Antiviral resistance during the 2009 influenza A H1N1 pandemic: public health, laboratory, and clinical perspectives

Hurt, Aeron C.; Chotpitayasunondh, Tawee; Cox, Nancy J.; Daniels, Rod S.; Fry, Alicia M.; Gubareva, Larisa V.; Hayden, Frederick G.; Hui, David S.; Hungnes, Olav; Lackenby, Angie; Lim, Wilina; Meijer, Adam; Penn, Charles R.; Tashiro, Masato; Uyeki, Timothy M.; Zambon, Maria

doi:10.1016/s1473-3099(11)70318-8

Cited by 202 publications

(174 citation statements)

References 80 publications

Supporting

Mentioning

170

Contrasting

Order By: Relevance

“…As the structure of zanamivir closely resembles that of natural N-acetyl neuraminic acid (33, 34), it was proposed that NA mutations that prevent zanamivir binding might strongly alter the substrate binding properties of NA and thus result in loss of enzymatic activity (35-37). We found that the Q136K mutation not only reduced the enzymatic activity of NA but also reduced NA levels in viral particles, which readily explains the attenuated phenotype of zanamivir-resistant viruses carrying the Q136K mutation.The effect of the NA-H275Y mutation on fitness of pandemic H1N1 viruses varied considerably in published studies (7,28). In our study, the H275Y mutation alone did not negatively affect viral replication in MDCK-SIAT1 cells.…”

contrasting

confidence: 40%

Pandemic 2009 H1N1 Influenza A Virus Carrying a Q136K Mutation in the Neuraminidase Gene Is Resistant to Zanamivir but Exhibits Reduced Fitness in the Guinea Pig Transmission Model

Kaminski

Ohnemus

Staeheli

et al. 2013

J Virol

View full text Add to dashboard Cite

Resistance of influenza A viruses to neuraminidase inhibitors can arise through mutations in the neuraminidase (NA) gene. We show here that a Q136K mutation in the NA of the 2009 pandemic H1N1 virus confers a high degree of resistance to zanamivir. Resistance is accompanied by reduced numbers of NA molecules in viral particles and reduced intrinsic enzymatic activity of mutant NA. Interestingly, the Q136K mutation strongly impairs viral fitness in the guinea pig transmission model. N euraminidase (NA) inhibitors, such as oseltamivir and zanamivir, are the most commonly used antiviral drugs for the treatment of severe infections with influenza A virus (FLUAV). Oseltamivir is available only for oral intake (1), whereas zanamivir may be inhaled or given intravenously (2, 3). While oseltamivir resistance has been studied extensively in seasonal H1N1 (sH1N1) (4-7) and pandemic H1N1 (pH1N1) (7-11) FLUAV strains, there are only a few reports of zanamivir resistance. A Q136K mutation in the viral neuraminidase was shown to confer zanamivir resistance in seasonal H1N1 virus strains (12,13). An I223R mutation in the NA of a clinical pH1N1 isolate was reported to confer resistance to both oseltamivir and zanamivir (14,15). Both mutant viruses retained good transmissibility in the ferret transmission model (12, 15). Further, E119G or E119V mutations introduced by reverse genetics into the NA of a Canadian pH1N1 virus isolate were shown to confer multidrug resistance. However, both mutants exhibited severely compromised fitness (16). To date, there are no reports on NA mutations in the background of pH1N1 which would solely confer a high degree of resistance to zanamivir. Here, we investigated the potential of the pH1N1 strain A/Hansa Hamburg/01/2009 (identical to A/Hamburg/05/2009; GenBank accession numbers HQ111361 to HQ111368) to acquire zanamivir resistance.The virus was subjected to 11 serial passages on Madin-Darby canine kidney (MDCK) cells in the presence of escalating concentrations of zanamivir starting from 1 nM up to 2 mM in the final passage. Zanamivir resistance of the passaged viruses was determined by the NA-Star assay (Applied Biosystems) which measures neuraminidase activity with a defined substrate (17). The 50% inhibitory concentration (IC 50 ) values of zanamivir started to rise at passage 8 and reached a value of ϳ5 nM at passage 11 (Fig. 1A). Sequencing of plaque-purified viruses from passage 11 revealed a glutamine-to-lysine mutation at amino acid position 136 of NA (Q136K). This mutation, as well as the well-described H275Y oseltamivir resistance mutation in NA, was introduced into the wild-type virus using reverse genetics. We found that the virus carrying the Q136K mutation exhibited an 86-fold increase in the IC 50 for zanamivir compared to the wild-type virus (Fig. 1B) but remained sensitive to oseltamivir carboxylic acid (TRC Inc., North York, Canada). In agreement with previous results (11), the H275Y mutant virus exhibited a high degree of resistance to oseltamivir but remained susceptible to ...

