Leflunomide inhibition of BK virus replication in renal tubular epithelial cells.
The immunomodulatory drug leflunomide is frequently used for treating polyomavirus-associated nephropathy, yet its antiviral mechanism is unclear. We characterized the effects of the active leflunomide metabolite A771726 (LEF-A) on the polyomavirus BK (BKV) life cycle in human renal tubular epithelial cells. LEF-A at 10 microg/ml reduced the extracellular BKV load by 90% (IC(90)) but with significant host cytostatic effects. BKV genome replication, late protein expression, and virion assembly and release were inhibited with visible disruption of the nuclear replication architecture. Both host cell and antiviral effects were largely reversed by uridine addition, implicating nonspecific pyrimidine depletion as the major anti-BKV mechanism of leflunomide.
Bernhoff
Eva
E
Department of Microbiology and Infection Control, University Hospital of North Norway, P.O. Box 56, N-9038 Tromsø, Norway.
Tylden
Garth D
GD
Kjerpeseth
Lars J
LJ
Gutteberg
Tore J
TJ
Hirsch
Hans H
HH
Rinaldo
Christine H
CH
D000814:Aniline Compounds / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D001739:BK Virus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D002478:Cells, Cultured; D003437:Crotonates; D004261:DNA Replication / Q000187:drug effects; D004847:Epithelial Cells / Q000821:virology; D006801:Humans; D006885:Hydroxybutyrates / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology*; D007684:Kidney Tubules / Q000821:virology*; D000077339:Leflunomide; D046529:Microscopy, Electron, Transmission; D009570:Nitriles; D014052:Toluidines; D019562:Viral Load / Q000187:drug effects; D015678:Viral Structural Proteins / Q000378:metabolism; D019065:Virus Assembly / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
D000814:Aniline Compounds; D000998:Antiviral Agents; D003437:Crotonates; D006885:Hydroxybutyrates; D007555:Isoxazoles; D009570:Nitriles; D014052:Toluidines; D015678:Viral Structural Proteins; C527525:teriflunomide; D000077339:Leflunomide