Influenza Viruses Resistant to the Antiviral Drug Oseltamivir: Transmission Studies in Ferrets

Abstract

Three type A influenza viruses, each of which has a distinct neuraminidase-gene mutation and is resistant to the neuraminidase inhibitor oseltamivir, have been isolated. Previously, in the ferret model, an R292K mutant of a type A (H3N2) virus was not transmitted under conditions in which the wild-type virus was transmitted. This model was used to investigate whether the E119V mutant of a type A (H3N2) virus and the H274Y mutant of a type A (H1N1) virus would be transmitted under similar circumstances. Both mutant viruses were transmitted, although the H274Y mutant required a 100-fold-higher dose for infection of donor ferrets and was transmitted more slowly than was the wild type. Both the mutant and the wild-type viruses retained their genotypic characteristics.

Existing Influenza Antivirals: Their Mechanisms of Action and Potential in the Face of Avian Influenza

“…50 Recombinant viruses containing either the wild -type neuraminidase or a single amino acid change at residue 119 (E119V) or 292 (R292K) were generated in the infl uenza A (H3N2) infl uenza virus background by reverse genetics: Both mutants showed decreased sensitivity to oseltamivir, and the R292K virus showed cross -resistance to zanamivir. The R292K mutation was associated with compromised viral growth and transmissibility (in accordance with earlier studies 51,52 ), whereas the growth and transmissibility of the E119V virus was comparable to those of wild -type virus. 53 Of note, infl uenza virus A (H3N2) carrying the R292K mutation in the neuraminidase gene did not transmit to ferrets under conditions the wild -type virus was readily transmitted.…”

“…51 However, other mutant viruses of infl uenza A (H3N2) (i.e., E119V and H274Y, both engendering resistance to oseltamivir) were found to be readily transmissible in ferrets, although the H274Y mutant required a 100 -fold higher dose for infection and was transmitted more slowly than the wild type. 52 It has been hypothesized that neuraminidase inhibitors could, in theory, inhibit the 1918 pandemic virus. 54 In fact, recombinant viruses possessing the 1918 neuraminidase, or both the 1918 neuraminidase and 1918 hemagglutinin, were shown to be effectively inhibited, both in vitro and in vivo (mice) by the neuraminidase inhibitors zanamivir and oseltamivir; and a recombinant virus possessing the 1918 M2 ion channel could be effectively inhibited by amantadine and rimantadine.…”

Comparative Pathology in Ferrets Infected with H1N1 Influenza A Viruses Isolated from Different Hosts

“…Studies have shown that mutations that are part of the NA enzyme catalytic site or that surround it may impair virus fitness, and these mutations generally decrease susceptibility to neuraminidase inhibitors. In addition, human influenza virus isolates which harbor NA mutations that confer resistance to NA inhibitors have been generally attenuated in animal models (16,19). A recent study showed that a 2009 pandemic H1N1 isolate and its NA mutant counterpart, resistant to oseltamivir, caused a similar disease course in ferrets without apparent attenuation of clinical signs (8).…”

Lack of transmission of H5N1 avian–human reassortant influenza viruses in a ferret model

“…Although the exact contribution of each of these modes of transmission is not known, transmission of respiratory droplets, expelled when infected persons cough or sneeze, is likely the major mode of sustained viral spread in community settings during epidemics and pandemics (15). Several animal models have been used to investigate factors that contribute to influenza virus transmissibility (16)(17)(18)(19). Ferrets, like humans, have a predominance of ␣2,6 SA and a lesser amount of ␣2,3 SA on respiratory tract epithelial cells, exhibit preferential binding of H5N1 viruses in the lower respiratory tract similar to humans (20)(21)(22)(23)(24), and have been used previously to investigate transmissibility of human influenza viruses (17)(18)(19)25).…”