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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Oligonucleotide Motifs That Disappear during the Evolution of Influenza Virus in Humans Increase Alpha Interferon Secretion by Plasmacytoid Dendritic Cells
<xref ref-type="fn" rid="FN2"><sup>▿</sup>
</xref>
</title>
<author><name sortKey="Jimenez Baranda, Sonia" sort="Jimenez Baranda, Sonia" uniqKey="Jimenez Baranda S" first="Sonia" last="Jimenez-Baranda">Sonia Jimenez-Baranda</name>
<affiliation><nlm:aff id="aff1">New York University Langone Medical Center and New York University Cancer Institute, New York, New York</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Greenbaum, Benjamin" sort="Greenbaum, Benjamin" uniqKey="Greenbaum B" first="Benjamin" last="Greenbaum">Benjamin Greenbaum</name>
<affiliation><nlm:aff id="aff2">The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, New Jersey</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Manches, Olivier" sort="Manches, Olivier" uniqKey="Manches O" first="Olivier" last="Manches">Olivier Manches</name>
<affiliation><nlm:aff id="aff1">New York University Langone Medical Center and New York University Cancer Institute, New York, New York</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Handler, Jesse" sort="Handler, Jesse" uniqKey="Handler J" first="Jesse" last="Handler">Jesse Handler</name>
<affiliation><nlm:aff id="aff1">New York University Langone Medical Center and New York University Cancer Institute, New York, New York</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rabadan, Raul" sort="Rabadan, Raul" uniqKey="Rabadan R" first="Raúl" last="Rabadán">Raúl Rabadán</name>
<affiliation><nlm:aff id="aff3">Department of Biomedical Informatics, Center for Computational Biology and Bioinformatics, Columbia University College of Physicians and Surgeons, New York, New York</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Levine, Arnold" sort="Levine, Arnold" uniqKey="Levine A" first="Arnold" last="Levine">Arnold Levine</name>
<affiliation><nlm:aff id="aff2">The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, New Jersey</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bhardwaj, Nina" sort="Bhardwaj, Nina" uniqKey="Bhardwaj N" first="Nina" last="Bhardwaj">Nina Bhardwaj</name>
<affiliation><nlm:aff id="aff1">New York University Langone Medical Center and New York University Cancer Institute, New York, New York</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">21307198</idno>
<idno type="pmc">3126114</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126114</idno>
<idno type="RBID">PMC:3126114</idno>
<idno type="doi">10.1128/JVI.01908-10</idno>
<date when="2011">2011</date>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Oligonucleotide Motifs That Disappear during the Evolution of Influenza Virus in Humans Increase Alpha Interferon Secretion by Plasmacytoid Dendritic Cells
<xref ref-type="fn" rid="FN2"><sup>▿</sup>
</xref>
</title>
<author><name sortKey="Jimenez Baranda, Sonia" sort="Jimenez Baranda, Sonia" uniqKey="Jimenez Baranda S" first="Sonia" last="Jimenez-Baranda">Sonia Jimenez-Baranda</name>
<affiliation><nlm:aff id="aff1">New York University Langone Medical Center and New York University Cancer Institute, New York, New York</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Greenbaum, Benjamin" sort="Greenbaum, Benjamin" uniqKey="Greenbaum B" first="Benjamin" last="Greenbaum">Benjamin Greenbaum</name>
<affiliation><nlm:aff id="aff2">The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, New Jersey</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Manches, Olivier" sort="Manches, Olivier" uniqKey="Manches O" first="Olivier" last="Manches">Olivier Manches</name>
<affiliation><nlm:aff id="aff1">New York University Langone Medical Center and New York University Cancer Institute, New York, New York</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Handler, Jesse" sort="Handler, Jesse" uniqKey="Handler J" first="Jesse" last="Handler">Jesse Handler</name>
<affiliation><nlm:aff id="aff1">New York University Langone Medical Center and New York University Cancer Institute, New York, New York</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rabadan, Raul" sort="Rabadan, Raul" uniqKey="Rabadan R" first="Raúl" last="Rabadán">Raúl Rabadán</name>
<affiliation><nlm:aff id="aff3">Department of Biomedical Informatics, Center for Computational Biology and Bioinformatics, Columbia University College of Physicians and Surgeons, New York, New York</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Levine, Arnold" sort="Levine, Arnold" uniqKey="Levine A" first="Arnold" last="Levine">Arnold Levine</name>
<affiliation><nlm:aff id="aff2">The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, New Jersey</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bhardwaj, Nina" sort="Bhardwaj, Nina" uniqKey="Bhardwaj N" first="Nina" last="Bhardwaj">Nina Bhardwaj</name>
<affiliation><nlm:aff id="aff1">New York University Langone Medical Center and New York University Cancer Institute, New York, New York</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Journal of Virology</title>
<idno type="ISSN">0022-538X</idno>
<idno type="eISSN">1098-5514</idno>
<imprint><date when="2011">2011</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
