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.

Treatment for presumed BK polyomavirus nephropathy and risk of urinary tract cancers among kidney transplant recipients in the United States

“…Secondly, recipients with tBKVN were more likely to have received T-cell depletion induction (51.8% vs. 41.3%) and less likely to have received mTOR inhibitors (2.3% vs. 7.7%) when compared with those without tBKVN. These observations are consistent with previous reports on this topic suggesting that T-cell depletion induction is strongly correlated with increased incidence of BKVN, and that mTOR inhibitor use might be protective (45). Thirdly, recipients with tBKVN were much more likely to progress to graft failure attributed to BKVN (unadjusted IRR 19.3, 95%CI 16.1–23.2).…”

Pretransplantation Donor–Recipient Pair Seroreactivity Against BK Polyomavirus Predicts Viremia and Nephropathy After Kidney Transplantation

“…Immunosuppressive treatment with tacrolimus and rejection treatment with prednisolone have been shown to increase the risk of BKPyVAN (2,10,14,18). Despite intensive study, pretransplantation risk factors for BKPyV viremia and BKPyVAN including age, sex, ethnicity, retransplantation, immunosuppressive regimen, ischemiareperfusion injury, prior acute rejection episodes, corticosteroid therapy, percentage of panel reactive antibodies (PRA), HLA mismatches, blood group incompatibility, underlying conditions and comorbidities have not been identified (2,10,(13)(14)(15)19,20).…”

Imperfect Symmetry of Sp1 and Core Promoter Sequences Regulates Early and Late Virus Gene Expression of the Bidirectional BK Polyomavirus Noncoding Control Region

“…However, immu-nosuppressive drug-specific effects (20,30) and viral determinants (31,32) may also contribute to the evolution, kinetics, and severity of disease. At the core of what distinguishes archetype BKPyV strains with a low replicative capacity from the highly replicative strains found in kidney transplant patients are changes in the noncoding control region (NCCR) of the BKPyV genome (33).…”