Characteristic amino acid changes of influenza A(H1N1)pdm09 virus PA protein enhance A(H7N9) viral polymerase activity

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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Whole-Genome Sequences of Influenza A(H1N1)pdm09 Virus Isolates from Kerala, India

Genome Announcements ◽

10.1128/genomea.00598-17 ◽

2017 ◽

Vol 5 (28) ◽

Cited By ~ 1

Author(s):

Sara Jones ◽

Raji Prasad ◽

Anjana S. Nair ◽

Sanjai Dharmaseelan ◽

Remya Usha ◽

...

Keyword(s):

Amino Acid ◽

Amino Acid Analysis ◽

Influenza A ◽

Whole Genome Sequence ◽

Whole Genome ◽

H1n1 Pandemic ◽

Genome Sequences ◽

Influenza A H1n1 ◽

Virus Isolates ◽

New Mutations

ABSTRACT We report here the whole-genome sequence of six clinical isolates of influenza A(H1N1)pdm09, isolated from Kerala, India. Amino acid analysis of all gene segments from the A(H1N1)pdm09 isolates obtained in 2014 and 2015 identified several new mutations compared to the 2009 A(H1N1) pandemic strain.

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Multiple polymerase acidic (PA) I38X substitutions in influenza A(H1N1)pdm09 virus permit polymerase activity and cause reduced baloxavir inhibition

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa527 ◽

2020 ◽

Author(s):

Jeremy C Jones ◽

Philippe N Q Pascua ◽

Walter N Harrington ◽

Richard J Webby ◽

Elena A Govorkova

Keyword(s):

Inhibitory Activity ◽

Influenza A ◽

Antiviral Drug ◽

Polymerase Activity ◽

Resistance Marker ◽

Complex Activity ◽

Replication Complex ◽

Virus Rescue ◽

Influenza A H1n1 ◽

Targeted Approach

Abstract Background Baloxavir marboxil is an antiviral drug that targets the endonuclease activity of the influenza virus polymerase acidic (PA) protein. PA I38T/M/F substitutions reduce its antiviral efficacy. Objectives To understand the effects of the 19 possible amino acid (AA) substitutions at PA 38 on influenza A(H1N1)pdm09 polymerase activity and inhibition by baloxavir acid, the active metabolite of baloxavir marboxil. Methods Influenza A(H1N1)pdm09 viral polymerase complexes containing all 19 I38X AA substitutions were reconstituted in HEK293T cells in a mini-replicon assay. Polymerase complex activity and baloxavir inhibitory activity were measured in the presence or absence of 50 nM baloxavir acid. Results Only three substitutions (R, K, P) reduced polymerase activity to <79% of I38-WT. When compared with the prototypical baloxavir marboxil resistance marker T38, 5 substitutions conferred 10%–35% reductions in baloxavir acid inhibitory activity (M, L, F, Y, C) and 11 substitutions conferred >50% reductions (R, K, S, N, G, W, A, Q, E, D, H), while two substitutions (V, P) maintained baloxavir acid inhibitory activity. Conclusions Most PA 38 substitutions permit a functional replication complex retaining some drug resistance in the mini-replicon assay. This study provides a targeted approach for virus rescue and analysis of novel baloxavir marboxil reduced-susceptibility markers, supports the consideration of a broader range of these markers during antiviral surveillance and adds to the growing knowledge of baloxavir marboxil resistance profiles.

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Evolution and Adaptation of the Avian H7N9 Virus into the Human Host

Microorganisms ◽

10.3390/microorganisms8050778 ◽

2020 ◽

Vol 8 (5) ◽

pp. 778

Author(s):

Andrew T. Bisset ◽

Gerard F. Hoyne

Keyword(s):

Amino Acid ◽

Avian Influenza ◽

Influenza A ◽

Amino Acid Sequences ◽

Influenza Viruses ◽

Amino Acid Substitutions ◽

Upper Respiratory Tract ◽

Viral Polymerase ◽

Evolutionary Changes ◽

Avian Origin

Influenza viruses arise from animal reservoirs, and have the potential to cause pandemics. In 2013, low pathogenic novel avian influenza A(H7N9) viruses emerged in China, resulting from the reassortment of avian-origin viruses. Following evolutionary changes, highly pathogenic strains of avian influenza A(H7N9) viruses emerged in late 2016. Changes in pathogenicity and virulence of H7N9 viruses have been linked to potential mutations in the viral glycoproteins hemagglutinin (HA) and neuraminidase (NA), as well as the viral polymerase basic protein 2 (PB2). Recognizing that effective viral transmission of the influenza A virus (IAV) between humans requires efficient attachment to the upper respiratory tract and replication through the viral polymerase complex, experimental evidence demonstrates the potential H7N9 has for increased binding affinity and replication, following specific amino acid substitutions in HA and PB2. Additionally, the deletion of extended amino acid sequences in the NA stalk length was shown to produce a significant increase in pathogenicity in mice. Research shows that significant changes in transmissibility, pathogenicity and virulence are possible after one or a few amino acid substitutions. This review aims to summarise key findings from that research. To date, all strains of H7N9 viruses remain restricted to avian reservoirs, with no evidence of sustained human-to-human transmission, although mutations in specific viral proteins reveal the efficacy with which these viruses could evolve into a highly virulent and infectious, human-to-human transmitted virus.

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Mutations in the PA Protein of Avian H5N1 Influenza Viruses Affect Polymerase Activity and Mouse Virulence

Journal of Virology ◽

10.1128/jvi.01557-17 ◽

2017 ◽

pp. JVI.01557-17 ◽

Cited By ~ 5

Author(s):

Gongxun Zhong ◽

Mai Quynh Le ◽

Tiago J.S. Lopes ◽

Peter Halfmann ◽

Masato Hatta ◽

...

