Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA.
Identifieur interne : 000963 ( PubMed/Checkpoint ); précédent : 000962; suivant : 000964Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA.
Auteurs : François Ferron [France] ; Lorenzo Subissi [France] ; Ana Theresa Silveira De Morais [France] ; Nhung Thi Tuyet Le [France] ; Marion Sevajol [France] ; Laure Gluais [France] ; Etienne Decroly [France] ; Clemens Vonrhein [Royaume-Uni] ; Gérard Bricogne [Royaume-Uni] ; Bruno Canard [France] ; Isabelle Imbert [France]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 1091-6490 ] ; 2018.
Descripteurs français
- KwdFr :
- ARN viral (génétique), ARN viral (métabolisme), Antiviraux (métabolisme), Antiviraux (pharmacologie), Coronavirus (), Coronavirus (génétique), Coronavirus (métabolisme), Cristallographie aux rayons X, Domaines protéiques, Exoribonucleases (), Exoribonucleases (génétique), Exoribonucleases (métabolisme), Humains, Liaison aux protéines, Methyltransferases (), Methyltransferases (génétique), Methyltransferases (métabolisme), Modèles moléculaires, Protéines virales non structurales (), Protéines virales non structurales (génétique), Protéines virales non structurales (métabolisme), Ribavirine (métabolisme), Ribavirine (pharmacologie), Réplication virale, Syndrome respiratoire aigu sévère (virologie).
- MESH :
- génétique : ARN viral, Coronavirus, Exoribonucleases, Methyltransferases, Protéines virales non structurales.
- métabolisme : ARN viral, Antiviraux, Coronavirus, Exoribonucleases, Methyltransferases, Protéines virales non structurales, Ribavirine.
- pharmacologie : Antiviraux, Ribavirine.
- virologie : Syndrome respiratoire aigu sévère.
- Coronavirus, Cristallographie aux rayons X, Domaines protéiques, Exoribonucleases, Humains, Liaison aux protéines, Methyltransferases, Modèles moléculaires, Protéines virales non structurales, Réplication virale.
English descriptors
- KwdEn :
- Antiviral Agents (metabolism), Antiviral Agents (pharmacology), Coronavirus (drug effects), Coronavirus (genetics), Coronavirus (metabolism), Crystallography, X-Ray, Exoribonucleases (chemistry), Exoribonucleases (genetics), Exoribonucleases (metabolism), Humans, Methyltransferases (chemistry), Methyltransferases (genetics), Methyltransferases (metabolism), Models, Molecular, Protein Binding, Protein Domains, RNA, Viral (genetics), RNA, Viral (metabolism), Ribavirin (metabolism), Ribavirin (pharmacology), Severe Acute Respiratory Syndrome (virology), Viral Nonstructural Proteins (chemistry), Viral Nonstructural Proteins (genetics), Viral Nonstructural Proteins (metabolism), Virus Replication.
- MESH :
- chemical , chemistry : Exoribonucleases, Methyltransferases, Viral Nonstructural Proteins.
- chemical , genetics : Exoribonucleases, Methyltransferases, RNA, Viral, Viral Nonstructural Proteins.
- chemical , metabolism : Antiviral Agents, Exoribonucleases, Methyltransferases, RNA, Viral, Ribavirin, Viral Nonstructural Proteins.
- chemical , pharmacology : Antiviral Agents, Ribavirin.
- drug effects : Coronavirus.
- genetics : Coronavirus.
- metabolism : Coronavirus.
- virology : Severe Acute Respiratory Syndrome.
- Crystallography, X-Ray, Humans, Models, Molecular, Protein Binding, Protein Domains, Virus Replication.
Abstract
Coronaviruses (CoVs) stand out among RNA viruses because of their unusually large genomes (∼30 kb) associated with low mutation rates. CoVs code for nsp14, a bifunctional enzyme carrying RNA cap guanine N7-methyltransferase (MTase) and 3'-5' exoribonuclease (ExoN) activities. ExoN excises nucleotide mismatches at the RNA 3'-end in vitro, and its inactivation in vivo jeopardizes viral genetic stability. Here, we demonstrate for severe acute respiratory syndrome (SARS)-CoV an RNA synthesis and proofreading pathway through association of nsp14 with the low-fidelity nsp12 viral RNA polymerase. Through this pathway, the antiviral compound ribavirin 5'-monophosphate is significantly incorporated but also readily excised from RNA, which may explain its limited efficacy in vivo. The crystal structure at 3.38 Å resolution of SARS-CoV nsp14 in complex with its cofactor nsp10 adds to the uniqueness of CoVs among RNA viruses: The MTase domain presents a new fold that differs sharply from the canonical Rossmann fold.
