Sirolimus and other mTOR inhibitors directly activate latent pathogenic human polyomavirus replication.
Identifieur interne : 000046 ( Main/Exploration ); précédent : 000045; suivant : 000047Sirolimus and other mTOR inhibitors directly activate latent pathogenic human polyomavirus replication.
Auteurs : Jennifer Alvarez Orellana [États-Unis] ; Hyun Jin Kwun [États-Unis] ; Sara Artusi [États-Unis] ; Yuan Chang [États-Unis] ; Patrick S. Moore [États-Unis]Source :
- The Journal of infectious diseases [ 1537-6613 ] ; 2020.
Abstract
BACKGROUND
Human polyomaviruses can reactivate in transplant patients causing nephropathy, progressive multifocal leukoencephalopathy, Merkel cell carcinoma, pruritic rash or trichodysplasia spinulosa. Sirolimus and related mTOR inhibitors are transplant immunosuppressants. It is unknown if they directly reactivate polyomavirus replication from latency beyond their general effects on immunosuppression.
METHODS
In vitro expression and turnover of large T (LT) proteins from BK, JC, Merkel cell, HPyV7 and trichodysplasia spinulosa polyomaviruses after drug treatment were determined by immunoblotting, proximity ligation, replicon DNA replication and whole virus immunofluorescence assays.
RESULTS
mTOR inhibition increased LT protein expression for all 5 pathogenic polyomaviruses tested. This correlated with LT stabilization, decrease in the Skp2 E3 ligase targeting these LT proteins for degradation, as well as increase in virus replication for JCV, MCV, TSV and HPyV7. Treatment with sirolimus, but not the calcineurin inhibitor tacrolimus, at levels routinely achieved in patients, resulted in a dose-dependent increase in viral DNA replication for BKV, MCV and HPyV7.
CONCLUSIONS
mTOR inhibitors, at therapeutic levels, directly activate polyomavirus replication through a Skp2-dependent mechanism, revealing a proteostatic latency mechanism common to polyomaviruses. Modifying existing drug regimens for transplant patients with polyomavirus-associated diseases may reduce symptomatic polyomavirus replication while maintaining allograft-sparing immune suppression. immunosuppression.
DOI: 10.1093/infdis/jiaa071
PubMed: 32060513
Affiliations:
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Moore</name><affiliation><nlm:affiliation>Cancer Virology Program, Hillman Cancer Centre.</nlm:affiliation><wicri:noCountry code="subField">Hillman Cancer Centre</wicri:noCountry></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology & Molecular Genetics, University of Pittsburgh, PA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Microbiology & Molecular Genetics, University of Pittsburgh</wicri:cityArea></affiliation></author></analytic><series><title level="j">The Journal of infectious diseases</title><idno type="eISSN">1537-6613</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><b>BACKGROUND</b></p><p>Human polyomaviruses can reactivate in transplant patients causing nephropathy, progressive multifocal leukoencephalopathy, Merkel cell carcinoma, pruritic rash or trichodysplasia spinulosa. Sirolimus and related mTOR inhibitors are transplant immunosuppressants. It is unknown if they directly reactivate polyomavirus replication from latency beyond their general effects on immunosuppression.</p></div><div type="abstract" xml:lang="en"><p><b>METHODS</b></p><p>In vitro expression and turnover of large T (LT) proteins from BK, JC, Merkel cell, HPyV7 and trichodysplasia spinulosa polyomaviruses after drug treatment were determined by immunoblotting, proximity ligation, replicon DNA replication and whole virus immunofluorescence assays.</p></div><div type="abstract" xml:lang="en"><p><b>RESULTS</b></p><p>mTOR inhibition increased LT protein expression for all 5 pathogenic polyomaviruses tested. This correlated with LT stabilization, decrease in the Skp2 E3 ligase targeting these LT proteins for degradation, as well as increase in virus replication for JCV, MCV, TSV and HPyV7. Treatment with sirolimus, but not the calcineurin inhibitor tacrolimus, at levels routinely achieved in patients, resulted in a dose-dependent increase in viral DNA replication for BKV, MCV and HPyV7.</p></div><div type="abstract" xml:lang="en"><p><b>CONCLUSIONS</b></p><p>mTOR inhibitors, at therapeutic levels, directly activate polyomavirus replication through a Skp2-dependent mechanism, revealing a proteostatic latency mechanism common to polyomaviruses. Modifying existing drug regimens for transplant patients with polyomavirus-associated diseases may reduce symptomatic polyomavirus replication while maintaining allograft-sparing immune suppression. immunosuppression.</p></div></front></TEI><pubmed><MedlineCitation Status="Publisher" Owner="NLM"><PMID Version="1">32060513</PMID><DateRevised><Year>2020</Year><Month>02</Month><Day>15</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1537-6613</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2020</Year><Month>Feb</Month><Day>15</Day></PubDate></JournalIssue><Title>The Journal of infectious diseases</Title><ISOAbbreviation>J Infect Dis</ISOAbbreviation></Journal><ArticleTitle>Sirolimus and other mTOR inhibitors directly activate latent pathogenic human polyomavirus replication.