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Functional Evolution of the 2009 Pandemic H1N1 Influenza Virus NS1 and PA in Humans.
J Virol. 2018 10 01; 92(19)JV

Abstract

In 2009, a pandemic H1N1 influenza A virus (IAV) (pH1N1) emerged in the human population from swine causing a pandemic. Importantly, this virus is still circulating in humans seasonally. To analyze the evolution of pH1N1 in humans, we sequenced viral genes encoding proteins inhibiting general gene expression (nonstructural protein 1 [NS1] and PA-X) from circulating seasonal viruses and compared them to the viruses isolated at the origin of the pandemic. Recent pH1N1 viruses contain amino acid changes in the NS1 protein (E55K, L90I, I123V, E125D, K131E, and N205S), as previously described (A. M. Clark, A. Nogales, L. Martinez-Sobrido, D. J. Topham, and M. L. DeDiego, J Virol 91:e00721-17, 2017, https://doi.org/10.1128/JVI.00721-17), and amino acid changes in the PA-X protein (V100I, N204S, R221Q, and L229S). These amino acid differences between early and more recent pH1N1 isolates are responsible for increased NS1-mediated inhibition of host gene expression and decreased PA-X-mediated shutoff, including innate immune response genes. In addition, currently circulating pH1N1 viruses have acquired amino acid changes in the PA protein (V100I, P224S, N321K, I330V, and R362K). A recombinant pH1N1 virus containing PA, PA-X, and NS1 genes from currently circulating viruses is fitter in replication in cultured cells and in mice and is slightly more pathogenic than the original ancestor pH1N1 virus. These results demonstrate the need to monitor the evolution of pH1N1 in humans for mutations in the viral genome that could result in enhanced virulence. Importantly, these results further support our previous findings suggesting that inhibition of global gene expression mediated by NS1 and PA-X proteins is subject to a balance which can determine virus pathogenesis and fitness.IMPORTANCE IAVs emerge in humans from animal reservoirs, causing unpredictable pandemics. One of these pandemics was caused by an H1N1 virus in 2009, and this virus is still circulating seasonally. To analyze host-virus adaptations likely affecting influenza virus pathogenesis, protein amino acid sequences from viruses circulating at the beginning of the pandemic and those circulating currently were compared. Currently circulating viruses have incorporated amino acid changes in two viral proteins (NS1 and PA-X), affecting innate immune responses, and in the PA gene. These amino acid differences led to increased NS1-mediated and decreased PA-X-mediated inhibition of host gene expression. A recombinant pH1N1 virus containing PA, PA-X, and NS1 genes from recently circulating viruses is fitter in replication in tissue culture cells and in mice, and the virus is more pathogenic in vivo Importantly, these results suggest that a balance in the abilities of NS1 and PA-X to induce host shutoff is beneficial for IAVs.

Authors+Show Affiliations

Department of Microbiology and Immunology, University of Rochester, Rochester, New York, USA Aitor_Nogales@URMC.rochester.edu Marta_Lopez@URMC.rochester.edu.Department of Microbiology and Immunology, University of Rochester, Rochester, New York, USA.Department of Microbiology and Immunology, University of Rochester, Rochester, New York, USA. David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, New York, USA.Department of Microbiology and Immunology, University of Rochester, Rochester, New York, USA. David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, New York, USA.Department of Microbiology and Immunology, University of Rochester, Rochester, New York, USA Aitor_Nogales@URMC.rochester.edu Marta_Lopez@URMC.rochester.edu. David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, New York, USA. Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30021892

