUP], Andrei A Ivashchenko[SUP] 2 [/SUP], Mary Lea Killian[SUP] 3 [/SUP], Mia K Torchetti[SUP] 3 [/SUP], Kristina Lantz[SUP] 3 [/SUP], David E Wentworth[SUP] 1 [/SUP], Charles T Davis[SUP] 1 [/SUP], Alexandre V Ivachtchenko[SUP] 4 [/SUP], Larisa V Gubareva[SUP] 5 [/SUP]
Affiliations
- PMID: 37494978
- DOI: 10.1016/j.antiviral.2023.105679
Clade 2.3.4.4 b highly pathogenic avian influenza (HPAI) A (H5N1) viruses that are responsible for devastating outbreaks in birds and mammals pose a potential threat to public health. Here, we evaluated their susceptibility to influenza antivirals. Of 1015 sequences of HPAI A (H5N1) viruses collected in the United States during 2022, eight viruses (∼0.8%) had a molecular marker of drug resistance to an FDA-approved antiviral: three adamantane-resistant (M2-V27A), four oseltamivir-resistant (NA-H275Y), and one baloxavir-resistant (PA-I38T). Additionally, 31 viruses contained mutations that may reduce susceptibility to inhibitors of neuraminidase (NA) (n = 20) or cap-dependent endonuclease (CEN) (n = 11). A panel of 22 representative viruses was tested phenotypically. Overall, clade 2.3.4.4 b A (H5N1) viruses lacking recognized resistance mutations were susceptible to FDA-approved antivirals. Oseltamivir was least potent at inhibiting NA activity, while the investigational NA inhibitor AV5080 was most potent, including against NA mutants. A novel NA substitution T438N conferred 12-fold reduced inhibition by zanamivir, and in combination with the known marker N295S, synergistically affected susceptibility to all five NA inhibitors. In cell culture-based assays HINT and IRINA, the PA-I38T virus displayed 75- to 108-fold and 37- to 78-fold reduced susceptibility to CEN inhibitors baloxavir and investigational AV5116, respectively. Viruses with PA-I38M or PA-A37T showed 5- to 10-fold reduced susceptibilities. As HPAI A (H5N1) viruses continue to circulate and evolve, close monitoring of drug susceptibility is needed for risk assessment and to inform decisions regarding antiviral stockpiling.
Keywords: AV5080; Antiviral resistance; Baloxavir; CEN inhibitor; Neuraminidase inhibitors.