tetano
Editor, Senior Moderator
J Virol
. 2020 Oct 14;JVI.01679-20.
doi: 10.1128/JVI.01679-20. Online ahead of print.
In vitro profiling of laninamivir-resistant substitutions in N3 to N9 avian influenza neuraminidase subtypes and their association with in vivo susceptibility
Ju Hwan Jeong[SUP] 1 [/SUP], Won-Suk Choi[SUP] 1 [/SUP], Khristine Joy C Antigua[SUP] 1 [/SUP], Young Ki Choi[SUP] 1 [/SUP], Elena A Govorkova[SUP] 2 [/SUP], Richard J Webby[SUP] 2 [/SUP], Yun Hee Baek[SUP] 3 [/SUP], Min-Suk Song[SUP] 4 [/SUP]
Affiliations
Abstract
Laninamivir (LAN) is a long-acting neuraminidase (NA) inhibitor (NAI) with a similar binding profile in the influenza NA enzyme active site as that of other NAIs, oseltamivir (OS), zanamivir (ZAN), and peramivir, and may share common resistance markers with these NAIs. We screened viruses with NA substitutions previously found during OS and ZAN selection in avian influenza viruses (AIV) of the N3 to N9 subtypes for LAN susceptibility. Of the 72 NA substitutions, 19 conferred resistance to LAN, which ranged from an 11.2- to 549.8-fold decreased inhibitory activity over that of their parental viruses. Ten NA substitutions reduced the susceptibility to all four NAIs, whereas the remaining 26 substitutions yielded susceptibility to one or more NAIs. To determine whether the in vitro susceptibility of multi-NAI resistant AIVs is associated with in vivo susceptibility, we infected BALB/c mice with recombinant AIVs with R292K (ma81k-N3[SUB]R292K[/SUB]) or Q136K (ma81k-N8[SUB]Q136K[/SUB]) NA substitutions, which impart in vitro susceptibility only to LAN or OS, respectively. Both ma81k-N3[SUB]R292K[/SUB]- and ma81k-N8[SUB]Q136K[/SUB] virus-infected mice exhibited reduced weight loss, mortality, and lung viral titers when treated with their susceptible NAIs, confirming the in vitro susceptibility of these substitutions. Together, LAN resistance profiling of AIVs of a range of NA subtypes improves understanding of NAI-resistance mechanisms. Furthermore, the association of in vitro and in vivo NAI-susceptibility indicates that our models are useful tools for monitoring NAI-susceptibility of AIVs.IMPORTANCE The chemical structures of neuraminidase inhibitors (NAIs) possess similarities, but slight differences can result in variable susceptibility of avian influenza viruses (AIVs) carrying resistance-associated NA substitutions. Therefore, comprehensive susceptibility profiling of these substitutions in AIVs is critical for understanding the mechanism of antiviral resistance. In this study, we profiled resistance to the anti-influenza drug laninamivir in AIVs with substitutions known to impart resistance to other NAIs. We found 10 substitutions that conferred resistance to all four NAIs tested. On the other hand, we found the remaining 26 NA substitutions susceptible to at least one or more NAIs and showed for a small selection that in vitro data predicted in vivo behavior. Therefore, our findings highlight the usefulness of screening resistance markers in NA enzyme inhibition assay and animal models of AIV infections.
. 2020 Oct 14;JVI.01679-20.
doi: 10.1128/JVI.01679-20. Online ahead of print.
In vitro profiling of laninamivir-resistant substitutions in N3 to N9 avian influenza neuraminidase subtypes and their association with in vivo susceptibility
Ju Hwan Jeong[SUP] 1 [/SUP], Won-Suk Choi[SUP] 1 [/SUP], Khristine Joy C Antigua[SUP] 1 [/SUP], Young Ki Choi[SUP] 1 [/SUP], Elena A Govorkova[SUP] 2 [/SUP], Richard J Webby[SUP] 2 [/SUP], Yun Hee Baek[SUP] 3 [/SUP], Min-Suk Song[SUP] 4 [/SUP]
Affiliations
- PMID: 33055248
- DOI: 10.1128/JVI.01679-20
Abstract
Laninamivir (LAN) is a long-acting neuraminidase (NA) inhibitor (NAI) with a similar binding profile in the influenza NA enzyme active site as that of other NAIs, oseltamivir (OS), zanamivir (ZAN), and peramivir, and may share common resistance markers with these NAIs. We screened viruses with NA substitutions previously found during OS and ZAN selection in avian influenza viruses (AIV) of the N3 to N9 subtypes for LAN susceptibility. Of the 72 NA substitutions, 19 conferred resistance to LAN, which ranged from an 11.2- to 549.8-fold decreased inhibitory activity over that of their parental viruses. Ten NA substitutions reduced the susceptibility to all four NAIs, whereas the remaining 26 substitutions yielded susceptibility to one or more NAIs. To determine whether the in vitro susceptibility of multi-NAI resistant AIVs is associated with in vivo susceptibility, we infected BALB/c mice with recombinant AIVs with R292K (ma81k-N3[SUB]R292K[/SUB]) or Q136K (ma81k-N8[SUB]Q136K[/SUB]) NA substitutions, which impart in vitro susceptibility only to LAN or OS, respectively. Both ma81k-N3[SUB]R292K[/SUB]- and ma81k-N8[SUB]Q136K[/SUB] virus-infected mice exhibited reduced weight loss, mortality, and lung viral titers when treated with their susceptible NAIs, confirming the in vitro susceptibility of these substitutions. Together, LAN resistance profiling of AIVs of a range of NA subtypes improves understanding of NAI-resistance mechanisms. Furthermore, the association of in vitro and in vivo NAI-susceptibility indicates that our models are useful tools for monitoring NAI-susceptibility of AIVs.IMPORTANCE The chemical structures of neuraminidase inhibitors (NAIs) possess similarities, but slight differences can result in variable susceptibility of avian influenza viruses (AIVs) carrying resistance-associated NA substitutions. Therefore, comprehensive susceptibility profiling of these substitutions in AIVs is critical for understanding the mechanism of antiviral resistance. In this study, we profiled resistance to the anti-influenza drug laninamivir in AIVs with substitutions known to impart resistance to other NAIs. We found 10 substitutions that conferred resistance to all four NAIs tested. On the other hand, we found the remaining 26 NA substitutions susceptible to at least one or more NAIs and showed for a small selection that in vitro data predicted in vivo behavior. Therefore, our findings highlight the usefulness of screening resistance markers in NA enzyme inhibition assay and animal models of AIV infections.