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


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • BK Virus / physiology*
  • Blotting, Western
  • Cells, Cultured
  • Epithelial Cells / metabolism
  • Epithelial Cells / virology*
  • Fluorescent Antibody Technique
  • Humans
  • Immunosuppressive Agents / therapeutic use
  • Infant
  • Kidney Tubules / metabolism
  • Kidney Tubules / virology*
  • Polyomavirus Infections / drug therapy
  • Polyomavirus Infections / metabolism
  • Polyomavirus Infections / virology
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sirolimus / pharmacology*
  • Tacrolimus / pharmacology*
  • Tacrolimus Binding Protein 1A / antagonists & inhibitors
  • Tacrolimus Binding Protein 1A / genetics
  • Tacrolimus Binding Protein 1A / metabolism*
  • Tumor Virus Infections / drug therapy
  • Tumor Virus Infections / metabolism
  • Tumor Virus Infections / virology
  • Virus Replication / drug effects*


  • Immunosuppressive Agents
  • RNA, Messenger
  • RNA, Small Interfering
  • Tacrolimus Binding Protein 1A
  • Sirolimus
  • Tacrolimus