Anti-BK Virus Mechanisms of Sirolimus and Leflunomide Alone and in Combination: Toward a New Therapy for BK Virus Infection

Abstract

On the basis of these results, we suggest that inhibition of protein kinase pathways with a combination of sirolimus and leflunomide may be an effective therapy for BK virus reactivation. Because both sirolimus and leflunomide possess immunosuppressive activity, combination therapy may reduce BK pathogenesis while maintaining appropriate transplant immunosuppression.

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“…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.…”

“…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. 10,11 Therefore, mean leflunomide level, although slightly low in our cohort, should not explain the failure of viremia clearance.…”

“…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.…”

“…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. 8 In this retrospective cohort study, we reviewed the clinical data of all renal allograft recipients transplanted from June 2006 to December 2010 at…”