Sirolimus and Other Mechanistic Target of Rapamycin Inhibitors Directly Activate Latent Pathogenic Human Polyomavirus Replication
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 mechanistic target of rapamycin (mTOR) inhibitors are transplant...
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| Veröffentlicht in: | The Journal of infectious diseases 2021-10, Vol.224 (7), p.1160-1169 |
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| creator | Alvarez Orellana, Jennifer Kwun, Hyun Jin Artusi, Sara Chang, Yuan Moore, Patrick S |
| description | 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 mechanistic target of rapamycin (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 virus, JC virus (JCV), Merkel cell polyomavirus (MCV), human polyomavirus 7 (HPyV7), and trichodysplasia spinulosa polyomavirus (TSV) 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 S-phase kinase-associated protein 2 (Skp2) E3 ligase targeting these LT proteins for degradation, and 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 immunosuppression.
Polyomaviruses possess a poorly understood latent life cycle allowing persistent lifelong infection. This study reveals that polyomavirus latency is regulated by cellular degradation of the polyomavirus replication protein, large T. The mTOR inhibitors used in transplant immunosuppression can inhibit this process, promoting polyomavirus replication. |
| doi_str_mv | 10.1093/infdis/jiaa071 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8514189</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><oup_id>10.1093/infdis/jiaa071</oup_id><sourcerecordid>2597849339</sourcerecordid><originalsourceid>FETCH-LOGICAL-c518t-92dc7d3f54b1a4713de636695bc1dc2bbc9c1d0d7ecd3a766c1c8ecdddbe67b63</originalsourceid><addsrcrecordid>eNqFkc9vFCEUx4nR2LV69WhIvOhhWhgGZuZi0tQfbbKmTa1n8gaYHTYzMAKzyR79z6XZtVEvXuAlfPjwHl-EXlNyRknLzq3rtY3nWwtAavoErShndSEEZU_RipCyLGjTtifoRYxbQkjFRP0cnbCSCMIpW6Gf32zwo52WiMFpfJMGE_BXowZwNiar8D2EjUnY9_gOZpj2yjp87Qbb2eRDxB9tMCqNe3yhkt1BMnidF5fwLaTBb4zLiqtlAodv_bj3E-xsyG_dmXm0CpL17iV61sMYzavjfoq-f_50f3lVrG--XF9erAvFaZOKttSq1qznVUehqinTRjAhWt4pqlXZdarNBdG1UZpBLYSiqsm11p0RdSfYKfpw8M5LNxmtcpMBRjkHO0HYSw9W_n3i7CA3ficbTqv8iVnw7igI_sdiYpKTjcqMIzjjlyhLxnnLGkJ4Rt_-g279ElweT5a8rZuqZexBeHagVPAxBtM_NkOJfEhXHtKVx3TzhTd_jvCI_44zA-8PgF_m_8l-Ad2atZY</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2597849339</pqid></control><display><type>article</type><title>Sirolimus and Other Mechanistic Target of Rapamycin Inhibitors Directly Activate Latent Pathogenic Human Polyomavirus Replication</title><source>Oxford University Press Journals All Titles (1996-Current)</source><source>MEDLINE</source><source>Alma/SFX Local Collection</source><creator>Alvarez Orellana, Jennifer ; Kwun, Hyun Jin ; Artusi, Sara ; Chang, Yuan ; Moore, Patrick S</creator><creatorcontrib>Alvarez Orellana, Jennifer ; Kwun, Hyun Jin ; Artusi, Sara ; Chang, Yuan ; Moore, Patrick S</creatorcontrib><description>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 mechanistic target of rapamycin (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 virus, JC virus (JCV), Merkel cell polyomavirus (MCV), human polyomavirus 7 (HPyV7), and trichodysplasia spinulosa polyomavirus (TSV) 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 S-phase kinase-associated protein 2 (Skp2) E3 ligase targeting these LT proteins for degradation, and 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 immunosuppression.
