Hirsch, H. H. and Yakhontova, K. and Lu, M. and Manzetti, J.. (2016) BK Polyomavirus Replication in Renal Tubular Epithelial Cells Is Inhibited by Sirolimus, but Activated by Tacrolimus Through a Pathway Involving FKBP-12. Am J Transplant, 16 (3). pp. 821-832.
Full text not available from this repository.
Official URL: https://edoc.unibas.ch/61885/
Downloads: Statistics Overview
Abstract
BK polyomavirus (BKPyV) replication causes nephropathy and premature kidney transplant failure. Insufficient BKPyV-specific T cell control is regarded as a key mechanism, but direct effects of immunosuppressive drugs on BKPyV replication might play an additional role. We compared the effects of mammalian target of rapamycin (mTOR)- and calcineurin-inhibitors on BKPyV replication in primary human renal tubular epithelial cells. Sirolimus impaired BKPyV replication with a 90% inhibitory concentration of 4 ng/mL by interfering with mTOR-SP6-kinase activation. Sirolimus inhibition was rapid and effective up to 24 h postinfection during viral early gene expression, but not thereafter, during viral late gene expression. The mTORC-1 kinase inhibitor torin-1 showed a similar inhibition profile, supporting the notion that early steps of BKPyV replication depend on mTOR activity. Cyclosporine A also inhibited BKPyV replication, while tacrolimus activated BKPyV replication and reversed sirolimus inhibition. FK binding protein 12kda (FKBP-12) siRNA knockdown abrogated sirolimus inhibition and increased BKPyV replication similar to adding tacrolimus. Thus, sirolimus and tacrolimus exert opposite effects on BKPyV replication in renal tubular epithelial cells by a mechanism involving FKBP-12 as common target. Immunosuppressive drugs may therefore contribute directly to the risk of BKPyV replication and nephropathy besides suppressing T cell functions. The data provide rationales for clinical trials aiming at reducing the risk of BKPyV replication and disease in kidney transplantation.
Faculties and Departments: | 03 Faculty of Medicine > Departement Biomedizin > Division of Medical Microbiology > Transplantation Virology (Hirsch) |
---|---|
UniBasel Contributors: | Hirsch, Hans H. |
Item Type: | Article, refereed |
Article Subtype: | Research Article |
ISSN: | 1600-6143 (Electronic) 1600-6135 (Linking) |
Note: | Publication type according to Uni Basel Research Database: Journal article |
Related URLs: | |
Identification Number: |
|
Last Modified: | 31 May 2020 21:18 |
Deposited On: | 31 May 2020 21:18 |
Repository Staff Only: item control page