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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Fitness Barriers Limit Reversion of a Proofreading-Deficient Coronavirus</title><author><name sortKey="Graepel, Kevin W" sort="Graepel, Kevin W" uniqKey="Graepel K" first="Kevin W." last="Graepel">Kevin W. Graepel</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Agostini, Maria L" sort="Agostini, Maria L" uniqKey="Agostini M" first="Maria L." last="Agostini">Maria L. Agostini</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lu, Xiaotao" sort="Lu, Xiaotao" uniqKey="Lu X" first="Xiaotao" last="Lu">Xiaotao Lu</name><affiliation><nlm:aff id="aff2"><addr-line>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sexton, Nicole R" sort="Sexton, Nicole R" uniqKey="Sexton N" first="Nicole R." last="Sexton">Nicole R. Sexton</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Denison, Mark R" sort="Denison, Mark R" uniqKey="Denison M" first="Mark R." last="Denison">Mark R. Denison</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31341046</idno><idno type="pmc">6798108</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798108</idno><idno type="RBID">PMC:6798108</idno><idno type="doi">10.1128/JVI.00711-19</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000C96</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000C96</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Fitness Barriers Limit Reversion of a Proofreading-Deficient Coronavirus</title><author><name sortKey="Graepel, Kevin W" sort="Graepel, Kevin W" uniqKey="Graepel K" first="Kevin W." last="Graepel">Kevin W. Graepel</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Agostini, Maria L" sort="Agostini, Maria L" uniqKey="Agostini M" first="Maria L." last="Agostini">Maria L. Agostini</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lu, Xiaotao" sort="Lu, Xiaotao" uniqKey="Lu X" first="Xiaotao" last="Lu">Xiaotao Lu</name><affiliation><nlm:aff id="aff2"><addr-line>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sexton, Nicole R" sort="Sexton, Nicole R" uniqKey="Sexton N" first="Nicole R." last="Sexton">Nicole R. Sexton</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Denison, Mark R" sort="Denison, Mark R" uniqKey="Denison M" first="Mark R." last="Denison">Mark R. Denison</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line></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="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Coronaviruses encode an exoribonuclease (ExoN) that is important for viral replication, fitness, and virulence, yet coronaviruses with a defective ExoN (ExoN-AA) have not reverted under diverse experimental conditions. In this study, we identify multiple impediments to MHV-ExoN-AA reversion. We show that ExoN-AA reversion is possible but evolutionarily unfavorable. Instead, compensatory mutations outside ExoN-AA motif I are more accessible and beneficial than partial reversion. We also show that coevolution between replicase proteins over long-term passage partially compensates for ExoN-AA motif I but renders the virus inhospitable to a reverted ExoN. Our results reveal the evolutionary basis for the genetic stability of ExoN-inactivating mutations, illuminate complex functional and evolutionary relationships between coronavirus replicase proteins, and identify potential mechanisms for stabilization of ExoN-AA coronavirus mutants.</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="iso-abbrev">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">31341046</article-id><article-id pub-id-type="pmc">6798108</article-id><article-id pub-id-type="publisher-id">00711-19</article-id><article-id pub-id-type="doi">10.1128/JVI.00711-19</article-id><article-categories><subj-group subj-group-type="heading"><subject>Genetic Diversity and Evolution</subject></subj-group></article-categories><title-group><article-title>Fitness Barriers Limit Reversion of a Proofreading-Deficient Coronavirus</article-title><alt-title alt-title-type="running-head">Barriers to Reversion of a Debilitated Coronavirus</alt-title><alt-title alt-title-type="short-authors">Graepel et al.</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Graepel</surname><given-names>Kevin W.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Agostini</surname><given-names>Maria L.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lu</surname><given-names>Xiaotao</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sexton</surname><given-names>Nicole R.</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Denison</surname><given-names>Mark R.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><aff id="aff1"><label>a</label><addr-line>Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line></aff><aff id="aff2"><label>b</label><addr-line>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line></aff><aff id="aff3"><label>c</label><addr-line>Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA</addr-line></aff><aff id="aff4"><label>d</label><addr-line>Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA</addr-line></aff></contrib-group><contrib-group><contrib contrib-type="editor"><name><surname>Gallagher</surname><given-names>Tom</given-names></name><role>Editor</role><aff>Loyola University Chicago</aff></contrib></contrib-group><author-notes><corresp id="cor1">Address correspondence to Mark R. Denison, <email>mark.denison@vumc.org</email>.</corresp><fn fn-type="other"><p><bold>Citation</bold> Graepel KW, Agostini ML, Lu X, Sexton NR, Denison MR. 2019. Fitness barriers limit reversion of a proofreading-deficient coronavirus. J Virol 93:e00711-19. <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.00711-19">https://doi.org/10.1128/JVI.00711-19</ext-link>.</p></fn></author-notes><pub-date pub-type="epreprint"><day>24</day><month>7</month><year>2019</year></pub-date><pub-date pub-type="epub"><day>30</day><month>9</month><year>2019</year></pub-date><pub-date pub-type="collection"><day>15</day><month>10</month><year>2019</year></pub-date><volume>93</volume><issue>20</issue><elocation-id>e00711-19</elocation-id><history><date date-type="received"><day>29</day><month>4</month><year>2019</year></date><date date-type="accepted"><day>5</day><month>7</month><year>2019</year></date></history><permissions><copyright-statement>Copyright © 2019 American Society for Microbiology.