Polyomaviruses possess a poorly understood latent life cycle allowing persistent lifelong infection. This study reveals that polyomavirus latency is regulated by cellular degradation of the polyomavirus replication protein, large T. The mTOR inhibitors used in transplant immunosuppression can inhibit this process, promoting polyomavirus replication.</description><identifier>ISSN: 0022-1899</identifier><identifier>ISSN: 1537-6613</identifier><identifier>EISSN: 1537-6613</identifier><identifier>DOI: 10.1093/infdis/jiaa071</identifier><identifier>PMID: 32060513</identifier><language>eng</language><publisher>US: Oxford University Press</publisher><subject>Antigen T (large) ; BK Virus ; Calcineurin ; Calcineurin inhibitors ; Deoxyribonucleic acid ; DNA ; DNA biosynthesis ; DNA Replication - drug effects ; DNA viruses ; DNA, Viral ; Humans ; Immunoblotting ; Immunofluorescence ; Immunosuppression ; Immunosuppressive agents ; Inhibitor drugs ; JC Virus ; Latency ; Leukoencephalopathy ; Major and Brief Reports ; Merkel cell polyomavirus ; MTOR Inhibitors - pharmacology ; Nephropathy ; Pathogenesis ; Polyomavirus - drug effects ; Polyomavirus - genetics ; Polyomavirus Infections - drug therapy ; Progressive multifocal leukoencephalopathy ; Rapamycin ; Replication ; S-Phase Kinase-Associated Proteins ; Sirolimus - pharmacology ; Skin cancer ; Tacrolimus ; Tacrolimus - pharmacology ; TOR protein ; TOR Serine-Threonine Kinases ; Ubiquitin-protein ligase ; Viral infections ; Virus Replication - drug effects</subject><ispartof>The Journal of infectious diseases, 2021-10, Vol.224 (7), p.1160-1169</ispartof><rights>The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. 2020</rights><rights>The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c518t-92dc7d3f54b1a4713de636695bc1dc2bbc9c1d0d7ecd3a766c1c8ecdddbe67b63</citedby><cites>FETCH-LOGICAL-c518t-92dc7d3f54b1a4713de636695bc1dc2bbc9c1d0d7ecd3a766c1c8ecdddbe67b63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,1578,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32060513$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Alvarez Orellana, Jennifer</creatorcontrib><creatorcontrib>Kwun, Hyun Jin</creatorcontrib><creatorcontrib>Artusi, Sara</creatorcontrib><creatorcontrib>Chang, Yuan</creatorcontrib><creatorcontrib>Moore, Patrick S</creatorcontrib><title>Sirolimus and Other Mechanistic Target of Rapamycin Inhibitors Directly Activate Latent Pathogenic Human Polyomavirus Replication</title><title>The Journal of infectious diseases</title><addtitle>J Infect Dis</addtitle><description>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 mechanistic target of rapamycin (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 virus, JC virus (JCV), Merkel cell polyomavirus (MCV), human polyomavirus 7 (HPyV7), and trichodysplasia spinulosa polyomavirus (TSV) 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 S-phase kinase-associated protein 2 (Skp2) E3 ligase targeting these LT proteins for degradation, and 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 immunosuppression.
