Dataset Information

Appearance of L90I and N205S Mutations in Effector Domain of NS1 Gene of pdm (09) H1N1 Virus from India during 2009-2013.

ABSTRACT: In the present study, full length sequencing of NS gene was done in 91 samples which were obtained from patients over the time period of five years from 2009 to 2013. The sequencing of NS gene was undertaken in order to determine the changes/mutations taking place in the NS gene of A H1N1 pdm (09) since its emergence in 2009. Analysis has shown that the majority of samples belong to New York (G1 type) strain with valine at position 123. Effector domain of NS1 protein displays the appearance of three mutations L90I, I123V, and N205S in almost all the samples from 2010 onwards. Phylogenetic analysis of available NS1 sequences from India has grouped all the sequences into four clusters with mean genetic distance ranging from 12% to 24% between the clusters. Variability in length of NS1 protein was seen in sequences from these clusters, 230-amino-acid-residue NS1 for all strains from year 2007 to 2008 and for 21 strains from year 2009 and 219-residue products for 37 strains from year 2009 and all strains from year 2010 to 2013. Mutations like K62R, K131Q, L147R, and A202P were observed for the first time in NS1 protein and their function remains to be determined.

SUBMITTER: Kumar S

PROVIDER: S-EPMC4181907 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Appearance of L90I and N205S Mutations in Effector Domain of NS1 Gene of pdm (09) H1N1 Virus from India during 2009-2013.

Kumar Sachin S Khare Shashi S Saidullah Bano B Gandhoke Inderjeet I Ram Hanu H Singh Supriya S Chauhan L S LS Rai Arvind A

Advances in virology 20140915

In the present study, full length sequencing of NS gene was done in 91 samples which were obtained from patients over the time period of five years from 2009 to 2013. The sequencing of NS gene was undertaken in order to determine the changes/mutations taking place in the NS gene of A H1N1 pdm (09) since its emergence in 2009. Analysis has shown that the majority of samples belong to New York (G1 type) strain with valine at position 123. Effector domain of NS1 protein displays the appearance of t ...[more]

PMID: 25309598

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Project description: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.

Project description:In 2009, a novel H1N1 influenza virus emerged in humans, causing a global pandemic. It was previously shown that the NS1 protein from this human 2009 pandemic H1N1 (pH1N1) virus was an effective interferon (IFN) antagonist but could not inhibit general host gene expression, unlike other NS1 proteins from seasonal human H1N1 and H3N2 viruses. Here we show that the NS1 protein from currently circulating pH1N1 viruses has evolved to encode 6 amino acid changes (E55K, L90I, I123V, E125D, K131E, and N205S) with respect to the original protein. Notably, these 6 residue changes restore the ability of pH1N1 NS1 to inhibit general host gene expression, mainly by their ability to restore binding to the cellular factor CPSF30. This is the first report describing the ability of the pH1N1 NS1 protein to naturally acquire mutations that restore this function. Importantly, a recombinant pH1N1 virus containing these 6 amino acid changes in the NS1 protein (pH1N1/NSs-6mut) inhibited host IFN and proinflammatory responses to a greater extent than that with the parental virus (pH1N1/NS1-wt), yet virus titers were not significantly increased in cell cultures or in mouse lungs, and the disease was partially attenuated. The pH1N1/NSs-6mut virus grew similarly to pH1N1/NSs-wt in mouse lungs, but infection with pH1N1/NSs-6mut induced lower levels of proinflammatory cytokines, likely due to a general inhibition of gene expression mediated by the mutated NS1 protein. This lower level of inflammation induced by the pH1N1/NSs-6mut virus likely accounts for the attenuated disease phenotype and may represent a host-virus adaptation affecting influenza virus pathogenesis.IMPORTANCE Seasonal influenza A viruses (IAVs) are among the most common causes of respiratory infections in humans. In addition, occasional pandemics are caused when IAVs circulating in other species emerge in the human population. In 2009, a swine-origin H1N1 IAV (pH1N1) was transmitted to humans, infecting people then and up to the present. It was previously shown that the NS1 protein from the 2009 pandemic H1N1 (pH1N1) virus is not able to inhibit general gene expression. However, currently circulating pH1N1 viruses have evolved to encode 6 amino acid changes (E55K, L90I, I123V, E125D, K131E, and N205S) that allow the NS1 protein of contemporary pH1N1 strains to inhibit host gene expression, which correlates with its ability to interact with CPSF30. Infection with a recombinant pH1N1 virus encoding these 6 amino acid changes (pH1N1/NSs-6mut) induced lower levels of proinflammatory cytokines, resulting in viral attenuation in vivo This might represent an adaptation of pH1N1 virus to humans.

Dataset Information

Appearance of L90I and N205S Mutations in Effector Domain of NS1 Gene of pdm (09) H1N1 Virus from India during 2009-2013.

Publications

Appearance of L90I and N205S Mutations in Effector Domain of NS1 Gene of pdm (09) H1N1 Virus from India during 2009-2013.

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