</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>American Society for Microbiology</copyright-holder><license license-type="asm" xlink:href="https://doi.org/10.1128/ASMCopyrightv2"><license-p><ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/ASMCopyrightv2">All Rights Reserved</ext-link>.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="JVI.00711-19.pdf"></self-uri><abstract abstract-type="precis"><p>Coronaviruses encode an exoribonuclease (ExoN) that is important for viral replication, fitness, and virulence, yet coronaviruses with a defective ExoN (ExoN-AA) have not reverted under diverse experimental conditions. In this study, we identify multiple impediments to MHV-ExoN-AA reversion. We show that ExoN-AA reversion is possible but evolutionarily unfavorable. Instead, compensatory mutations outside ExoN-AA motif I are more accessible and beneficial than partial reversion. We also show that coevolution between replicase proteins over long-term passage partially compensates for ExoN-AA motif I but renders the virus inhospitable to a reverted ExoN. Our results reveal the evolutionary basis for the genetic stability of ExoN-inactivating mutations, illuminate complex functional and evolutionary relationships between coronavirus replicase proteins, and identify potential mechanisms for stabilization of ExoN-AA coronavirus mutants.</p></abstract><abstract><title>ABSTRACT</title><p>The 3′-to-5′ exoribonuclease in coronavirus (CoV) nonstructural protein 14 (nsp14-ExoN) mediates RNA proofreading during genome replication. ExoN catalytic residues are arranged in three motifs: I (DE), II (E), and III (D). Alanine replacement of the motif I residues (AA-E-D; four nucleotide substitutions) in murine hepatitis virus (MHV) and severe acute respiratory syndrome (SARS)-CoV yields viable mutants with impaired replication and fitness, increased mutation rates, and attenuated virulence <italic>in vivo</italic>. Despite these impairments, MHV- and SARS-CoV ExoN motif I AA mutants (ExoN-AA) have not reverted at motif I in diverse <italic>in vitro</italic> and <italic>in vivo</italic> environments, suggesting that profound fitness barriers prevent motif I reversion. To test this hypothesis, we engineered MHV-ExoN-AA with 1, 2, or 3 nucleotide mutations along genetic pathways to AA-to-DE reversion. We show that engineered intermediate revertants were viable but had no increased replication or competitive fitness compared to that of MHV-ExoN-AA. In contrast, a low-passage-number (passage 10 [P10]) MHV-ExoN-AA showed increased replication and competitive fitness without reversion of ExoN-AA. Finally, engineered reversion of ExoN-AA to ExoN-DE in the presence of ExoN-AA passage-adaptive mutations resulted in significant fitness loss. These results demonstrate that while reversion is possible, at least one alternative adaptive pathway is more rapidly advantageous than intermediate revertants and may alter the genetic background to render reversion detrimental to fitness. Our results provide an evolutionary rationale for lack of ExoN-AA reversion, illuminate potential multiprotein replicase interactions and coevolution, and support future studies aimed at stabilizing attenuated CoV ExoN-AA mutants.</p><p><bold>IMPORTANCE</bold> Coronaviruses encode an exoribonuclease (ExoN) that is important for viral replication, fitness, and virulence, yet coronaviruses with a defective ExoN (ExoN-AA) have not reverted under diverse experimental conditions. In this study, we identify multiple impediments to MHV-ExoN-AA reversion. We show that ExoN-AA reversion is possible but evolutionarily unfavorable. Instead, compensatory mutations outside ExoN-AA motif I are more accessible and beneficial than partial reversion. We also show that coevolution between replicase proteins over long-term passage partially compensates for ExoN-AA motif I but renders the virus inhospitable to a reverted ExoN. Our results reveal the evolutionary basis for the genetic stability of ExoN-inactivating mutations, illuminate complex functional and evolutionary relationships between coronavirus replicase proteins, and identify potential mechanisms for stabilization of ExoN-AA coronavirus mutants.</p></abstract><kwd-group><title>KEYWORDS</title><kwd>RNA virus</kwd><kwd>adaptive evolution</kwd><kwd>competitive fitness</kwd><kwd>coronavirus</kwd><kwd>exoribonuclease</kwd><kwd>plus-strand RNA virus</kwd><kwd>proofreading</kwd><kwd>replication fidelity</kwd></kwd-group><funding-group><award-group id="award1"><funding-source><institution-wrap><institution>HHS | National Institutes of Health (NIH)</institution><institution-id>https://doi.org/10.13039/100000002</institution-id></institution-wrap></funding-source><award-id>T32-GM007347</award-id><award-id>T32-AI089554</award-id><principal-award-recipient><name><surname>Graepel</surname><given-names>Kevin</given-names></name></principal-award-recipient><principal-award-recipient><name><surname>Agostini</surname><given-names>Maria L.</given-names></name></principal-award-recipient><principal-award-recipient><name><surname>Sexton</surname><given-names>Nicole R.</given-names></name></principal-award-recipient></award-group><award-group id="award2"><funding-source><institution-wrap><institution>HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)</institution><institution-id>https://doi.org/10.13039/100000060</institution-id></institution-wrap></funding-source><award-id>R01-AI108197</award-id><award-id>F30-AI129229</award-id><award-id>F31-AI133952</award-id><principal-award-recipient><name><surname>Denison</surname><given-names>Mark R.</given-names></name></principal-award-recipient><principal-award-recipient><name><surname>Graepel</surname><given-names>Kevin</given-names></name></principal-award-recipient><principal-award-recipient><name><surname>Agostini</surname><given-names>Maria L.</given-names></name></principal-award-recipient></award-group></funding-group><counts><fig-count count="5"></fig-count><table-count count="2"></table-count><equation-count count="0"></equation-count><ref-count count="38"></ref-count><page-count count="11"></page-count><word-count count="7049"></word-count></counts><custom-meta-group><custom-meta><meta-name>cover-date</meta-name><meta-value>October 2019</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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