Adaptation of Pandemic H1N1 Influenza Viruses in Mice

Ilyushina, Natalia A.; Khalenkov, Alexey M.; Seiler, J.; Forrest, H. S.; Bovin, Nicolai V.; Marjuki, Henju; Barman, Subrata; Webster, Robert G.; Webby, Richard J.

doi:10.1128/jvi.00159-10

Cited by 198 publications

(218 citation statements)

References 58 publications

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“…Reassortment experiments with 2009 H1N1 isolates have also shown that PA is important for the polymerase activity and virulence of A/California/04/2009 in mice, providing further evidence for a crucial role of the PA subunit (33,43). Finally, mutations in PA that arose during the creation of a highly pathogenic 2009 pH1N1 variant created by serial passage in mice contributed to enhanced polymerase function and, potentially, the highly pathogenic phenotype (18). Whether PA T552 in 2009 pH1N1 viruses will mutate to S552, or if this change increases polymerase activity in 2009 pH1N1, remains to be determined, although this mutation has not arisen during multiple adaptation experiments (18,53).…”

Section: Discussionmentioning

confidence: 99%

“…Finally, mutations in PA that arose during the creation of a highly pathogenic 2009 pH1N1 variant created by serial passage in mice contributed to enhanced polymerase function and, potentially, the highly pathogenic phenotype (18). Whether PA T552 in 2009 pH1N1 viruses will mutate to S552, or if this change increases polymerase activity in 2009 pH1N1, remains to be determined, although this mutation has not arisen during multiple adaptation experiments (18,53).…”

Section: Discussionmentioning

confidence: 99%

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Reassortment and Mutation of the Avian Influenza Virus Polymerase PA Subunit Overcome Species Barriers

Mehle

Dugan

Taubenberger

et al. 2012

J Virol

119

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The emergence of new pandemic influenza A viruses requires overcoming barriers to cross-species transmission as viruses move from animal reservoirs into humans. This complicated process is driven by both individual gene mutations and genome reassortments. The viral polymerase complex, composed of the proteins PB1, PB2, and PA, is a major factor controlling host adaptation, and reassortment events involving polymerase gene segments occurred with past pandemic viruses. Here we investigate the ability of polymerase reassortment to restore the activity of an avian influenza virus polymerase that is normally impaired in human cells. Our data show that the substitution of human-origin PA subunits into an avian influenza virus polymerase alleviates restriction in human cells and increases polymerase activity in vitro. Reassortants with 2009 pandemic H1N1 PA proteins were the most active. Mutational analyses demonstrated that the majority of the enhancing activity in human PA results from a threonine-to-serine change at residue 552. Reassortant viruses with avian polymerases and human PA subunits, or simply the T552S mutation, displayed faster replication kinetics in culture and increased pathogenicity in mice compared to those containing a wholly avian polymerase complex. Thus, the acquisition of a human PA subunit, or the signature T552S mutation, is a potential mechanism to overcome the species-specific restriction of avian polymerases and increase virus replication. Our data suggest that the human, avian, swine, and 2009 H1N1-like viruses that are currently cocirculating in pig populations set the stage for PA reassortments with the potential to generate novel viruses that could possess expanded tropism and enhanced pathogenicity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Reassortment and Mutation of the Avian Influenza Virus Polymerase PA Subunit Overcome Species Barriers

Mehle

Dugan

Taubenberger

et al. 2012

J Virol

119

View full text Add to dashboard Cite

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“…The progeny viruses carried K119N, G155E, S183P, R221K, or D222G hemagglutinin protein mutations and were more virulent than the unpassaged A(H1N1)pdm09 virus. 54 The implications of this study for pathogenesis of the virus in other mammals remains unknown, even though D222G has been associated with increased virulence in humans. [42][43][44][45] However, a reverse genetics hemagglutinin protein D222G A(H1N1)pdm09 mutant was generated and inoculated into ferrets without any increase in virulence.…”

Section: Molecular Markers Of Virulencementioning

confidence: 99%

“…These mutations occurred upon serial passage in mice and were shown to be responsible for enhanced transcription and replication of the virus. 54,61 Nonstructural protein 1 is another influenza protein well known to be involved in virulence. A(H1N1)pdm09 viruses possess a truncated nonstructural protein 1 of 220 amino acids.…”

