Characterization of Drug-Resistant Influenza A(H7N9) Variants Isolated From an Oseltamivir-Treated Patient in Taiwan

• Published in: The Journal of infectious diseases Vol. 211; no. 2; pp. 249 - 257
• Main Authors: Marjuki, Henju, Mishin, Vasiliy P., Chesnokov, Anton P., Jones, Joyce, De La Cruz, Juan A., Sleeman, Katrina, Tamura, Daisuke, Nguyen, Ha T., Wu, Ho-Sheng, Chang, Feng-Yee, Liu, Ming-Tsan, Fry, Alicia M., Cox, Nancy J., Villanueva, Julie M., Davis, Charles T., Gubareva, Larisa V.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 15.01.2015
• Subjects: Animals; Antiviral Agents - therapeutic use; Disease Models, Animal; Drug Resistance, Viral; Ferrets; Humans; Influenza A Virus, H7N9 Subtype - drug effects; Influenza A Virus, H7N9 Subtype - enzymology; Influenza A Virus, H7N9 Subtype - genetics; Influenza A Virus, H7N9 Subtype - isolation & purification; Influenza, Human - drug therapy; Influenza, Human - virology; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mustela; Mutant Proteins - genetics; Mutation, Missense; Neuraminidase - genetics; Orthomyxoviridae Infections - pathology; Orthomyxoviridae Infections - virology; Oseltamivir - therapeutic use; Viral Proteins - genetics; Virus Cultivation; Virus Replication; VIRUSES; ISEW, Taiwan; E119V; I222R; ferrets; influenza virus; R292K; peramivir; H7N9; oseltamivir; mice; I222K
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiu447

Background. Patients contracting influenza A(H7N9) infection often developed severe disease causing respiratory failure. Neuraminidase (NA) inhibitors (NAIs) are the primary option for treatment, but information on drug-resistance markers for influenza A(H7N9) is limited. Methods. Four NA variants of A/Taiwan/1/2013(H7N9) virus containing a single substitution (NA-E119V, NAI222K, NA-I222R, or NA-R292K) recovered from an oseltamivir-treated patient were tested for NAI susceptibility in vitro; their replicative fitness was evaluated in cell culture, mice, and ferrets. Results. NA-R292K led to highly reduced inhibition by oseltamivir and peramivir, while NA-E119V, NA-I222K, and NA-I222R caused reduced inhibition by oseltamivir. Mice infected with any virus showed severe clinical signs with high mortality rates. NA-I222K virus was the most virulent in mice, whereas virus lacking NA change (NAWT) and NA-R292K virus seemed the least virulent. Sequence analysis suggests that PB2-S714N increased virulence of NA-I222K virus in mice; NS1-K126R, alone or in combination with PB2-V227M, produced contrasting effects in NA-WT and NA-R292K viruses. In ferrets, all viruses replicated to high titers in the upper respiratory tract but produced only mild illness. NA-R292K virus, showed reduced replicative fitness in this animal model. Conclusions. Our data highlight challenges in assessment of the replicative fitness of H7N9 NA variants that emerged in NAI-treated patients.