BACKGROUND: Neuraminidase inhibitors (NAIs) play a key role in the management of influenza epidemics and pandemics. Given the novel pandemic influenza A(H1N1) (pH1N1) virus and the restricted number of approved anti-influenza drugs, evaluation of potential drug-resistant variants is of high priority. METHODS: Recombinant pH1N1 viruses were generated by reverse genetics, expressing either the wild-type or any of 9 mutant neuraminidase (NA) proteins (N2 numbering: E119G, E119V, D198G, I222V, H274Y, N294S, S334N, I222V-H274Y, and H274Y-S334N). We evaluated these recombinant viruses for their resistance phenotype to 4 NAIs (oseltamivir, zanamivir, peramivir, and A-315675), NA enzymatic activity, and replicative capacity. RESULTS: The E119G and E119V mutations conferred a multidrug resistance phenotype to many NAIs but severely compromised viral fitness. The oseltamivir- and peramivir-resistance phenotype was confirmed for the H274Y and N294S mutants, although both viruses remained susceptible to zanamivir. Remarkably, the I222V mutation had a synergistic effect on the oseltamivir- and peramivir-resistance phenotype of H274Y and compensated for reduced viral fitness, raising concerns about the potential emergence and dissemination of this double-mutant virus. CONCLUSIONS: This study highlights the importance of continuous monitoring of antiviral drug resistance in clinical samples as well as the need to develop new agents and combination strategies.
BACKGROUND: Neuraminidase inhibitors (NAIs) play a key role in the management of influenza epidemics and pandemics. Given the novel pandemic influenza A(H1N1) (pH1N1) virus and the restricted number of approved anti-influenza drugs, evaluation of potential drug-resistant variants is of high priority. METHODS: Recombinant pH1N1 viruses were generated by reverse genetics, expressing either the wild-type or any of 9 mutant neuraminidase (NA) proteins (N2 numbering: E119G, E119V, D198G, I222V, H274Y, N294S, S334N, I222V-H274Y, and H274Y-S334N). We evaluated these recombinant viruses for their resistance phenotype to 4 NAIs (oseltamivir, zanamivir, peramivir, and A-315675), NA enzymatic activity, and replicative capacity. RESULTS: The E119G and E119V mutations conferred a multidrug resistance phenotype to many NAIs but severely compromised viral fitness. The oseltamivir- and peramivir-resistance phenotype was confirmed for the H274Y and N294S mutants, although both viruses remained susceptible to zanamivir. Remarkably, the I222V mutation had a synergistic effect on the oseltamivir- and peramivir-resistance phenotype of H274Y and compensated for reduced viral fitness, raising concerns about the potential emergence and dissemination of this double-mutant virus. CONCLUSIONS: This study highlights the importance of continuous monitoring of antiviral drug resistance in clinical samples as well as the need to develop new agents and combination strategies.
Authors: Menno D de Jong; Tan Thanh Tran; Huu Khanh Truong; Minh Hien Vo; Gavin J D Smith; Vinh Chau Nguyen; Van Cam Bach; Tu Qui Phan; Quang Ha Do; Yi Guan; J S Malik Peiris; Tinh Hien Tran; Jeremy Farrar Journal: N Engl J Med Date: 2005-12-22 Impact factor: 91.245
Authors: Arnold S Monto; Jennifer L McKimm-Breschkin; Catherine Macken; Alan W Hampson; Alan Hay; Alexander Klimov; Masato Tashiro; Robert G Webster; Michelle Aymard; Frederick G Hayden; Maria Zambon Journal: Antimicrob Agents Chemother Date: 2006-07 Impact factor: 5.191
Authors: Khristine Kaith S Lloren; Jin Jung Kwon; Won-Suk Choi; Ju Hwan Jeong; Su Jeong Ahn; Young Ki Choi; Yun Hee Baek; Min-Suk Song Journal: J Virol Date: 2019-03-05 Impact factor: 5.103