{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:51:04Z","timestamp":1782175864000,"version":"3.54.5"},"reference-count":59,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,11,3]],"date-time":"2020-11-03T00:00:00Z","timestamp":1604361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS055644"],"award-info":[{"award-number":["R01 NS055644"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20 GM21288"],"award-info":[{"award-number":["P20 GM21288"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Progressive Multifocal Leukoencephalopathy (PML) is a fatal demyelinating disease of the CNS, resulting from the lytic infection of oligodendrocytes by the human neurotropic polyomavirus JC (JCPyV), typically associated with severe immunocompromised states and, in recent years, with the use of immunotherapies. Apoptosis is a homeostatic mechanism to dispose of senescent or damaged cells, including virally infected cells, triggered in the vast majority of viral infections of the brain. Previously, we showed upregulation of the normally dormant anti-apoptotic protein Survivin in cases of PML, which\u2014in vitro\u2014resulted in protection from apoptosis in JCPyV-infected primary cultures of astrocytes and oligodendrocytes. In the present study, we first demonstrate the absence of apoptotic DNA fragmentation and the lack of caspase activity in 16 cases of PML. We also identified the viral protein large T-Antigen as being responsible for the activation of the Survivin promoter. Chromatin Immunoprecipitation assay shows a direct binding between T-Antigen and the Survivin promoter DNA. Finally, we have identified the specific region of T-Antigen, spanning from amino acids 266 and 688, which binds to Survivin and translocates it to the nucleus, providing evidence of a mechanism that results in the efficient replication of JCPyV and a potential target for novel therapies.<\/jats:p>","DOI":"10.3390\/v12111253","type":"journal-article","created":{"date-parts":[[2020,11,3]],"date-time":"2020-11-03T09:09:32Z","timestamp":1604394572000},"page":"1253","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["JCPyV T-Antigen Activation of the Anti-Apoptotic Survivin Promoter\u2014Its Role in the Development of Progressive Multifocal Leukoencephalopathy"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3894-9206","authenticated-orcid":false,"given":"Luis","family":"Del Valle","sequence":"first","affiliation":[{"name":"Neurological Cancer Research, Stanley S. Scott Cancer Center, Departments of Medicine &amp; Pathology, Louisiana State University Health, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thersa","family":"Sweet","sequence":"additional","affiliation":[{"name":"Infectious Diseases &amp; AIDS Epidemiology, Department of Epidemiology &amp; Biostatistics, Drexel University Dornsife School of Public Health, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Parker-Struckhoff","sequence":"additional","affiliation":[{"name":"Neurological Cancer Research, Stanley S. Scott Cancer Center, Louisiana State University Health, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgina","family":"Perez-Liz","sequence":"additional","affiliation":[{"name":"A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0987-0251","authenticated-orcid":false,"given":"Sergio","family":"Pi\u00f1a-Oviedo","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1099\/jgv.0.000839","article-title":"ICTV Virus taxonomy profile: Polyomaviridae","volume":"98","author":"Moens","year":"2017","journal-title":"J. Gen. Virol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5","DOI":"10.3109\/13550289509111006","article-title":"Progressive Multifocal Leukoencephalopathy: The evolution of a disease once considered rare","volume":"1","author":"Berger","year":"1995","journal-title":"J. Neurovirol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"718","DOI":"10.2741\/1830","article-title":"HIV disorders of the brain: Pathology and pathogenesis","volume":"11","year":"2006","journal-title":"Front. Biosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S0140-6736(06)69157-5","article-title":"HIV\/AIDS epidemiology, pathogenesis, prevention, and treatment","volume":"368","author":"Simon","year":"2006","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"969","DOI":"10.2165\/11537510-000000000-00000","article-title":"Progressive Multifocal Leukoencephalopathy and newer biological agents","volume":"33","author":"Berger","year":"2010","journal-title":"Drug Saf. Int. J. Med. Toxicol. Drug Exp."