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<front><div type="abstract" xml:lang="en"><p>CpG motifs in an A/U context have been preferentially eliminated from classical H1N1 influenza virus genomes during virus evolution in humans. The hypothesis of the current work is that CpG motifs in a uracil context represent sequence patterns with the capacity to induce an immune response, and the avoidance of this immunostimulatory signal is the reason for the observed preferential decline. To analyze the immunogenicity of these domains, we used plasmacytoid dendritic cells (pDCs). pDCs express pattern recognition receptors, including Toll-like receptor 7 (TLR7), which recognizes guanosine- and uridine-rich viral single-stranded RNA (ssRNA), including influenza virus ssRNA. The signaling through TLR7 results in the induction of inflammatory cytokines and type I interferon (IFN-I), an essential process for the induction of specific adaptive immune responses and for mounting a robust antiviral response mediated by IFN-α. Secretion of IFN-α is also linked to the activation of other immune cells, potentially amplifying the effect of an initial IFN-α secretion. We therefore also examined the role of IFN-α-driven activation of NK cells as another source of selective pressure on the viral genome. We found direct evidence that CpG RNA motifs in a U-rich context control pDC activation and IFN-α-driven activation of NK cells, likely through TLR7. These data provide a potential explanation for the loss of CpG motifs from avian influenza viruses as they adapt to mammalian hosts. The selective decrease of CpG motifs surrounded by U/A may be a viral strategy to avoid immune recognition, a strategy likely shared by highly expressed human immune genes.</p>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Virol</journal-id>
<journal-id journal-id-type="hwp">jvi</journal-id>
<journal-id journal-id-type="pmc">jvi</journal-id>
<journal-id journal-id-type="publisher-id">JVI</journal-id>
<journal-title-group><journal-title>Journal of Virology</journal-title>
</journal-title-group>
<issn pub-type="ppub">0022-538X</issn>
<issn pub-type="epub">1098-5514</issn>
<publisher><publisher-name>American Society for Microbiology</publisher-name>
<publisher-loc>1752 N St., N.W., Washington, DC</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">21307198</article-id>
<article-id pub-id-type="pmc">3126114</article-id>
<article-id pub-id-type="publisher-id">1908-10</article-id>
<article-id pub-id-type="doi">10.1128/JVI.01908-10</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Pathogenesis and Immunity</subject>
</subj-group>
</article-categories>
<title-group><article-title>Oligonucleotide Motifs That Disappear during the Evolution of Influenza Virus in Humans Increase Alpha Interferon Secretion by Plasmacytoid Dendritic Cells
<xref ref-type="fn" rid="FN2"><sup>▿</sup>
</xref>
</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Jimenez-Baranda</surname>
<given-names>Sonia</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Greenbaum</surname>
<given-names>Benjamin</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="FN1">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Manches</surname>
<given-names>Olivier</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="FN1">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Handler</surname>
<given-names>Jesse</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rabadán</surname>
<given-names>Raúl</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Levine</surname>
<given-names>Arnold</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bhardwaj</surname>
<given-names>Nina</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="corresp" rid="cor1">*</xref>
</contrib>
<aff id="aff1"><label>1</label>
New York University Langone Medical Center and New York University Cancer Institute, New York, New York</aff>
<aff id="aff2"><label>2</label>
The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, New Jersey</aff>
<aff id="aff3"><label>3</label>
Department of Biomedical Informatics, Center for Computational Biology and Bioinformatics, Columbia University College of Physicians and Surgeons, New York, New York</aff>
</contrib-group>
<author-notes><corresp id="cor1"><label>*</label>
Corresponding author. Mailing address: <addr-line>New York University Langone Medical Center, Smilow Research Building, 522 First Avenue, Room 1303, New York, NY 10016</addr-line>
. Phone: <phone>(212) 263-5814</phone>
. Fax: <fax>(212) 263-6729</fax>
. E-mail: <email>Nina.Bhardwaj@med.nyu.edu</email>
.</corresp>
<fn id="FN1" fn-type="equal"><label>†</label>
<p>B.G. and O.M. contributed equally to this work.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><month>4</month>
<year>2011</year>
</pub-date>
<volume>85</volume>
<issue>8</issue>
<fpage>3893</fpage>
<lpage>3904</lpage>
<history><date date-type="received"><day>9</day>
<month>9</month>
<year>2010</year>
</date>
<date date-type="accepted"><day>29</day>
<month>1</month>
<year>2011</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2011, American Society for Microbiology</copyright-statement>
<copyright-year>2011</copyright-year>
<copyright-holder>American Society for Microbiology</copyright-holder>
</permissions>
<self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zjv00811003893.pdf"></self-uri>
<abstract><p>CpG motifs in an A/U context have been preferentially eliminated from classical H1N1 influenza virus genomes during virus evolution in humans. The hypothesis of the current work is that CpG motifs in a uracil context represent sequence patterns with the capacity to induce an immune response, and the avoidance of this immunostimulatory signal is the reason for the observed preferential decline. To analyze the immunogenicity of these domains, we used plasmacytoid dendritic cells (pDCs). pDCs express pattern recognition receptors, including Toll-like receptor 7 (TLR7), which recognizes guanosine- and uridine-rich viral single-stranded RNA (ssRNA), including influenza virus ssRNA. The signaling through TLR7 results in the induction of inflammatory cytokines and type I interferon (IFN-I), an essential process for the induction of specific adaptive immune responses and for mounting a robust antiviral response mediated by IFN-α. Secretion of IFN-α is also linked to the activation of other immune cells, potentially amplifying the effect of an initial IFN-α secretion. We therefore also examined the role of IFN-α-driven activation of NK cells as another source of selective pressure on the viral genome. We found direct evidence that CpG RNA motifs in a U-rich context control pDC activation and IFN-α-driven activation of NK cells, likely through TLR7. These data provide a potential explanation for the loss of CpG motifs from avian influenza viruses as they adapt to mammalian hosts. The selective decrease of CpG motifs surrounded by U/A may be a viral strategy to avoid immune recognition, a strategy likely shared by highly expressed human immune genes.</p>
</abstract>
</article-meta>
</front>
</pmc>
</record>
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