Section: Molecular Markers Of Virulencementioning

confidence: 99%

Evolution and adaptation of the pandemic A/H1N1 2009 influenza virus

Ducatez¹,

Fabrizio²,

Webby³

2011

VAAT

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Abstract:The emergence of the 2009 H1N1 pandemic influenza virus [A(H1N1)pdm09] has provided the public health community with many challenges, but also the scientific community with an opportunity to monitor closely its evolution through the processes of drift and shift. To date, and despite having circulated in humans for nearly two years, little antigenic variation has been observed in the A(H1N1)pdm09 viruses. However, as the A(H1N1)pdm09 virus continues to circulate and the immunologic pressure within the human population increases, future antigenic change is almost a certainty. Several coinfections of A(H1N1)pdm09 and seasonal A(H1N1) or A(H3N2) viruses have been observed, but no reassortant viruses have been described in humans, suggesting a lack of fitness of reassortant viruses or a lack of opportunities for interaction of different viral lineages. In contrast, multiple reassortment events have been detected in swine populations between A(H1N1) pdm09 and other endemic swine viruses. Somewhat surprisingly, many of the well characterized influenza virus virulence markers appear to have limited impact on the phenotype of the A(H1N1)pdm09 viruses when they have been introduced into mutant viruses in laboratory settings. As such, it is unclear what the evolutionary path of the pandemic virus will be, but the monitoring of any changes in the circulating viruses will remain a global public and animal health priority.

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“…Furthermore, PA-P149S, R266H, L357I, and T515S have been reported to increase the polymerase activity of H5N1 viruses in 293T cells (20). Many PA amino acid mutations in H1 and H7 subtype viruses also contribute to overcoming host species barriers (17,(22)(23)(24)(25)(26)(27)(28).…”

mentioning

confidence: 99%

Mammalian Adaptive Mutations of the PA Protein of Highly Pathogenic Avian H5N1 Influenza Virus

Yamaji

Yamada

et al. 2015

J Virol

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Highly pathogenic H5N1 influenza A viruses continue to circulate among avian species and cause sporadic cases of human infection. Therefore, the threat of a pandemic persists. However, the human cases of H5N1 infection have been limited mainly to individuals in close contact with infected poultry. These findings suggest that the H5N1 viruses need to acquire adaptive mutations to gain a replicative advantage in mammalian cells to break through the species barrier. Many amino acid mutations of the polymerase complex have been reported to enhance H5N1 virus growth in mammalian cells; however, the mechanism for H5N1 virus of adaptation to humans remains unclear. Here, we propose that the PA of an H5N1 influenza virus isolated from a human in Vietnam Moreover, these mutations increased the pathogenicity of the virus in mice, suggesting that they contribute to adaptation to mammalian hosts. Intriguingly, PA-241Y, which 36285 encodes, is conserved in more than 90% of human seasonal H1N1 viruses, suggesting that PA-241Y contributes to virus adaptation to human lung cells and mammalian hosts. IMPORTANCEMany amino acid substitutions in highly pathogenic H5N1 avian influenza viruses have been shown to contribute to adaptation to mammalian hosts. However, no naturally isolated H5N1 virus has caused extensive human-to-human transmission, suggesting that additional, as-yet unidentified amino acid mutations are needed for adaptation to humans. Here, we report that five amino acid substitutions in PA (V44I, V127A, C241Y, A343T, and I573V) contribute to the replicative efficiency of H5N1 viruses in human lung cells and to high virulence in mice. These results are helpful for assessing the pandemic risk of isolates and further our understanding of the mechanism of H5N1 virus adaptation to mammalian hosts.

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Adaptation of Pandemic H1N1 Influenza Viruses in Mice

Cited by 198 publications

References 58 publications

Reassortment and Mutation of the Avian Influenza Virus Polymerase PA Subunit Overcome Species Barriers

Reassortment and Mutation of the Avian Influenza Virus Polymerase PA Subunit Overcome Species Barriers

Evolution and adaptation of the pandemic A/H1N1 2009 influenza virus

Mammalian Adaptive Mutations of the PA Protein of Highly Pathogenic Avian H5N1 Influenza Virus

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