Suppression of early and chronic BK polyoma virus replication by mycophenolic acid in Vero cells

Abstract

Summary Consensus is lacking about which immunosuppressant agents potentiate BK virus infection. The effects of mycophenolic acid (MPA) were investigated in BK virus (BKV)‐infected Vero E6 cells. MPA (1–16 mg/l) exhibited a dose‐dependent anti‐viral effect (101–104 fold reduction in BKV DNA copies/ml) in supernatant, similar to cidofovir (2.5–25 mg/l). This effect was observed for early and persistent infection, and infection with noncoding control region (NCCR) rearranged BKV. MPA reduced BKV DNA copies/ml by >1 log after day 14 in three patient isolates before and after NCCR rearrangement, and in cells. MPA reduced total cellular protein levels, consistent with an anti‐metabolite effect without increased cytopathic activity. BKV infection was associated with a transient, significant reduction of collagen 1A1 on day 7 but not on days 14, 21, and 28 or in the presence of MPA. Reduction of alpha smooth muscle actin mRNA was observed only in the BKV + MPA group, and only on day 7. There was no significant alteration of heat shock protein 47 or transforming growth factor‐β mRNA expression. These in vitro data suggest that MPA may have a protective, anti‐viral effect in BKV‐infected renal tubular cells with an anti‐viral response. Maintaining, or even increasing, the MPA dose should be evaluated for reduction of BKV viremia levels.

Maintenance Immunosuppressive Agents as Risk Factors for BK Virus Nephropathy: A Case-Control Study

“…Recently, Acott et al (33) reported in vitro data on inhibitory properties of mycophenolic acid (MPA) on BK virus replication. In this study, the BK virus infected Vero cells of kidney cell origin that were cultured in MPA media (2 and 8 mg/L) were found to have greater than 1 log reduction in BK viral copies after 14 days of incubation.…”

BK Polyomavirus Replication in Renal Tubular Epithelial Cells Is Inhibited by Sirolimus, but Activated by Tacrolimus Through a Pathway Involving FKBP-12

“…Accordingly, TAC and SIR appear to influence the overall renal tubular epithelial cell milieu by rendering these cells more or less conducive to BKPyV replication, respectively (Figure 9). The direct effects of mycophenolate have been examined in monkey Vero‐E6 cells, and were reported to inhibit BKPyV replication 61, but investigating this mycophenolate effect in human RPTECs may be warranted.…”

Polyomavirus BK Replication in De Novo Kidney Transplant Patients Receiving Tacrolimus or Cyclosporine: A Prospective, Randomized, Multicenter Study

“…Although Tac and CsA both inhibit the calcineurin phosphatase required for interleukin-2 expression in T-lymphocytes subsequent to T cell receptor activation, they have different molecular targets: CsA binds to cyclophilins while tacrolimus binds to FK-binding protein 12. Interestingly, in vitro studies indicate that CsA and MPA inhibit BKV replication 31–33, whereas Tac activates BKV replication via FK-binding protein 12 in primary human tubular epithelial cells 34. The “net state of immunosuppression” coined by Rubin and Fishman 35 may be used to also integrate net effects on virus replication by different drugs as well as quantitative and qualitative differences of virus-specific T cell repertoire in the individual transplant recipients 36.…”