show abstract

contrasting

confidence: 40%

Pandemic 2009 H1N1 Influenza A Virus Carrying a Q136K Mutation in the Neuraminidase Gene Is Resistant to Zanamivir but Exhibits Reduced Fitness in the Guinea Pig Transmission Model

Kaminski

Ohnemus

Staeheli

et al. 2013

J Virol

View full text Add to dashboard Cite

show abstract

“…As was the case for human A/H1N1 viruses that circulated before the 2009 pandemic, the majority of drug-resistant A(H1N1)pdm09 viruses harbored the H275Y (N1 numbering) NA mutation. Since its introduction in humans in April 2009, the transmission of the A(H1N1)pdm09 H275Y variant in the community has remained limited (8). Such a low level of drug resistance contrasts with the situation observed with the seasonal influenza virus A/Brisbane/59/2007 (H1N1) H275Y variant, which began to circulate in Europe and the United States in 2007 to 2008 before spreading worldwide during the subsequent season (9).…”

mentioning

confidence: 98%

Impact of Potential Permissive Neuraminidase Mutations on Viral Fitness of the H275Y Oseltamivir-Resistant Influenza A(H1N1)pdm09 VirusIn Vitro, in Mice and in Ferrets

Abed

Pizzorno

Bouhy

et al. 2014

J Virol

View full text Add to dashboard Cite

, and H275Y/V241I/N369K (a natural variant) NA mutants were generated by reverse genetics. Replication kinetics were performed by using ST6GalI-MDCK cells. Virulence was assessed in C57BL/6 mice, and contact transmission was evaluated in ferrets. The H275Y mutation significantly reduced viral titers during the first 12 to 36 h postinfection (p.i.) in vitro. Nevertheless, the WT and H275Y viruses induced comparable mortality rates, weight loss, and lung titers in mice. The T289M mutation eliminated the detrimental effect caused by the H275Y change in vitro while causing greater weight loss and mortality in mice, with significantly higher lung viral titers on days 3 and 6 p.i. than with the H275Y mutant. In index ferrets, the WT, H275Y, H275Y/T289M, and H275Y/V241I/N369K recombinants induced comparable fever, weight loss, and nasal wash viral titers. All tested viruses were transmitted at comparable rates in contact ferrets, with the H275Y/V241I/N369K recombinant demonstrating higher nasal wash viral titers than the H275Y mutant. Permissive mutations may enhance the fitness of A(H1N1)pdm09 H275Y viruses in vitro and in vivo. The emergence of such variants should be carefully monitored.

show abstract

“…Further, seasonal vaccines provide little protection from avian-origin viruses, such as H5N1 and H7N9 (5). With growing demand for broader therapeutic agents (6) and the rising number of viral isolates resistant to current antiviral treatments (7,8), a broadly protective universal vaccine would be an important development toward curtailing the impact of influenza virus on the human population.…”

mentioning

confidence: 99%

Influenza-Specific Antibody-Dependent Cellular Cytotoxicity: Toward a Universal Influenza Vaccine

Jegaskanda

Reading

Kent

2014

The Journal of Immunology

114

137

View full text Add to dashboard Cite

There is an urgent need for universal influenza vaccines that can control emerging pandemic influenza virus threats without the need to generate new vaccines for each strain. Neutralizing Abs to the influenza virus hemagglutinin glycoprotein are effective at controlling influenza infection but generally target highly variable regions. Abs that can mediate other functions, such as killing influenza-infected cells and activating innate immune responses (termed “Ab-dependent cellular cytotoxicity [ADCC]-mediating Abs”), may assist in protective immunity to influenza. ADCC-mediating Abs can target more conserved regions of influenza virus proteins and recognize a broader array of influenza strains. We review recent research on influenza-specific ADCC Abs and their potential role in improved influenza-vaccination strategies.

show abstract

Antiviral resistance during the 2009 influenza A H1N1 pandemic: public health, laboratory, and clinical perspectives

Cited by 202 publications

References 80 publications

Pandemic 2009 H1N1 Influenza A Virus Carrying a Q136K Mutation in the Neuraminidase Gene Is Resistant to Zanamivir but Exhibits Reduced Fitness in the Guinea Pig Transmission Model

Pandemic 2009 H1N1 Influenza A Virus Carrying a Q136K Mutation in the Neuraminidase Gene Is Resistant to Zanamivir but Exhibits Reduced Fitness in the Guinea Pig Transmission Model

Impact of Potential Permissive Neuraminidase Mutations on Viral Fitness of the H275Y Oseltamivir-Resistant Influenza A(H1N1)pdm09 VirusIn Vitro, in Mice and in Ferrets

Influenza-Specific Antibody-Dependent Cellular Cytotoxicity: Toward a Universal Influenza Vaccine

Contact Info

Product

Resources

About