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1146\/annurev.med.080708.082655","article-title":"Progressive Multifocal Leukoencephalopathy in patients on immunomodulatory therapies","volume":"61","author":"Major","year":"2010","journal-title":"Annu. Rev. Med."},{"key":"ref_7","first-page":"93","article-title":"Progressive Multifocal Leuko-encephalopathy; a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin\u2019s disease","volume":"81","author":"Mancall","year":"1958","journal-title":"Brain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"711","DOI":"10.3389\/fonc.2019.00711","article-title":"Human Polyomavirus JCPyV and Its role in Progressive Multifocal Leukoencephalopathy and oncogenesis","volume":"9","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.nic.2007.12.009","article-title":"Neuropathology of viral infections of the Central Nervous System","volume":"18","author":"Shankar","year":"2008","journal-title":"Neuroimaging Clin. N. Am."},{"key":"ref_10","first-page":"79","article-title":"HSV-induced apoptosis in herpes encephalitis","volume":"289","author":"Aurelian","year":"2005","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1086\/345375","article-title":"Central Nervous System apoptosis in human herpes simplex virus and cytomegalovirus encephalitis","volume":"186","author":"DeBiasi","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1111\/j.1365-2990.1997.tb01205.x","article-title":"Apoptosis in measles virus-infected human Central Nervous System tissues","volume":"23","author":"McQuaid","year":"1997","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1177\/08830738020170101101","article-title":"Neurodegenerative mechanisms in subacute sclerosing panencephalitis","volume":"17","author":"Hayashi","year":"2002","journal-title":"J. Child Neurol."},{"key":"ref_14","first-page":"25","article-title":"Poliovirus, pathogenesis of poliomyelitis, and apoptosis","volume":"289","author":"Blondel","year":"2005","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.virusres.2006.05.002","article-title":"Rabies virus-induced apoptosis involves caspase-dependent and caspase-independent pathways","volume":"121","author":"Sarmento","year":"2006","journal-title":"Virus Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4015","DOI":"10.1523\/JNEUROSCI.22-10-04015.2002","article-title":"Caspase cascades in Human Immunodeficiency Virus-associated neurodegeneration","volume":"22","author":"Garden","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_17","first-page":"S38","article-title":"Neuronal apoptosis in human immunodeficiency virus infection","volume":"6","author":"Gray","year":"2000","journal-title":"J. Neurovirol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1080\/jnv.10.s1.102.107","article-title":"Gene expression in TUNEL-positive neurons in human immunodeficiency virus-infected brain","volume":"10","author":"Kolson","year":"2004","journal-title":"J. Neurovirol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/S0304-3940(02)00340-3","article-title":"Coxsackievirus B4-induced neuronal apoptosis in rat cortical cultures","volume":"326","author":"Joo","year":"2002","journal-title":"Neurosci. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1016\/S0002-9440(10)63496-7","article-title":"Coxsackievirus B3 and the neonatal CNS: The roles of stem cells, developing neurons, and apoptosis in infection, viral dissemination, and disease","volume":"163","author":"Feuer","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.neulet.2007.04.071","article-title":"Japanese encephalitis virus infection decrease endogenous IL-10 production: Correlation with microglial activation and neuronal death","volume":"420","author":"Swarup","year":"2007","journal-title":"Neurosci. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"599","DOI":"10.3109\/01913129309027796","article-title":"Ultrastructural studies in the lytic phase of Progressive Multifocal Leukoencephalopathy in AIDS patients","volume":"17","author":"Boldorini","year":"1993","journal-title":"Ultrastruct. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4884","DOI":"10.1128\/JVI.78.9.4884-4891.2004","article-title":"JC Virus induces non-apoptotic cell death of human central nervous system progenitor cell-derived astrocytes","volume":"78","author":"Seth","year":"2004","journal-title":"J. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.2353\/ajpath.2007.060689","article-title":"Effects of JC Virus infection on anti-apoptotic protein Survivin in Progressive Multifocal Leukoencephalopathy","volume":"170","author":"Urbanska","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2353\/ajpath.2006.060121","article-title":"Role of the Survivin gene in pathophysiology","volume":"169","author":"Li","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"11177","DOI":"10.1074\/jbc.273.18.11177","article-title":"Induction of apoptosis and inhibition of cell proliferation by Survivin gene targeting","volume":"273","author":"Ambrosini","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/25141","article-title":"Control of apoptosis and mitotic spindle checkpoint by Survivin","volume":"396","author":"Li","year":"1998","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8581","DOI":"10.1038\/sj.onc.1207113","article-title":"Survivin, versatile modulation of cell division and apoptosis in cancer","volume":"22","author":"Altieri","year":"2003","journal-title":"Oncogene"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1042\/bj3440305","article-title":"Transcriptional analysis of human Survivin gene expression","volume":"344","author":"Li","year":"1999","journal-title":"Biochem. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1002\/ijc.23183","article-title":"Transcriptional regulation of human Survivin by early growth response (Egr)-1 transcription factor","volume":"122","author":"Wagner","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7703","DOI":"10.1128\/MCB.01991-06","article-title":"E-cadherin is required for caveolin-1-mediated down-regulation of the inhibitor of apoptosis protein Survivin via reduced beta-catenin-Tcf\/Lef-dependent transcription","volume":"27","author":"Torres","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Siddiqa, A., Long, L.M., Li, L., Marciniak, R.A., and Kazhdan, I. (2008). Expression of HER-2 in MCF-7 breast cancer cells modulates anti-apoptotic proteins Survivin and Bcl-2 via the extracellular signal-related kinase (ERK) and phosphoinositide-3 kinase (PI3K) signalling pathways. BMC Cancer, 8.","DOI":"10.1186\/1471-2407-8-129"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1016\/j.exphem.2007.03.007","article-title":"Contribution of STAT3 to the activation of Survivin by GM-CSF in CD34+ cell lines","volume":"35","author":"Gu","year":"2007","journal-title":"Exp. Hematol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2390","DOI":"10.1093\/nar\/gkm149","article-title":"Molecular mechanism of upregulation of Survivin transcription by the AT-rich DNA-binding ligand, Hoechst33342: Evidence for Survivin involvement in drug resistance","volume":"35","author":"Wu","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"25903","DOI":"10.1074\/jbc.M603414200","article-title":"Cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-1alpha signal pathways increases resistance to apoptosis by up-regulating Survivin gene expression","volume":"281","author":"Peng","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3296","DOI":"10.1038\/sj.onc.1209363","article-title":"The expression of antiapoptotic protein Survivin is transcriptionally upregulated by DEC1 primarily through multiple sp1 binding sites in the proximal promoter","volume":"25","author":"Li","year":"2006","journal-title":"Oncogene"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1093\/jnci\/94.7.522","article-title":"Activation of cancer-specific gene expression by the Survivin promoter","volume":"94","author":"Bao","year":"2002","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1002\/ijc.20768","article-title":"Nuclear or cytoplasmic expression of Survivin: What is the significance?","volume":"114","author":"Li","year":"2005","journal-title":"Int. J. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/nrc968","article-title":"Validating Survivin as a cancer therapeutic target","volume":"3","author":"Altieri","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1158\/0008-5472.CAN-07-3027","article-title":"Survival advantage of EBV-associated gastric carcinoma: Survivin up-regulation by viral latent membrane protein 2A","volume":"68","author":"Hino","year":"2008","journal-title":"Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1099\/vir.0.81067-0","article-title":"Effects of human papillomavirus type 16 oncoproteins on Survivin gene expression","volume":"87","author":"Borbely","year":"2006","journal-title":"J. Gen. Virol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1002\/jmv.20466","article-title":"Hepatitis B virus X protein upregulates Survivin expression in hepatoma tissues","volume":"77","author":"Zhang","year":"2005","journal-title":"J. Med. Virol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2729","DOI":"10.1093\/emboj\/cdg263","article-title":"HBXIP functions as a cofactor of Survivin in apoptosis suppression","volume":"22","author":"Marusawa","year":"2003","journal-title":"EMBO J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1023\/A:1021653119934","article-title":"Upregulation of Survivin by HIV-1 Vpr","volume":"8","author":"Zhu","year":"2003","journal-title":"Apoptosis"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1002\/ijc.20954","article-title":"Transcriptional activation of Survivin through the NF-kappaB pathway by human T-cell leukemia virus type I tax","volume":"115","author":"Kawakami","year":"2005","journal-title":"Int. J. Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6689","DOI":"10.1128\/jvi.67.11.6689-6697.1993","article-title":"Efficient transcriptional activation of many simple modular promoters by Simian Virus 40 large T-Antigen","volume":"67","author":"Rice","year":"1993","journal-title":"J. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"16-160","DOI":"10.1016\/S0021-9258(18)71601-3","article-title":"Stimulation of the human heat shock protein 70 promoter in vitro by Simian Virus 40 large T-Antigen","volume":"264","author":"Taylor","year":"1989","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/0042-6822(73)90341-3","article-title":"A new technique for the assay of infectivity of human adenovirus 5 DNA","volume":"52","author":"Graham","year":"1973","journal-title":"Virology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/sj.onc.1202278","article-title":"Human ubiquitous JCV(CY) T-Antigen gene induces brain tumors in experimental animals","volume":"18","author":"Krynska","year":"1999","journal-title":"Oncogene"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"7923","DOI":"10.1158\/0008-5472.CAN-08-0817","article-title":"Nuclear Survivin abrogates multiple cell cycle checkpoints and enhances viral oncolysis","volume":"68","author":"Connell","year":"2008","journal-title":"Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3289","DOI":"10.1074\/jbc.M704461200","article-title":"Nuclear Survivin has reduced stability and is not cytoprotective","volume":"283","author":"Connell","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5999","DOI":"10.1158\/0008-5472.CAN-07-0494","article-title":"Nuclear and cytoplasmic Survivin: Molecular mechanism, prognostic, and therapeutic potential","volume":"67","author":"Stauber","year":"2007","journal-title":"Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"10638","DOI":"10.1128\/JVI.77.19.10638-10644.2003","article-title":"JC Virus-induced changes in cellular gene expression in primary human astrocytes","volume":"77","author":"Radhakrishnan","year":"2003","journal-title":"J. Virol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3247","DOI":"10.1074\/jbc.M106643200","article-title":"Transcriptional repression of the anti-apoptotic Survivin gene by wild type p53","volume":"277","author":"Hoffman","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2613","DOI":"10.1038\/sj.onc.1205353","article-title":"Human Survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway","volume":"21","author":"Mirza","year":"2002","journal-title":"Oncogene"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1002\/(SICI)1097-4644(19971101)67:2<223::AID-JCB7>3.0.CO;2-Z","article-title":"Role of cell cycle regulators in tumor formation in transgenic mice expressing the human neurotropic virus, JCV, early protein","volume":"67","author":"Krynska","year":"1997","journal-title":"J. Cell. Biochem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"7628","DOI":"10.1038\/sj.onc.1210576","article-title":"A novel role of Rac1 GTPase in JCV T-Antigen-mediated beta-catenin stabilization","volume":"26","author":"Bhattacharyya","year":"2007","journal-title":"Oncogene"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.brainresrev.2005.04.007","article-title":"Human polyomaviruses and brain tumors","volume":"50","author":"White","year":"2005","journal-title":"Brain Res. Brain Res. Rev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1097\/NEN.0b013e318180e631","article-title":"Potential mechanisms of the human Polyomavirus JC in neural oncogenesis","volume":"67","author":"White","year":"2008","journal-title":"J. Neuropathol. Exp. Neurol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/11\/1253\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:28:49Z","timestamp":1760178529000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/11\/1253"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,3]]},"references-count":59,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["v12111253"],"URL":"https:\/\/doi.org\/10.3390\/v12111253","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,3]]}}}