MultiDrug-Resistant 2009 Pandemic Influenza A(H1N1) Viruses Maintain Fitness and Transmissibility in Ferrets

Memoli, Matthew J.; Davis, A. Sally; Proudfoot, Kathleen; Chertow, Daniel S.; Hrabal, Rachel J.; Bristol, Tyler; Taubenberger, Jeffery K.

doi:10.1093/infdis/jiq067

Cited by 66 publications

(70 citation statements)

References 27 publications

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“…While previous studies have assessed the replication efficiency of pure populations of H1N1pdm09-WT and H1N1pdm09-MUT in vitro and in ferrets (15,31,38), most have found similar levels of virus production by the two strains (as we have found), suggesting similar replication capacities. Two recent studies did perform a mixed-infection experiment (12,45), one of which concluded that the replication capacities were equal (45) while the other found that H1N1pdm09-MUT growth was impaired (12).…”

Section: Discussionsupporting

confidence: 74%

“…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). 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).…”

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confidence: 95%

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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

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et al. 2012

J Virol

111

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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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Section: Discussionsupporting

confidence: 74%

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confidence: 95%

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

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Abed

et al. 2012

J Virol

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225

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“…Such variants are also resistant to peramivir but retain susceptibility to zanamivir and laninamivir (Pizzorno et al, 2011;Samson et al, 2014). Interestingly, our group and other investigators reported that A(H1N1)pdm09 H275Y variants conserved a good fitness and exhibited efficient contact transmission when assessed in ferrets and guinea pigs (Hamelin et al, 2010;Memoli et al, 2011;Seibert et al, 2010;Wong et al, 2012). Furthermore, we previously demonstrated that the A(H1N1)pdm09 H275Y mutant was at least as virulent as the WT virus in BALB/c (Hamelin et al, 2010) and C57BL/6 mice.…”

Section: Discussionmentioning

confidence: 78%

The E119D neuraminidase mutation identified in a multidrug-resistant influenza A(H1N1)pdm09 isolate severely alters viral fitness in vitro and in animal models

et al. 2016

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Keyword: Influenza A(H1N1)pdm09 Resistance Neuraminidase E119D Zanamivir a b s t r a c tWe recently isolated an influenza A(H1N1)pdm09 E119D/H275Y neuraminidase (NA) variant from an immunocompromised patient who received oseltamivir and zanamivir therapies. This variant demonstrated cross resistance to zanamivir, oseltamivir, peramivir and laninamivir. In this study, the viral fitness of the recombinant wild-type (WT), E119D and E119D/H275Y A(H1N1)pdm09 viruses was evaluated in vitro and in experimentally-infected C57BL/6 mice and guinea pigs. In replication kinetics experiments, viral titers obtained with the E119D and E119D/H275Y recombinants were up to 2-and 4-log lower compared to the WT virus in MDCK and ST6GalI-MDCK cells, respectively. Enzymatic studies revealed that the E119D mutation significantly decreased the surface NA activity. In experimentallyinfected mice, a 50% mortality rate was recorded in the group infected with the WT recombinant virus whereas no mortality was observed in the E119D and E119D/H275Y groups. Mean lung viral titers on day 5 post-inoculation for the WT (1.2 ± 0.57 Â 10 8 PFU/ml) were significantly higher than those of the E119D (9.75 ± 0.41 Â 10 5 PFU/ml, P < 0.01) and the E119D/H275Y (1.47 ± 0.61 Â 10 6 PFU/ml, P < 0.01) groups. In guinea pigs, comparable seroconversion rates and viral titers in nasal washes (NW) were obtained for the WT and mutant index and contact groups. However, the D119E reversion was observed in most NW samples of the E119D and E119D/H275Y animals. In conclusion, the E119D NA mutation that could emerge in A(H1N1)pdm09 viruses during zanamivir therapy has a significant impact on viral fitness and such mutant is unlikely to be highly transmissible.

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“…The swine-origin H1N1 isolates that have replaced the typical human H1N1 viruses since 2009 show as yet a low frequency of oseltamivir resistance that has not been generally transmitted. The sporadic H275Y mutation does not reduce virus replication and transmission in the guinea pig or ferret models but to date has not spread amongst humans 7576–80 .…”

Section: Na Inhibitors and Resistance Mutationsmentioning

confidence: 94%

Influenza neuraminidase

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2011

Influenza Resp Viruses

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216

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Influenza neuraminidase is the target of two licensed antivirals that have been very successful, with several more in development. However, neuraminidase has been largely ignored as a vaccine target despite evidence that inclusion of neuraminidase in the subunit vaccine gives increased protection. This article describes current knowledge on the structure, enzyme activity and antigenic significance of neuraminidase.

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MultiDrug-Resistant 2009 Pandemic Influenza A(H1N1) Viruses Maintain Fitness and Transmissibility in Ferrets

Cited by 66 publications

References 27 publications

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

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

The E119D neuraminidase mutation identified in a multidrug-resistant influenza A(H1N1)pdm09 isolate severely alters viral fitness in vitro and in animal models

Influenza neuraminidase

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