DOI: 10.1073/pnas.1718806115
PubMed: 29279395
Affiliations:
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pubmed:29279395Le document en format XML
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral Agents (metabolism)</term>
<term>Antiviral Agents (pharmacology)</term>
<term>Coronavirus (drug effects)</term>
<term>Coronavirus (genetics)</term>
<term>Coronavirus (metabolism)</term>
<term>Crystallography, X-Ray</term>
<term>Exoribonucleases (chemistry)</term>
<term>Exoribonucleases (genetics)</term>
<term>Exoribonucleases (metabolism)</term>
<term>Humans</term>
<term>Methyltransferases (chemistry)</term>
<term>Methyltransferases (genetics)</term>
<term>Methyltransferases (metabolism)</term>
<term>Models, Molecular</term>
<term>Protein Binding</term>
<term>Protein Domains</term>
<term>RNA, Viral (genetics)</term>
<term>RNA, Viral (metabolism)</term>
<term>Ribavirin (metabolism)</term>
<term>Ribavirin (pharmacology)</term>
<term>Severe Acute Respiratory Syndrome (virology)</term>
<term>Viral Nonstructural Proteins (chemistry)</term>
<term>Viral Nonstructural Proteins (genetics)</term>
<term>Viral Nonstructural Proteins (metabolism)</term>
<term>Virus Replication</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>ARN viral (génétique)</term>
<term>ARN viral (métabolisme)</term>
<term>Antiviraux (métabolisme)</term>
<term>Antiviraux (pharmacologie)</term>
<term>Coronavirus ()</term>
<term>Coronavirus (génétique)</term>
<term>Coronavirus (métabolisme)</term>
<term>Cristallographie aux rayons X</term>
<term>Domaines protéiques</term>
<term>Exoribonucleases ()</term>
<term>Exoribonucleases (génétique)</term>
<term>Exoribonucleases (métabolisme)</term>
<term>Humains</term>
<term>Liaison aux protéines</term>
<term>Methyltransferases ()</term>
<term>Methyltransferases (génétique)</term>
<term>Methyltransferases (métabolisme)</term>
<term>Modèles moléculaires</term>
<term>Protéines virales non structurales ()</term>
<term>Protéines virales non structurales (génétique)</term>
<term>Protéines virales non structurales (métabolisme)</term>
<term>Ribavirine (métabolisme)</term>
<term>Ribavirine (pharmacologie)</term>
<term>Réplication virale</term>
<term>Syndrome respiratoire aigu sévère (virologie)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Exoribonucleases</term>
<term>Methyltransferases</term>
<term>Viral Nonstructural Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Exoribonucleases</term>
<term>Methyltransferases</term>
<term>RNA, Viral</term>
<term>Viral Nonstructural Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antiviral Agents</term>
<term>Exoribonucleases</term>
<term>Methyltransferases</term>
<term>RNA, Viral</term>
<term>Ribavirin</term>
<term>Viral Nonstructural Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term>
<term>Ribavirin</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Coronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Coronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>ARN viral</term>
<term>Coronavirus</term>
<term>Exoribonucleases</term>
<term>Methyltransferases</term>
<term>Protéines virales non structurales</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Coronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>ARN viral</term>
<term>Antiviraux</term>
<term>Coronavirus</term>
<term>Exoribonucleases</term>
<term>Methyltransferases</term>
<term>Protéines virales non structurales</term>
<term>Ribavirine</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term>
<term>Ribavirine</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Crystallography, X-Ray</term>
<term>Humans</term>
<term>Models, Molecular</term>
<term>Protein Binding</term>
<term>Protein Domains</term>
<term>Virus Replication</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Coronavirus</term>
<term>Cristallographie aux rayons X</term>
<term>Domaines protéiques</term>
<term>Exoribonucleases</term>
<term>Humains</term>
<term>Liaison aux protéines</term>
<term>Methyltransferases</term>
<term>Modèles moléculaires</term>
<term>Protéines virales non structurales</term>
<term>Réplication virale</term>
