Assessment of development of resistance to antivirals in the ferret model of influenza virus infection.
We attempted to develop in vivo resistance of influenza virus to amantadine and to zanamivir, by use of the ferret model of influenza virus infection. Resistance of influenza virus A/LosAngeles/1/87 (H3N2) to amantadine was generated within 6 days, during a single course of treatment, and mutations in the M2 gene that are characteristic of human infections were observed. In contrast, during an identical single course of treatment with zanamivir, no evidence of reduced susceptibility was demonstrated. Pooled virus shed by zanamivir-treated ferrets was used to infect another group of ferrets. Twenty virus clones grew in plaque assays containing zanamivir, indicating possible reduced susceptibility; however, none exhibited reduced susceptibility to zanamivir in neuraminidase (NA) inhibition assays. Sequencing of the NA gene of these clones revealed only a noncoding nucleotide mutation at position 685. Sequencing of the hemagglutinin gene revealed mutations at positions 53, 106, 138, 145, 166, and 186. Similar to the situation in humans, amantadine use in ferrets rapidly produces antiviral resistance, but zanamivir use does not, although nucleotide changes were observed.
Herlocher
M Louise
ML
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan 48109, USA. louise@umich.edu.
Truscon
Rachel
R
Fenton
Rob
R
Klimov
Alexander
A
Elias
Stephanie
S
Ohmit
Suzanne E
SE
Monto
Arnold S
AS
D000547:Amantadine / Q000627:therapeutic use*; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral / Q000235:genetics; D005289:Ferrets / Q000821:virology*; D006146:Guanidines; D006385:Hemagglutination Inhibition Tests; D009980:Influenza A virus / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism; D008297:Male; D009976:Orthomyxoviridae Infections / Q000188:drug therapy*; D017354:Point Mutation / Q000235:genetics; D011714:Pyrans; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D012794:Sialic Acids / Q000627:therapeutic use*; D053243:Zanamivir
D000998:Antiviral Agents; D006146:Guanidines; D011714:Pyrans; D012367:RNA, Viral; D012794:Sialic Acids; D000547:Amantadine; D053243:Zanamivir