Therapeutic-induced chromatin remodeling via AP-1/SWI-SNF enhances BK Polyomavirus replication in urothelial cells

Hemorrhagic cystitis (HC) caused by BK polyomavirus (BKPyV) reactivation is a serious complication in immunocompromised patients especially in hematopoietic stem cell transplant recipients, yet the effects of conditioning regimens on viral replication remain undefined. Current therapies for HC are largely supportive, and no specific antiviral drugs are approved for BKPyV reactivation, underscoring an urgent need for new interventions. Here, using a cellular model of HC, we provide the first mechanistic evidence that physiologic concentrations of genotoxic chemotherapy, immune-conditioning, and antiviral exposures commonly enhance BKPyV replication by reprogramming host chromatin remodeling machinery independently of immune suppression. Transcriptomic and epigenomic profiling of urothelial cells revealed that these treatments induce host and virus chromatin remodeling, specifically, the SWI/SNF ATP-dependent remodeling complex is activated and creates a regulatory landscape enriched for AP-1 transcription factor motifs, implicating the AP-1/SWI-SNF axis as a key regulator of viral replication. Functional inhibition of SWI/SNF with AU-15330 and FHD-286 consistently suppressed BKPyV replication across all tested therapeutic conditions. Patient urine samples and cellular experiments demonstrated these effects are independent of viral genomic changes. These findings suggest chromatin remodeling as the mechanistic driver of therapy-associated BKPyV reactivation and propose SWI/SNF inhibition as a translational therapeutic strategy to mitigate hemorrhagic cystitis.