</ArticleTitle><ELocationID EIdType="pii" ValidYN="Y">jiaa071</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1093/infdis/jiaa071</ELocationID><Abstract><AbstractText Label="BACKGROUND" NlmCategory="BACKGROUND">Human polyomaviruses can reactivate in transplant patients causing nephropathy, progressive multifocal leukoencephalopathy, Merkel cell carcinoma, pruritic rash or trichodysplasia spinulosa. Sirolimus and related mTOR inhibitors are transplant immunosuppressants. It is unknown if they directly reactivate polyomavirus replication from latency beyond their general effects on immunosuppression.</AbstractText><AbstractText Label="METHODS" NlmCategory="METHODS">In vitro expression and turnover of large T (LT) proteins from BK, JC, Merkel cell, HPyV7 and trichodysplasia spinulosa polyomaviruses after drug treatment were determined by immunoblotting, proximity ligation, replicon DNA replication and whole virus immunofluorescence assays.</AbstractText><AbstractText Label="RESULTS" NlmCategory="RESULTS">mTOR inhibition increased LT protein expression for all 5 pathogenic polyomaviruses tested. This correlated with LT stabilization, decrease in the Skp2 E3 ligase targeting these LT proteins for degradation, as well as increase in virus replication for JCV, MCV, TSV and HPyV7. Treatment with sirolimus, but not the calcineurin inhibitor tacrolimus, at levels routinely achieved in patients, resulted in a dose-dependent increase in viral DNA replication for BKV, MCV and HPyV7.</AbstractText><AbstractText Label="CONCLUSIONS" NlmCategory="CONCLUSIONS">mTOR inhibitors, at therapeutic levels, directly activate polyomavirus replication through a Skp2-dependent mechanism, revealing a proteostatic latency mechanism common to polyomaviruses. Modifying existing drug regimens for transplant patients with polyomavirus-associated diseases may reduce symptomatic polyomavirus replication while maintaining allograft-sparing immune suppression. immunosuppression.</AbstractText><CopyrightInformation>© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Alvarez Orellana</LastName><ForeName>Jennifer</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Cancer Virology Program, Hillman Cancer Centre.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology & Molecular Genetics, University of Pittsburgh, PA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kwun</LastName><ForeName>Hyun Jin</ForeName><Initials>HJ</Initials><AffiliationInfo><Affiliation>Cancer Virology Program, Hillman Cancer Centre.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, Penn State University, Hershey, PA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Artusi</LastName><ForeName>Sara</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Microbiology & Molecular Genetics, University of Pittsburgh, PA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chang</LastName><ForeName>Yuan</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Cancer Virology Program, Hillman Cancer Centre.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Pathology, University of Pittsburgh, PA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Moore</LastName><ForeName>Patrick S</ForeName><Initials>PS</Initials><AffiliationInfo><Affiliation>Cancer Virology Program, Hillman Cancer Centre.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology & Molecular Genetics, University of Pittsburgh, PA.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>02</Month><Day>15</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Infect Dis</MedlineTA><NlmUniqueID>0413675</NlmUniqueID><ISSNLinking>0022-1899</ISSNLinking></MedlineJournalInfo><CitationSubset>AIM</CitationSubset><CitationSubset>IM</CitationSubset><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">BKV</Keyword><Keyword MajorTopicYN="N">HPyV7</Keyword><Keyword MajorTopicYN="N">JC</Keyword><Keyword MajorTopicYN="N">MCPyV</Keyword><Keyword MajorTopicYN="N">Skp2</Keyword><Keyword MajorTopicYN="N">TSPyV</Keyword><Keyword MajorTopicYN="N">human polyomavirus</Keyword><Keyword MajorTopicYN="N">large T antigen</Keyword><Keyword MajorTopicYN="N">latency</Keyword><Keyword MajorTopicYN="N">mTOR inhibition</Keyword><Keyword MajorTopicYN="N">proteostasis</Keyword><Keyword MajorTopicYN="N">sirolimus</Keyword><Keyword MajorTopicYN="N">tacrolimus</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2019</Year><Month>11</Month><Day>29</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>2</Month><Day>16</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>2</Month><Day>16</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>2</Month><Day>16</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>aheadofprint</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">32060513</ArticleId><ArticleId IdType="pii">5736392</ArticleId><ArticleId IdType="doi">10.1093/infdis/jiaa071</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>États-Unis</li></country><region><li>Pennsylvanie</li></region></list><tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Alvarez Orellana, Jennifer" sort="Alvarez Orellana, Jennifer" uniqKey="Alvarez Orellana J" first="Jennifer" last="Alvarez Orellana">Jennifer Alvarez Orellana</name></region><name sortKey="Artusi, Sara" sort="Artusi, Sara" uniqKey="Artusi S" first="Sara" last="Artusi">Sara Artusi</name><name sortKey="Chang, Yuan" sort="Chang, Yuan" uniqKey="Chang Y" first="Yuan" last="Chang">Yuan Chang</name><name sortKey="Kwun, Hyun Jin" sort="Kwun, Hyun Jin" uniqKey="Kwun H" first="Hyun Jin" last="Kwun">Hyun Jin Kwun</name><name sortKey="Moore, Patrick S" sort="Moore, Patrick S" uniqKey="Moore P" first="Patrick S" last="Moore">Patrick S. 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