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<front><div type="abstract" xml:lang="en">Coronaviruses (CoVs) stand out among RNA viruses because of their unusually large genomes (∼30 kb) associated with low mutation rates. CoVs code for nsp14, a bifunctional enzyme carrying RNA cap guanine N7-methyltransferase (MTase) and 3'-5' exoribonuclease (ExoN) activities. ExoN excises nucleotide mismatches at the RNA 3'-end in vitro, and its inactivation in vivo jeopardizes viral genetic stability. Here, we demonstrate for severe acute respiratory syndrome (SARS)-CoV an RNA synthesis and proofreading pathway through association of nsp14 with the low-fidelity nsp12 viral RNA polymerase. Through this pathway, the antiviral compound ribavirin 5'-monophosphate is significantly incorporated but also readily excised from RNA, which may explain its limited efficacy in vivo. The crystal structure at 3.38 Å resolution of SARS-CoV nsp14 in complex with its cofactor nsp10 adds to the uniqueness of CoVs among RNA viruses: The MTase domain presents a new fold that differs sharply from the canonical Rossmann fold.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">29279395</PMID>
<DateCompleted><Year>2018</Year>
<Month>07</Month>
<Day>17</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>04</Month>
<Day>01</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1091-6490</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>115</Volume>
<Issue>2</Issue>
<PubDate><Year>2018</Year>
<Month>01</Month>
<Day>09</Day>
</PubDate>
</JournalIssue>
<Title>Proceedings of the National Academy of Sciences of the United States of America</Title>
<ISOAbbreviation>Proc. Natl. Acad. Sci. U.S.A.</ISOAbbreviation>
</Journal>
<ArticleTitle>Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA.</ArticleTitle>
<Pagination><MedlinePgn>E162-E171</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1073/pnas.1718806115</ELocationID>
<Abstract><AbstractText>Coronaviruses (CoVs) stand out among RNA viruses because of their unusually large genomes (∼30 kb) associated with low mutation rates. CoVs code for nsp14, a bifunctional enzyme carrying RNA cap guanine N7-methyltransferase (MTase) and 3'-5' exoribonuclease (ExoN) activities. ExoN excises nucleotide mismatches at the RNA 3'-end in vitro, and its inactivation in vivo jeopardizes viral genetic stability. Here, we demonstrate for severe acute respiratory syndrome (SARS)-CoV an RNA synthesis and proofreading pathway through association of nsp14 with the low-fidelity nsp12 viral RNA polymerase. Through this pathway, the antiviral compound ribavirin 5'-monophosphate is significantly incorporated but also readily excised from RNA, which may explain its limited efficacy in vivo. The crystal structure at 3.38 Å resolution of SARS-CoV nsp14 in complex with its cofactor nsp10 adds to the uniqueness of CoVs among RNA viruses: The MTase domain presents a new fold that differs sharply from the canonical Rossmann fold.</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Ferron</LastName>
<ForeName>François</ForeName>
<Initials>F</Initials>
<AffiliationInfo><Affiliation>Centre National de la Recherche Scientifique, Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 13009 Marseille, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Subissi</LastName>
<ForeName>Lorenzo</ForeName>
<Initials>L</Initials>
<AffiliationInfo><Affiliation>Centre National de la Recherche Scientifique, Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 13009 Marseille, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Silveira De Morais</LastName>
<ForeName>Ana Theresa</ForeName>
<Initials>AT</Initials>
<AffiliationInfo><Affiliation>Centre National de la Recherche Scientifique, Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 13009 Marseille, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Le</LastName>
<ForeName>Nhung Thi Tuyet</ForeName>
<Initials>NTT</Initials>
<AffiliationInfo><Affiliation>Centre National de la Recherche Scientifique, Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 13009 Marseille, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Sevajol</LastName>
<ForeName>Marion</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Centre National de la Recherche Scientifique, Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 13009 Marseille, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Gluais</LastName>
<ForeName>Laure</ForeName>
<Initials>L</Initials>
<AffiliationInfo><Affiliation>Centre National de la Recherche Scientifique, Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 13009 Marseille, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Decroly</LastName>
<ForeName>Etienne</ForeName>
<Initials>E</Initials>
<AffiliationInfo><Affiliation>Centre National de la Recherche Scientifique, Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 13009 Marseille, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Vonrhein</LastName>