Polyomaviruses possess a poorly understood latent life cycle allowing persistent lifelong infection. This study reveals that polyomavirus latency is regulated by cellular degradation of the polyomavirus replication protein, large T. The mTOR inhibitors used in transplant immunosuppression can inhibit this process, promoting polyomavirus replication.</description><subject>Antigen T (large)</subject><subject>BK Virus</subject><subject>Calcineurin</subject><subject>Calcineurin inhibitors</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA biosynthesis</subject><subject>DNA Replication - drug effects</subject><subject>DNA viruses</subject><subject>DNA, Viral</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Immunofluorescence</subject><subject>Immunosuppression</subject><subject>Immunosuppressive agents</subject><subject>Inhibitor drugs</subject><subject>JC Virus</subject><subject>Latency</subject><subject>Leukoencephalopathy</subject><subject>Major and Brief Reports</subject><subject>Merkel cell polyomavirus</subject><subject>MTOR Inhibitors - pharmacology</subject><subject>Nephropathy</subject><subject>Pathogenesis</subject><subject>Polyomavirus - drug effects</subject><subject>Polyomavirus - genetics</subject><subject>Polyomavirus Infections - drug therapy</subject><subject>Progressive multifocal leukoencephalopathy</subject><subject>Rapamycin</subject><subject>Replication</subject><subject>S-Phase Kinase-Associated Proteins</subject><subject>Sirolimus - pharmacology</subject><subject>Skin cancer</subject><subject>Tacrolimus</subject><subject>Tacrolimus - pharmacology</subject><subject>TOR protein</subject><subject>TOR Serine-Threonine Kinases</subject><subject>Ubiquitin-protein ligase</subject><subject>Viral infections</subject><subject>Virus Replication - drug effects</subject><issn>0022-1899</issn><issn>1537-6613</issn><issn>1537-6613</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><sourceid>EIF</sourceid><recordid>eNqFkc9vFCEUx4nR2LV69WhIvOhhWhgGZuZi0tQfbbKmTa1n8gaYHTYzMAKzyR79z6XZtVEvXuAlfPjwHl-EXlNyRknLzq3rtY3nWwtAavoErShndSEEZU_RipCyLGjTtifoRYxbQkjFRP0cnbCSCMIpW6Gf32zwo52WiMFpfJMGE_BXowZwNiar8D2EjUnY9_gOZpj2yjp87Qbb2eRDxB9tMCqNe3yhkt1BMnidF5fwLaTBb4zLiqtlAodv_bj3E-xsyG_dmXm0CpL17iV61sMYzavjfoq-f_50f3lVrG--XF9erAvFaZOKttSq1qznVUehqinTRjAhWt4pqlXZdarNBdG1UZpBLYSiqsm11p0RdSfYKfpw8M5LNxmtcpMBRjkHO0HYSw9W_n3i7CA3ficbTqv8iVnw7igI_sdiYpKTjcqMIzjjlyhLxnnLGkJ4Rt_-g279ElweT5a8rZuqZexBeHagVPAxBtM_NkOJfEhXHtKVx3TzhTd_jvCI_44zA-8PgF_m_8l-Ad2atZY</recordid><startdate>20211013</startdate><enddate>20211013</enddate><creator>Alvarez Orellana, Jennifer</creator><creator>Kwun, Hyun Jin</creator><creator>Artusi, Sara</creator><creator>Chang, Yuan</creator><creator>Moore, Patrick S</creator><general>Oxford University Press</general><scope>TOX</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20211013</creationdate><title>Sirolimus and Other Mechanistic Target of Rapamycin Inhibitors Directly Activate Latent Pathogenic Human Polyomavirus Replication</title><author>Alvarez Orellana, Jennifer ; Kwun, Hyun Jin ; Artusi, Sara ; Chang, Yuan ; Moore, Patrick S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c518t-92dc7d3f54b1a4713de636695bc1dc2bbc9c1d0d7ecd3a766c1c8ecdddbe67b63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Antigen T (large)</topic><topic>BK Virus</topic><topic>Calcineurin</topic><topic>Calcineurin inhibitors</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA biosynthesis</topic><topic>DNA Replication - drug effects</topic><topic>DNA viruses</topic><topic>DNA, Viral</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>Immunofluorescence</topic><topic>Immunosuppression</topic><topic>Immunosuppressive agents</topic><topic>Inhibitor drugs</topic><topic>JC Virus</topic><topic>Latency</topic><topic>Leukoencephalopathy</topic><topic>Major and Brief