Leflunomide Inhibition of BK Virus Replication in Renal Tubular Epithelial Cells

Abstract

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 g/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.

Characterization of Immunodominant BK Polyomavirus 9mer Epitope T Cell Responses

“…PyVAN and PyVHC have a significant impact on morbidity and graft and patient survival 11, 12, 13, 14, 15, 16, 17, 18. Despite considerable virologic research 19, 20, 21, 22, 23, randomized clinical studies either are lacking or failed to demonstrate effective antiviral therapies 24. In kidney transplantation (KT), high‐level BKPyV viruria and viremia have been identified as markers of progression to PyVAN 25, thus current management strategies recommend screening KTRs for viremia followed by reducing immunosuppression 26, 27, 28.…”

Leflunomide an Immunosuppressive Drug for Antiviral Purpose in Treatment for BK Virus-Associated Nephropathy After Kidney Transplantation

“…Finally to date, no link between plasma concentrations and side effects has been shown (Bazin et al 2009). Yet in vitro studies seem to show a predictive correlation between concentrations and the www.intechopen.com viral inhibitory effect: 10 µg/mL reduced the extracellular BKV load by 90% (IC90) but with significant host cytostatic effects (see figure 2) (Bernhoff et al 2010). (Bernhoff et al 2010) …”

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“…In addition to its immunosuppressive property, leflunomide significantly inhibits BK virus DNA replication in vitro. 8,9 Sirolimus also is an interesting option because inhibition of the mTOR pathway can impair BK virus large T protein expression. 8 In 2010, Liacini and associates reported the use of leflunomide in combination with sirolimus to inhibit the protein kinase pathway in vivo.…”

“…A771726, the active metabolite of leflunomide, has antiviral effect by inhibiting pyrimidine synthesis at a low level (10 μg/mL) and tyrosine kinase at high level. 8,9 The effect on BK virus replication can be reversed by the addition of uridine at a leflunomide level of 10 μg/mL. 8,9 With leflunomide levels ≥ 40 μg/mL, the effect on BK virus replication cannot be reversed in vitro.…”

“…8,9 The effect on BK virus replication can be reversed by the addition of uridine at a leflunomide level of 10 μg/mL. 8,9 With leflunomide levels ≥ 40 μg/mL, the effect on BK virus replication cannot be reversed in vitro. 8 Nevertheless, the effect of high leflunomide level on BK virus replication remains controversial in vivo.…”