ArticleThe Journal of infectious diseases2021
Sirolimus and Other Mechanistic Target of Rapamycin Inhibitors Directly Activate Latent Pathogenic Human Polyomavirus Replication.
Article in The Journal of infectious diseases, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 28 citations in OpenAlex.
- Successful treatment of severe, refractory polyomavirus disease with partially HLA-matched donor-derived BKPyV-specific T cells in a pediatric kidney recipient.Pediatric nephrology (Berlin, Germany) · 2026Article
- Review
- Case Report: Late-onset BK polyomavirus-associated nephropathy in kidney transplant recipients: two cases and insights into underlying mechanisms.Frontiers in medicine · 2026Review
- Can BKPyV Infection Affect Neoplasm Transformation Among Kidney Transplant Recipients? A Case Series Study Report.Journal of clinical medicine · 2025Article
- Article
- Mapping of Human Polyomavirus in Renal Cell Carcinoma Tissues.International journal of molecular sciences · 2024Article
- Phosphorylation of Human Polyomavirus Large and Small T Antigens: An Ignored Research Field.Viruses · 2023Review
- Article
- Regulation of Transcriptional Activity of Merkel Cell Polyomavirus Large T-Antigen by PKA-Mediated Phosphorylation.International journal of molecular sciences · 2023Article
- Merkel cell polyomavirus small T antigen is a viral transcription activator that is essential for viral genome maintenance.PLoS pathogens · 2022Article
- Clinicopathological features, MCPyV status and outcomes of Merkel cell carcinoma in solid-organ transplant recipients: a retrospective, multicentre cohort study.Journal of the European Academy of Dermatology and Venereology : JEADV · 2022Article
- Article
- Ischemia-Reperfusion Injury and Immunosuppressants Promote Polyomavirus Replication Through Common Molecular Mechanisms.Frontiers in immunology · 2022Article
- Functional Domains of the Early Proteins and Experimental and Epidemiological Studies Suggest a Role for the Novel Human Polyomaviruses in Cancer.Frontiers in microbiology · 2022Review
- Article
- Chk1 and the Host Cell DNA Damage Response as a Potential Antiviral Target in BK Polyomavirus Infection.Viruses · 2021Article
- Targeting nucleotide metabolism as the nexus of viral infections, cancer, and the immune response.Science advances · 2021Review
- JCPyV VP1 Mutations in Progressive MultifocalLeukoencephalopathy: Altering Tropismor Mediating Immune Evasion?Viruses · 2020Review
- Merkel Cell Polyomavirus Large T Antigen Unique Domain Regulates Its Own Protein Stability and Cell Growth.Viruses · 2020Article
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundHuman 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.
methodsIn 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.
resultsmTOR 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.
conclusionsmTOR 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.
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Registered trials
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