Oseltamivir–Resistant Pandemic H1N1/2009 Influenza Virus Possesses Lower Transmissibility and Fitness in Ferrets

Duan, Susu; Boltz, David A.; Seiler, Patrick; Li, Jiang; Bragstad, Karoline; Nielsen, Lars Peter; Webby, Richard J.; Webster, Robert G.; Govorkova, Elena A.

doi:10.1371/journal.ppat.1001022

Cited by 99 publications

(112 citation statements)

References 39 publications

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“…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). In addition, the NA inhibitor-resistant mutant retained its ability to efficiently transmit by direct contact.…”

Section: Discussionmentioning

confidence: 99%

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

Smith

Nagy

Driskell

et al. 2011

J Virol

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Virus replication and pulmonary disease pathogenesis in ferrets following) were compared. Nasal wash virus titers were similar for Ncal99 and Sw30, with peak virus titers of 10 5.1 50% tissue culture infectious doses (TCID 50 )/ml and 10 5.5 TCID 50 /ml occurring at day 3 postinfection (p.i.), respectively. The mean peak titer for CA09 also occurred at day 3 p.i. but was higher (10 7 TCID 50 /ml). In contrast, the peak virus titers (10 3.6 to 10 4.3 TCID 50 /ml) for Mal08 were delayed, occurring between days 5 and 7 p.i. Disease pathogenesis was characterized by microscopic lesions in the nasal turbinates and lungs of all ferrets; however, Sw30 infection was associated with severe bronchointerstitial pneumonia. The results demonstrate that although CA09 is highly transmissible in the human population and replicates well in the ferret model, it causes modest disease compared to other H1N1 viruses, particularly Sw30 infection.

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Section: Discussionmentioning

confidence: 99%

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

Smith

Nagy

Driskell

et al. 2011

J Virol

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“…Contact transmissions of H1N1pdm09-MUT between ferrets have been successful in all of the experiments reported (15,16,35,38,45). The results concerning airborne transmission, however, have been mixed, with some studies finding comparable (45,46) or nonsignificant differences (12) in efficiency and others finding that H1N1pdm09-MUT was transmitted less efficiently (16) (P ϭ 0.04, two-tailed Mantel-Cox test; M. É. Hamelin, personal communication) or suffered a delay with respect to the susceptible strain (31). Concise reviews of this prior work can be found elsewhere (7,26,42).…”

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confidence: 95%

“…Unlike the growth of pre-2007 seasonal H1N1 strains, that of the H1N1pdm09 H275Y MUT (H1N1pdm09-MUT) strain is not severely compromised in vitro or in ferrets (9,12,15,31). Contact transmissions of H1N1pdm09-MUT between ferrets have been successful in all of the experiments reported (15,16,35,38,45).…”

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confidence: 97%

The H275Y Neuraminidase Mutation of the Pandemic A/H1N1 Influenza Virus Lengthens the Eclipse Phase and Reduces Viral Output of Infected Cells, Potentially Compromising Fitness in Ferrets