<ForeName>Clemens</ForeName>
<Initials>C</Initials>
<AffiliationInfo><Affiliation>Global Phasing Ltd., Cambridge CB3 0AX, England.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Bricogne</LastName>
<ForeName>Gérard</ForeName>
<Initials>G</Initials>
<AffiliationInfo><Affiliation>Global Phasing Ltd., Cambridge CB3 0AX, England.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Canard</LastName>
<ForeName>Bruno</ForeName>
<Initials>B</Initials>
<AffiliationInfo><Affiliation>Centre National de la Recherche Scientifique, Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 13009 Marseille, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Imbert</LastName>
<ForeName>Isabelle</ForeName>
<Initials>I</Initials>
<Identifier Source="ORCID">0000-0001-5630-9945</Identifier>
<AffiliationInfo><Affiliation>Centre National de la Recherche Scientifique, Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 13009 Marseille, France; isabelle.imbert@univ-amu.fr.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<DataBankList CompleteYN="Y"><DataBank><DataBankName>PDB</DataBankName>
<AccessionNumberList><AccessionNumber>5NFY</AccessionNumber>
</AccessionNumberList>
</DataBank>
</DataBankList>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2017</Year>
<Month>12</Month>
<Day>26</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>Proc Natl Acad Sci U S A</MedlineTA>
<NlmUniqueID>7505876</NlmUniqueID>
<ISSNLinking>0027-8424</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000998">Antiviral Agents</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C558878">Nsp10 protein, SARS virus</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D012367">RNA, Viral</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D017361">Viral Nonstructural Proteins</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>49717AWG6K</RegistryNumber>
<NameOfSubstance UI="D012254">Ribavirin</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.1.1.-</RegistryNumber>
<NameOfSubstance UI="D008780">Methyltransferases</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.1.1.56</RegistryNumber>
<NameOfSubstance UI="C525596">nsp14 protein, SARS coronavirus</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 3.1.-</RegistryNumber>
<NameOfSubstance UI="D005095">Exoribonucleases</NameOfSubstance>
</Chemical>
</ChemicalList>
<CitationSubset>IM</CitationSubset>
<MeshHeadingList><MeshHeading><DescriptorName UI="D000998" MajorTopicYN="N">Antiviral Agents</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D017934" MajorTopicYN="N">Coronavirus</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D018360" MajorTopicYN="N">Crystallography, X-Ray</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D005095" MajorTopicYN="N">Exoribonucleases</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008780" MajorTopicYN="N">Methyltransferases</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008958" MajorTopicYN="N">Models, Molecular</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D011485" MajorTopicYN="N">Protein Binding</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000072417" MajorTopicYN="N">Protein Domains</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D012367" MajorTopicYN="N">RNA, Viral</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D012254" MajorTopicYN="N">Ribavirin</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D045169" MajorTopicYN="N">Severe Acute Respiratory Syndrome</DescriptorName>
<QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D017361" MajorTopicYN="N">Viral Nonstructural Proteins</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D014779" MajorTopicYN="Y">Virus Replication</DescriptorName>
</MeshHeading>
</MeshHeadingList>
<KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">RNA virus</Keyword>
<Keyword MajorTopicYN="Y">fold evolution</Keyword>
<Keyword MajorTopicYN="Y">proofreading</Keyword>
<Keyword MajorTopicYN="Y">ribavirin</Keyword>
<Keyword MajorTopicYN="Y">virus replication</Keyword>
</KeywordList>
<CoiStatement>The authors declare no conflict of interest.</CoiStatement>
</MedlineCitation>
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<Month>12</Month>
<Day>28</Day>
<Hour>6</Hour>
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<PubMedPubDate PubStatus="medline"><Year>2018</Year>
<Month>7</Month>
<Day>18</Day>
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<PubMedPubDate PubStatus="entrez"><Year>2017</Year>
<Month>12</Month>
<Day>28</Day>
<Hour>6</Hour>
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