Reassortment between avian H5N1 and human H3N2 influenza viruses creates hybrid viruses with substantial virulence

Liu, Chengjun; Hatta, Masato; Nidom, Chairul A.; Muramoto, Yukiko; Watanabe, Shinji; Kawaoka, Yoshihiro

doi:10.1073/pnas.0912807107

Cited by 132 publications

(122 citation statements)

References 29 publications

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“…Poor growth as a result of hybrid polymerase complexes has been attributed to reductions in vRNA replication or mRNA transcription that limit the ability of viruses to package (29). As in other studies (27,28,30), we used a minigenome reporter assay to measure the activity of hybrid polymerase complexes, and we showed a reduction in polymerase activity when the Udorn PB1 gene was included in PR8 RNP complexes. However, we showed that this reduced intrinsic polymerase activity did not result in a decrease in the level of vRNA or mRNA in cells infected with the corresponding viruses.…”

Section: Discussionmentioning

confidence: 98%

“…However, in the model system, the comparison of potential progeny derived by reverse genetics revealed that the inclusion of Udorn PB1 had a significantly negative effect on the viral growth compared to the inclusion of PR8 PB1, resulting in lower yields of viral particles, infectious virions, and HAU. PB1, as part of the trimeric polymerase complex, is known to drive the transcription and replication of the viral genome (26), and previous studies have shown that viral growth can be altered by the presence of a hybrid polymerase containing components from viruses of different subtypes (27,28). Poor growth as a result of hybrid polymerase complexes has been attributed to reductions in vRNA replication or mRNA transcription that limit the ability of viruses to package (29).…”

Section: Discussionmentioning

confidence: 99%

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The Source of the PB1 Gene in Influenza Vaccine Reassortants Selectively Alters the Hemagglutinin Content of the Resulting Seed Virus

Cobbin

Verity

Gilbertson

et al. 2013

J Virol

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The yields of egg-grown influenza vaccines are maximized by the production of a seed strain using a reassortment of the seasonal influenza virus isolate with a highly egg-adapted strain. The seed virus is selected based on high yields of viral hemagglutinin (HA) and expression of the surface antigens from the seasonal isolate. The remaining proteins are usually derived from the highgrowth parent. However, a retrospective analysis of vaccine seeds revealed that the seasonal PB1 gene was selected in more than 50% of reassortment events. Using the model seasonal H3N2 virus A/Udorn/307/72 (Udorn) virus and the high-growth A/Puerto Rico/8/34 (PR8) virus, we assessed the influence of the source of the PB1 gene on virus growth and vaccine yield. Classical reassortment of these two strains led to the selection of viruses that predominantly had the Udorn PB1 gene. The presence of Udorn PB1 in the seed virus, however, did not result in higher yields of virus or HA compared to the yields in the corresponding seed virus with PR8 PB1. The 8-fold-fewer virions produced with the seed virus containing the Udorn PB1 were somewhat compensated for by a 4-fold increase in HA per virion. A higher HA/nucleoprotein (NP) ratio was found in past vaccine preparations when the seasonal PB1 was present, also indicative of a higher HA density in these vaccine viruses. As the HA viral RNA (vRNA) and mRNA levels in infected cells were similar, we propose that PB1 selectively alters the translation of viral mRNA. This study helps to explain the variability of vaccine seeds with respect to HA yield.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

The Source of the PB1 Gene in Influenza Vaccine Reassortants Selectively Alters the Hemagglutinin Content of the Resulting Seed Virus

Cobbin

Verity

Gilbertson

et al. 2013

J Virol

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“…The power of these methods can be increased when combined with approaches such as that of Li et al (30,31). In this work, all 256 possible output viruses were examined for their virulence potential.…”

