TY - JOUR
T1 - Influenza A(H7N9) virus gains neuraminidase inhibitor resistance without loss of in vivo virulence or transmissibility
AU - Hai, Rong
AU - Schmolke, Mirco
AU - Leyva-Grado, Victor H.
AU - Thangavel, Rajagowthamee R.
AU - Margine, Irina
AU - Jaffe, Eric L.
AU - Krammer, Florian
AU - Solórzano, Alicia
AU - García-Sastre, Adolfo
AU - Palese, Peter
AU - Bouvier, Nicole M.
N1 - Funding Information:
We are grateful to David Perlin and Steven Park of the Regional Biocontainment Laboratory at Rutgers, the State University of New Jersey, for making the facility available for the guinea pig transmission experiments and enabling their completion. We thank Richard Webby for providing the cDNA corresponding to the NA gene of the influenza A/Anhui/1/2013(H7N9) virus, and Richard Cadagan and Osman Lizardo for excellent technical assistance. This work was supported by the Center for Research in Influenza Pathogenesis (CRIP), a Center of Excellence in Influenza Research and Surveillance (CEIRS) funded by the NIH/NIAID (contract # HHSN266200700010C). F.K. is supported by an Erwin Schrödinger fellowship (J 3232) from the Austrian Science Fund (FWF). N.M.B. was supported by an NIH/NIAID Career Development Grant (K08 AI089940).
PY - 2013/12/10
Y1 - 2013/12/10
N2 - Without baseline human immunity to the emergent avian influenza A(H7N9) virus, neuraminidase inhibitors are vital for controlling viral replication in severe infections. An amino acid change in the viral neuraminidase associated with drug resistance, NA-R292K (N2 numbering), has been found in some H7N9 clinical isolates. Here we assess the impact of the NA-R292K substitution on antiviral sensitivity and viral replication, pathogenicity and transmissibility of H7N9 viruses. Our data indicate that an H7N9 isolate encoding the NA-R292K substitution is highly resistant to oseltamivir and peramivir and partially resistant to zanamivir. Furthermore, H7N9 reassortants with and without the resistance mutation demonstrate comparable viral replication in primary human respiratory cells, virulence in mice and transmissibility in guinea pigs. Thus, in stark contrast to oseltamivir-resistant seasonal influenza A(H3N2) viruses, H7N9 virus replication and pathogenicity in these models are not substantially altered by the acquisition of high-level oseltamivir resistance due to the NA-R292K mutation.
AB - Without baseline human immunity to the emergent avian influenza A(H7N9) virus, neuraminidase inhibitors are vital for controlling viral replication in severe infections. An amino acid change in the viral neuraminidase associated with drug resistance, NA-R292K (N2 numbering), has been found in some H7N9 clinical isolates. Here we assess the impact of the NA-R292K substitution on antiviral sensitivity and viral replication, pathogenicity and transmissibility of H7N9 viruses. Our data indicate that an H7N9 isolate encoding the NA-R292K substitution is highly resistant to oseltamivir and peramivir and partially resistant to zanamivir. Furthermore, H7N9 reassortants with and without the resistance mutation demonstrate comparable viral replication in primary human respiratory cells, virulence in mice and transmissibility in guinea pigs. Thus, in stark contrast to oseltamivir-resistant seasonal influenza A(H3N2) viruses, H7N9 virus replication and pathogenicity in these models are not substantially altered by the acquisition of high-level oseltamivir resistance due to the NA-R292K mutation.
UR - http://www.scopus.com/inward/record.url?scp=84890725745&partnerID=8YFLogxK
U2 - 10.1038/ncomms3854
DO - 10.1038/ncomms3854
M3 - Article
C2 - 24326875
AN - SCOPUS:84890725745
SN - 2041-1723
VL - 4
JO - Nature Communications
JF - Nature Communications
M1 - 2854
ER -