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Am J Transplant. 2016 Mar;16(3):821-32. doi: 10.1111/ajt.13541. Epub 2015 Dec 7.

BK Polyomavirus Replication in Renal Tubular Epithelial Cells Is Inhibited by Sirolimus, but Activated by Tacrolimus Through a Pathway Involving FKBP-12.

Author information

1
Transplantation & Clinical Virology, Department of Biomedicine (Haus Petersplatz), University of Basel, Basel, Switzerland.
2
Division Infection Diagnostics, Department of Biomedicine (Haus Petersplatz), University of Basel, Basel, Switzerland.
3
Infectious Diseases & Hospital Epidemiology, University Hospital Basel, Basel, Switzerland.

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.

KEYWORDS:

calcineurin inhibitor (CNI); calcineurin inhibitor: tacrolimus; immunosuppressant; infection and infectious agents; mechanistic target of rapamycin: sirolimus; viral: BK / JC / polyoma, kidney biology

PMID:
26639422
PMCID:
PMC5064607
DOI:
10.1111/ajt.13541
[Indexed for MEDLINE]
Free PMC Article

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