Pinilla

Holder

Abed

et al. 2012

J Virol

111

225

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The H275Y amino acid substitution of the neuraminidase gene is the most common mutation conferring oseltamivir resistance in the N1 subtype of the influenza virus. Using a mathematical model to analyze a set of in vitro experiments that allow for the full characterization of the viral replication cycle, we show that the primary effects of the H275Y substitution on the pandemic H1N1 (H1N1pdm09) strain are to lengthen the mean eclipse phase of infected cells (from 6.6 to 9.1 h) and decrease (by 7-fold) the viral burst size, i.e., the total number of virions produced per cell. We also find, however, that the infectious-unit-to-particle ratio of the H275Y mutant strain is 12-fold higher than that of the oseltamivir-susceptible strain (0.19 versus 0.016 per RNA copy). A parallel analysis of the H275Y mutation in the prior seasonal A/Brisbane/59/2007 background shows similar changes in the infection kinetic parameters, but in this background, the H275Y mutation also allows the mutant to infect cells five times more rapidly. Competitive mixed-strain infections in vitro, where the susceptible and resistant H1N1pdm09 strains must compete for cells, are characterized by higher viral production by the susceptible strain but suggest equivalent fractions of infected cells in the culture. In ferrets, however, the mutant strain appears to suffer a delay in its infection of the respiratory tract that allows the susceptible strain to dominate mixed-strain infections. In 2009, the World Health Organization (WHO) declared the first influenza pandemic of this century and described the virus (H1N1pdm09) as naturally resistant to adamantanes but susceptible to the neuraminidase (NA) inhibitors oseltamivir and zanamivir (10, 29). In the past 3 years, isolated cases of oseltamivir resistance in H1N1pdm09 strains have been reported-almost always associated with the H275Y mutation within the NA genebut the overall level of resistance has remained relatively low (42) at ϳ1% in the United States (47), Ͻ1% in Canada (40), ϳ2.5% in Europe (14, 26), and Ͻ1.6% worldwide (26). In the United States, the fraction of cases of resistance not associated with oseltamivir exposure increased significantly from 11% in (11,18). That dominance of an oseltamivir-resistant H275Y MUT strain was surprising at the time because it had been shown that the mutation usually compromised strain fitness (30). A return to widespread oseltamivir resistance, with a mutated H1N1pdm09 virus, could have significant public health consequences (19).Laboratory experiments have often been used to assess a particular influenza virus strain's phenotype in cell culture and animal models, particularly in relation to oseltamivir resistance. Prior to 2007, experiments demonstrated strongly attenuated growth of H275Y MUT strains of H1N1 in vitro (1, 21), a higher viral titer inoculum required for the infection of ferrets (21, 30), and generally less-pathogenic infections in ferrets, quantified by reduced fevers and smaller inflammatory cell counts in nasal washes (30). This mirrored...

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“…Our analyses were conducted on only four randomized isolates, which were collected in the same place in a short period of time and after a few months from the beginning of the pandemic, limiting the possibility of greater genetic variability. Worldwide, recent reports have shown that a small proportion of influenza A(H1N1)pdm09 viruses have an NA mutant substitution at H275Y (N1 numbering, H275Y) that has been reported to give a high degree of resistance to oseltamivir [17,18,19,20]. This mutant isolate of influenza A(H1N1)pdm09 virus was also detected in Vietnam [18,20,21].…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization of influenza A(H1N1)pdm09 virus circulating during the 2009 outbreak in Thua Thien Hue, Vietnam

Bao

Bach

et al. 2013

J Infect Dev Ctries

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Introduction: The influenza A(H1N1)pdm09 virus arrived in Vietnam in May 2009 via the United States and rapidly spread throughout the country. This study provides data on the viral diagnosis and molecular epidemiology of influenza A(H1N1)pdm09 virus isolated in Thua Thien Hue Province, central Vietnam. Methodology: Nasopharyngeal swabs and throat swabs from 53 clinically infected patients in the peak of the outbreak were processed for viral diagnosis by culture and RT-PCR. Sequencing of entire HA and NA genes of representative isolates and molecular epidemiological analysis were performed. Results: A total of 32 patients were positive for influenza A virus by virus culture and/or RT-PCR; of these 22 were positive both by viral isolation and RT-PCR, 2 only by virus culture and 8 only by RT-PCR. The novel subtype of influenza A(H1N1)pdm09 was present in 93.4% of the isolates. Phylogenetic analysis of the HA and NA gene sequences showed identities higher than 99.50% in both genes. They were also similar to reference isolates in HA sequences (> 99% identity) and in NA sequences (>98.50% identity). Amino acid sequences predicted for the HA gene were highly identical to reference strains. The NA amino acid substitutions identified did not include the oseltamivir-resistant H275Y substitution. Conclusion: viral isolation and RT-PCR together were useful for diagnosis of the influenza A(H1N1)pdm09 virus. Variations in HA and NA sequences are similar to those identified in worldwide reference isolates and no drug resistance was found.

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Oseltamivir–Resistant Pandemic H1N1/2009 Influenza Virus Possesses Lower Transmissibility and Fitness in Ferrets

Cited by 99 publications

References 39 publications

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

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

The H275Y Neuraminidase Mutation of the Pandemic A/H1N1 Influenza Virus Lengthens the Eclipse Phase and Reduces Viral Output of Infected Cells, Potentially Compromising Fitness in Ferrets

Molecular characterization of influenza A(H1N1)pdm09 virus circulating during the 2009 outbreak in Thua Thien Hue, Vietnam

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