Positive net antiviral benefit of bexarotene against patient-derived archetype and rearranged BK polyomavirus...

BK polyomavirus (BKPyV) reactivation can lead to allograft failure in kidney transplant recipients, yet no approved antivirals exist. Although archetype (ww-) strains predominate in patients, drug screening predominantly utilizes laboratory-adapted rearranged (rr-) strains, potentially limiting therapeutic translation. In this study, we employed a new replication assay to evaluate antiviral activity of retinoids and CDK inhibitors against patient-derived ww- and rr-BKPyV isolates. A viral dynamics model was used to estimate the net antiviral benefit (NAB) of compounds to identify antiviral effects independent of cell growth inhibition. As a result, bexarotene and fenretinide were effective against various patient-derived ww- and rr-BKPyV isolates. They had a stronger antiviral activity than acitretin, which was more strain-specific and tazarotenic acid showing only modest effects. In the model integrating all experimental datasets, bexarotene had a positive NAB in a broad concentration range with an EC₅₀ comparable to peak plasma levels observed in clinical trials. However, fenretinide displayed a positive NAB within a narrower concentration range. The CDK inhibitors Ro-3306 and roscovitine exhibited limited or no positive NAB, respectively. Notably, although the mTOR inhibitor sirolimus appeared to have additive antiviral effects when applied together with bexarotene, it displayed a negative NAB, rather attributing its activity to changes on cell growth/viability. In summary, bexarotene represents a promising therapeutic repurposing candidate for BKPyV reactivation in transplant patients, suggesting clinically achievable therapeutic efficacy. Clinical validation is warranted to translate these findings into therapeutic solutions for transplant recipients.