Citation

Nogales, Aitor, et al. "Functional Evolution of the 2009 Pandemic H1N1 Influenza Virus NS1 and PA in Humans." Journal of Virology, vol. 92, no. 19, 2018.
Nogales A, Martinez-Sobrido L, Chiem K, et al. Functional Evolution of the 2009 Pandemic H1N1 Influenza Virus NS1 and PA in Humans. J Virol. 2018;92(19).
Nogales, A., Martinez-Sobrido, L., Chiem, K., Topham, D. J., & DeDiego, M. L. (2018). Functional Evolution of the 2009 Pandemic H1N1 Influenza Virus NS1 and PA in Humans. Journal of Virology, 92(19). https://doi.org/10.1128/JVI.01206-18
Nogales A, et al. Functional Evolution of the 2009 Pandemic H1N1 Influenza Virus NS1 and PA in Humans. J Virol. 2018 10 1;92(19) PubMed PMID: 30021892.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Functional Evolution of the 2009 Pandemic H1N1 Influenza Virus NS1 and PA in Humans. AU - Nogales,Aitor, AU - Martinez-Sobrido,Luis, AU - Chiem,Kevin, AU - Topham,David J, AU - DeDiego,Marta L, Y1 - 2018/09/12/ PY - 2018/07/10/received PY - 2018/07/12/accepted PY - 2018/7/20/pubmed PY - 2018/9/19/medline PY - 2018/7/20/entrez KW - NS1 KW - PA-X KW - gene expression inhibition KW - inflammatory responses KW - influenza virus KW - innate immunity KW - interferon responses JF - Journal of virology JO - J Virol VL - 92 IS - 19 N2 - In 2009, a pandemic H1N1 influenza A virus (IAV) (pH1N1) emerged in the human population from swine causing a pandemic. Importantly, this virus is still circulating in humans seasonally. To analyze the evolution of pH1N1 in humans, we sequenced viral genes encoding proteins inhibiting general gene expression (nonstructural protein 1 [NS1] and PA-X) from circulating seasonal viruses and compared them to the viruses isolated at the origin of the pandemic. Recent pH1N1 viruses contain amino acid changes in the NS1 protein (E55K, L90I, I123V, E125D, K131E, and N205S), as previously described (A. M. Clark, A. Nogales, L. Martinez-Sobrido, D. J. Topham, and M. L. DeDiego, J Virol 91:e00721-17, 2017, https://doi.org/10.1128/JVI.00721-17), and amino acid changes in the PA-X protein (V100I, N204S, R221Q, and L229S). These amino acid differences between early and more recent pH1N1 isolates are responsible for increased NS1-mediated inhibition of host gene expression and decreased PA-X-mediated shutoff, including innate immune response genes. In addition, currently circulating pH1N1 viruses have acquired amino acid changes in the PA protein (V100I, P224S, N321K, I330V, and R362K). A recombinant pH1N1 virus containing PA, PA-X, and NS1 genes from currently circulating viruses is fitter in replication in cultured cells and in mice and is slightly more pathogenic than the original ancestor pH1N1 virus. These results demonstrate the need to monitor the evolution of pH1N1 in humans for mutations in the viral genome that could result in enhanced virulence. Importantly, these results further support our previous findings suggesting that inhibition of global gene expression mediated by NS1 and PA-X proteins is subject to a balance which can determine virus pathogenesis and fitness.IMPORTANCE IAVs emerge in humans from animal reservoirs, causing unpredictable pandemics. One of these pandemics was caused by an H1N1 virus in 2009, and this virus is still circulating seasonally. To analyze host-virus adaptations likely affecting influenza virus pathogenesis, protein amino acid sequences from viruses circulating at the beginning of the pandemic and those circulating currently were compared. Currently circulating viruses have incorporated amino acid changes in two viral proteins (NS1 and PA-X), affecting innate immune responses, and in the PA gene. These amino acid differences led to increased NS1-mediated and decreased PA-X-mediated inhibition of host gene expression. A recombinant pH1N1 virus containing PA, PA-X, and NS1 genes from recently circulating viruses is fitter in replication in tissue culture cells and in mice, and the virus is more pathogenic in vivo Importantly, these results suggest that a balance in the abilities of NS1 and PA-X to induce host shutoff is beneficial for IAVs. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/30021892/Functional_Evolution_of_the_2009_Pandemic_H1N1_Influenza_Virus_NS1_and_PA_in_Humans_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30021892/ DB - PRIME DP - Unbound Medicine ER -