Section: Discussionmentioning

confidence: 99%

Viral reassortment as an information exchange between viral segments

Greenbaum

Poon

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Viruses have an extraordinary ability to diversify and evolve. For segmented viruses, reassortment can introduce drastic genomic and phenotypic changes by allowing a direct exchange of genetic material between coinfecting strains. For instance, multiple influenza pandemics were caused by reassortments of viruses typically found in separate hosts. What is unclear, however, are the underlying mechanisms driving these events and the level of intrinsic bias in the diversity of strains that emerge from coinfection. To address this problem, previous experiments looked for correlations between segments of strains that coinfect cells in vitro. Here, we present an information theory approach as the natural mathematical framework for this question. We study, for influenza and other segmented viruses, the extent to which a virus's segments can communicate strain information across an infection and among one another. Our approach goes beyond previous association studies and quantifies how much the diversity of emerging strains is altered by patterns in reassortment, whether biases are consistent across multiple strains and cell types, and if significant information is shared among more than two segments. We apply our approach to a new experiment that examines reassortment patterns between the 2009 H1N1 pandemic and seasonal H1N1 strains, contextualizing its segmental information sharing by comparison with previously reported strain reassortments. We find evolutionary patterns across classes of experiments and previously unobserved higher-level structures. Finally, we show how this approach can be combined with virulence potentials to assess pandemic threats. viral evolution | systems biology | emerging infectious disease R eassortment of segmented viruses is a key mechanism for rapid novel virus creation. At least two human influenza pandemics in the last century were linked to lineages where some number of genomic segments reassorted with a genome of nonhuman origin (1, 2). This fact was reinforced by the emergence of the 2009 H1N1 pandemic (2009 pdm) virus (3-5). Novel reassortant strains can evade adaptive immunity by introducing antigens to a naïve host population or overly stimulate innate immunity by presenting a new host with abundant nonself molecular signals (6-10). Moreover, both sequence database studies and in vitro experiments have shown that genome reassortment between strains happens nonrandomly: If two strains coinfect the same cell, their progeny may not sample all possible strain/segment combinations uniformly (11)(12)(13)(14). These analyses focused on whether it is more likely that pairs of segments from the same strain appear together in reassortments, typically using chi-square tests to establish significance.Because influenza has eight segments, there are 256 possible reassortant viruses when a cell is coinfected by two strains. Each strain type and host cellular environment can influence reassortment differently, so it would seem impossible to predict whether a new pandemic strain can form. However, ...

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“…The decreased rate of fatality among human cases (from 60% to <20% as of January 2010) may reflect either a decline in the pathogenicity of the endemic H5N1 strain or improved clinical management. The recently reported reassortment between an avian HP H5N1 and a human seasonal H3N2 virus, generating hybrid viruses with substantial virulence (48), raises the specter of potential interhuman transmissibility of such reassortants. It is sobering to realize that ominous reassortment events remain possible as long as a virus continues to circulate; for example, swine H1N1 viruses recently reacquired pandemic-level transmissibility after an interval of nearly100 y.…”

Section: Vaccinementioning

confidence: 99%

Puzzling inefficiency of H5N1 influenza vaccines in Egyptian poultry

Kim

Kayali

Walker

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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In Egypt, efforts to control highly pathogenic H5N1 avian influenza virus in poultry and in humans have failed despite increased biosecurity, quarantine, and vaccination at poultry farms. The ongoing circulation of HP H5N1 avian influenza in Egypt has caused >100 human infections and remains an unresolved threat to veterinary and public health. Here, we describe that the failure of commercially available H5 poultry vaccines in Egypt may be caused in part by the passive transfer of maternal H5N1 antibodies to chicks, inhibiting their immune response to vaccination. We propose that the induction of a protective immune response to H5N1 is suppressed for an extended period in young chickens. This issue, among others, must be resolved and additional steps must be taken before the outbreaks in Egypt can be controlled.

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Reassortment between avian H5N1 and human H3N2 influenza viruses creates hybrid viruses with substantial virulence

Cited by 132 publications

References 29 publications

The Source of the PB1 Gene in Influenza Vaccine Reassortants Selectively Alters the Hemagglutinin Content of the Resulting Seed Virus

The Source of the PB1 Gene in Influenza Vaccine Reassortants Selectively Alters the Hemagglutinin Content of the Resulting Seed Virus

Viral reassortment as an information exchange between viral segments

Puzzling inefficiency of H5N1 influenza vaccines in Egyptian poultry

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