Keyword(s):

Amino Acid ◽

Case Fatality ◽

Polymerase Activity ◽

Influenza Viruses ◽

Viral Polymerase ◽

Highly Pathogenic ◽

H5n1 Influenza ◽

Increased Risk ◽

Severe Infections ◽

Viral Determinants

To study the influenza viral determinants of pathogenicity, we characterized two highly pathogenic avian H5N1 influenza viruses isolated in Vietnam in 2012 (A/duck/Vietnam/QT1480/2012; QT1480) and 2013 (A/duck/Vietnam/QT1728/2013; QT1728) and found that the activity of their polymerase complexes differed significantly, even though both viruses were highly pathogenic in mice. Further studies revealed that the PA-S343A/E347D mutations reduced viral polymerase activity and mouse virulence when tested in the genetic background of QT1728 virus. In contrast, the PA-343S/347E mutations increased the polymerase activity of QT1480 and the virulence of a low pathogenic H5N1 influenza virus. The PA-343S residue (which alone increased viral polymerase activity and mouse virulence significantly relative to viral replication complexes encoding PA-343A) is frequently found in H5N1 influenza viruses of several subclades; infection with a virus possessing this amino acid may pose an increased risk to humans.IMPORTANCEH5N1 influenza viruses cause severe infections in humans with a case fatality rate that exceeds 50%. The factors that determine the high virulence of these viruses in humans are not fully understood. Here, we identified two amino acid changes in the viral polymerase PA protein that affect the activity of the viral polymerase complex and virulence in mice. Infection with viruses possessing these amino acid changes may pose an increased risk to humans.

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MOLECULAR AND GENETIC CHARACTERISTICS OF SURFACE AND NONSTRUCTURE PROTEINS OF PANDEMIC INFLUENZA VIRUSES A(H1N1)PDM09 IN 2015-2016 EPIDEMIC SEASON

Bulletin of Taras Shevchenko National University of Kyiv Series Biology ◽

10.17721/1728_2748.2016.72.44-48 ◽

2016 ◽

Vol 72 (2) ◽

pp. 44-48

Author(s):

O. Smutko ◽

L. Radchenko ◽

A. Mironenko

Keyword(s):

Amino Acid ◽

Pandemic Influenza ◽

Influenza A ◽

Phylogenetic Trees ◽

Influenza Viruses ◽

Amino Acid Substitutions ◽

Ns1 Protein ◽

Genetic Characteristics ◽

Epidemic Season ◽

Influenza A H1n1

The aim of the present study was identifying of molecular and genetic changes in hemaglutinin (HA), neuraminidase (NA) and non-structure protein (NS1) genes of pandemic influenza A(H1N1)pdm09 strains, that circulated in Ukraine during 2015-2016 epidemic season. Samples (nasopharyngeal swabs from patients) were analyzed using real-time polymerase chain reaction (RTPCR). Phylogenetic trees were constructed using MEGA 7 software. 3D structures were constructed in Chimera 1.11.2rc software. Viruses were collected in 2015-2016 season fell into genetic group 6B and in two emerging subgroups, 6B.1 and 6B.2 by gene of HA and NA. Subgroups 6B.1 and 6B.2 are defined by the following amino acid substitutions. In the NS1 protein were identified new amino acid substitutions D2E, N48S, and E125D in 2015-2016 epidemic season. Specific changes were observed in HA protein antigenic sites, but viruses saved similarity to vaccine strain. NS1 protein acquired substitution associated with increased virulence of the influenza virus.

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Seroprevalence study of infection with influenza A(H1N1)pdm09 virus in San Felipe Town, Chile

World Journal of Cardiovascular Diseases ◽

10.4236/wjcd.2013.37075 ◽

2013 ◽

Vol 03 (07) ◽

pp. 476-482

Author(s):

Olea Andrea ◽

Fasce Rodrigo ◽

Aguilera Ximena ◽

Oliva Otavio ◽

Muñoz Sergio ◽

...

Keyword(s):

Influenza A ◽

Seroprevalence Study ◽

Pdm09 Virus ◽

Influenza A H1n1

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Fluctuations in influenza-like illness epidemics and suicide mortality: A time-series regression of 13-year mortality data in South Korea

PLoS ONE ◽

10.1371/journal.pone.0244596 ◽

2021 ◽

Vol 16 (2) ◽

pp. e0244596

Author(s):

Sun Jae Jung ◽

Sung-Shil Lim ◽

Jin-Ha Yoon

Keyword(s):

Time Series ◽

South Korea ◽

Influenza A ◽

Suicide Mortality ◽

Mortality Data ◽

Time Series Regression ◽

Influenza Like Illness ◽

Pdm09 Virus ◽

Influenza A H1n1 ◽

Novel Influenza A

Aims We explored the association between influenza epidemic and suicide mortality rates in a large population using a time-series regression of 13-year mortality data in South Korea. Methods Weekly suicide mortalities and influenza-like illness (ILI) were analyzed using time series regression. Regression coefficient for suicide mortality based on percentage change of ILI was calculated using a quasi-Poisson regression. Non-linear distributed lag models with quadratic function up to 24 weeks were constructed. Results The association between ILI and suicide mortality increased significantly up to 8 weeks post-influenza diagnosis. A significant positive association between ILI and suicide mortality was observed from 2009, when a novel influenza A(H1N1)pdm09 virus provoked a worldwide pandemic. No meaningful association between these factors was observed before 2009. Conclusion There was a significant positive relationship between ILI and suicide mortality after 2009, when a novel influenza A(H1N1)pdm09 virus provoked a worldwide pandemic.

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