Reports</topic><topic>Merkel cell polyomavirus</topic><topic>MTOR Inhibitors - pharmacology</topic><topic>Nephropathy</topic><topic>Pathogenesis</topic><topic>Polyomavirus - drug effects</topic><topic>Polyomavirus - genetics</topic><topic>Polyomavirus Infections - drug therapy</topic><topic>Progressive multifocal leukoencephalopathy</topic><topic>Rapamycin</topic><topic>Replication</topic><topic>S-Phase Kinase-Associated Proteins</topic><topic>Sirolimus - pharmacology</topic><topic>Skin cancer</topic><topic>Tacrolimus</topic><topic>Tacrolimus - pharmacology</topic><topic>TOR protein</topic><topic>TOR Serine-Threonine Kinases</topic><topic>Ubiquitin-protein ligase</topic><topic>Viral infections</topic><topic>Virus Replication - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Alvarez Orellana, Jennifer</creatorcontrib><creatorcontrib>Kwun, Hyun Jin</creatorcontrib><creatorcontrib>Artusi, Sara</creatorcontrib><creatorcontrib>Chang, Yuan</creatorcontrib><creatorcontrib>Moore, Patrick S</creatorcontrib><collection>Oxford Journals Open Access Collection</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of infectious diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Alvarez Orellana, Jennifer</au><au>Kwun, Hyun Jin</au><au>Artusi, Sara</au><au>Chang, Yuan</au><au>Moore, Patrick S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sirolimus and Other Mechanistic Target of Rapamycin Inhibitors Directly Activate Latent Pathogenic Human Polyomavirus Replication</atitle><jtitle>The Journal of infectious diseases</jtitle><addtitle>J Infect Dis</addtitle><date>2021-10-13</date><risdate>2021</risdate><volume>224</volume><issue>7</issue><spage>1160</spage><epage>1169</epage><pages>1160-1169</pages><issn>0022-1899</issn><issn>1537-6613</issn><eissn>1537-6613</eissn><abstract>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 mechanistic target of rapamycin (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 virus, JC virus (JCV), Merkel cell polyomavirus (MCV), human polyomavirus 7 (HPyV7), and trichodysplasia spinulosa polyomavirus (TSV) 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 S-phase kinase-associated protein 2 (Skp2) E3 ligase targeting these LT proteins for degradation, and 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 immunosuppression.
Polyomaviruses possess a poorly understood latent life cycle allowing persistent lifelong infection. This study reveals that polyomavirus latency is regulated by cellular degradation of the polyomavirus replication protein, large T. The mTOR inhibitors used in transplant immunosuppression can inhibit this process, promoting polyomavirus replication.</abstract><cop>US</cop><pub>Oxford University Press</pub><pmid>32060513</pmid><doi>10.1093/infdis/jiaa071</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Alma/SFX Local Collection |
| subjects | Antigen T (large) BK Virus Calcineurin Calcineurin inhibitors Deoxyribonucleic acid DNA DNA biosynthesis DNA Replication - drug effects DNA viruses DNA, Viral Humans Immunoblotting Immunofluorescence Immunosuppression Immunosuppressive agents Inhibitor drugs JC Virus Latency Leukoencephalopathy Major and Brief Reports Merkel cell polyomavirus MTOR Inhibitors - pharmacology Nephropathy Pathogenesis Polyomavirus - drug effects Polyomavirus - genetics Polyomavirus Infections - drug therapy Progressive multifocal leukoencephalopathy Rapamycin Replication S-Phase Kinase-Associated Proteins Sirolimus - pharmacology Skin cancer Tacrolimus Tacrolimus - pharmacology TOR protein TOR Serine-Threonine Kinases Ubiquitin-protein ligase Viral infections Virus Replication - drug effects |
| title | Sirolimus and Other Mechanistic Target of Rapamycin Inhibitors Directly Activate Latent Pathogenic Human Polyomavirus Replication |
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