Brincidofovir (CMX001) Inhibits BK Polyomavirus Replication in Primary Human Urothelial Cells

Abstract

e BK polyomavirus (BKPyV)-associated hemorrhagic cystitis (PyVHC) complicates 5 to 15% of allogeneic hematopoietic stem cell transplantations. Targeted antivirals are still unavailable. Brincidofovir (BCV; previously CMX001) has shown inhibitory activity against diverse viruses, including BKPyV in a primary human renal tubule cell culture model of polyomavirus-associated nephropathy. We investigated the effects of BCV in BKPyV-infected and uninfected primary human urothelial cells (HUCs), the target cells of BKPyV in PyVHC. The BCV concentrations causing 50 and 90% reductions (EC 50 and EC 90 ) in the number of intracellular BKPyV genome equivalents per cell (icBKPyV) were 0.27 M and 0.59 M, respectively. At 0.63 M, BCV reduced viral late gene expression by 90% and halted progeny release. Preinfection treatment for only 24 h reduced icBKPyV similarly to treatment from 2 to 72 h postinfection, while combined pre-and postinfection treatment suppressed icBKPyV completely. After investigating BCV's effects on HUC viability, mean selectivity indices at 50 and 90% inhibition (SI 50 and SI 90 ) calculated for cellular DNA replication were 2.7 and 2.9, respectively, those for mitochondrial activity were 8.9 and 10.4, those for total ATP were 8.6 and 8.2, and those for membrane integrity were 25.9 and 16.7. The antiviral and cytostatic effects, but less so the cytotoxic effects, were inversely related to cell density. The cytotoxic effects at concentrations of >10 M were rapid and likely related to BCV's lipid moiety. After carefully defining the antiviral, cytostatic, and cytotoxic properties of BCV in HUCs, we conclude that a preemptive or prophylactic approach in PyVHC is likely to give the best results.T he ubiquitous and usually quiescent BK polyomavirus (BKPyV) causes polyomavirus-associated nephropathy (PyVAN) and hemorrhagic cystitis (PyVHC) following kidney and hematopoietic stem cell transplantation (HSCT), respectively (1).PyVHC afflicts 5 to 15% of HSCT patients after engraftment (2-5). The pathogenesis of PyVHC is incompletely characterized but is believed to involve initial iatrogenic damage to the bladder mucosa during pretransplantation conditioning, which is subsequently aggravated by lytic BKPyV replication in urothelial cells in the absence of immune surveillance. This leads to exposure of both viral and host epitopes to the foreign, engrafting lymphoid cells and may contribute to graft-versus-host disease (GVHD) (6-10). Inflammation and the resultant denudation of the urothelium cause hemorrhagic cystitis ranging from microhematuria to macrohematuria, clot-related urinary retention, and postrenal failure (reviewed in reference 5).PyVAN occurs in transplanted kidneys in 1 to 10% of recipients and often results in graft loss via a combination of lytic and inflammatory destruction of the renal parenchyma (2, 5). The initial reactivation signal is unknown, but mathematical modeling supports initial reactivation in the tubular epithelial compartment, followed by viral efflux with amplification in the uroth...

Native kidney BK virus nephropathy, a systematic review

“…There is an extensive literature in the renal transplant population detailing use of mammalian target of rapamycin (mTOR) inhibitors, leflunomide, flouroquinolones, cidofovir, and intravenous immunoglobulin (IVIg) for the treatment of BKVN, but none have been shown to be particularly effective . Further research is ongoing, with newer agents such as brincidofovir, virus‐specific T lymphocytes, and IVIg being currently studied …”

BK virus: Current understanding of pathogenicity and clinical disease in transplantation

“…Brincidofovir is an oral lipid ester prodrug of cidofovir that has demonstrated promising antiviral action against several DNA viruses . It acts in a similar way to cidofovir by competitively inhibiting viral DNA synthesis . The lipid formulation allows for higher potency with intracellular release and dramatically reduced renal toxicity compared with the parent drug.…”

Antiviral Treatments

“…[114][115][116] Phase 2 trials are underway in hospitalized patients and adult HSCT and lung transplant recipients. [117][118][119][120] ALS-8176 ALS-8176, a nucleoside analogue targeting RSV polymerase, showed reduction of viral load and decreased disease severity in a human challenge model. 121 Studies in hospitalized infants are ongoing.…”