title: BK Polyomavirus Replication in Renal Tubular Epithelial Cells Is Inhibited by Sirolimus, but Activated by Tacrolimus Through a Pathway Involving FKBP-12.
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.
authors.affiliation: Transplantation & Clinical Virology, Department of Biomedicine (Haus Petersplatz), University of Basel, Basel, Switzerland.|Division Infection Diagnostics, Department of Biomedicine (Haus Petersplatz), University of Basel, Basel, Switzerland.|Infectious Diseases & Hospital Epidemiology, University Hospital Basel, Basel, Switzerland.
authors.forename: H H
authors.initials: HH
authors.lastname: Hirsch
authors.affiliation: Transplantation & Clinical Virology, Department of Biomedicine (Haus Petersplatz), University of Basel, Basel, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Yakhontova
authors.affiliation: Transplantation & Clinical Virology, Department of Biomedicine (Haus Petersplatz), University of Basel, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Lu
authors.affiliation: Transplantation & Clinical Virology, Department of Biomedicine (Haus Petersplatz), University of Basel, Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Manzetti
mesh_terms: D001739:BK Virus / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007223:Infant; D007684:Kidney Tubules / Q000378:metabolism / Q000821:virology*; D027601:Polyomavirus Infections / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology*; D016559:Tacrolimus / Q000494:pharmacology*; D022061:Tacrolimus Binding Protein 1A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014412:Tumor Virus Infections / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D022061:Tacrolimus Binding Protein 1A; D020123:Sirolimus; D016559:Tacrolimus
keywords: calcineurin inhibitor (CNI); calcineurin inhibitor: tacrolimus; immunosuppressant; infection and infectious agents; mechanistic target of rapamycin: sirolimus; viral: BK / JC / polyoma, kidney biology