Tumor Necrosis Factor-Alpha Inhibits the Replication of Patient-Derived Archetype BK Polyomavirus While Activating Rearranged Strains

Abstract

To date, no drugs are approved for BK polyomavirus (BKPyV) reactivation, a major cause of nephropathy after kidney transplantation. Recently, tumor necrosis factor‐α (TNF‐α) blockade has been proposed as a promising therapy, however, the effect of TNF‐α on the clinically most common archetype (ww) BKPyV remained unclear. Assays in primary renal proximal tubule epithelial cells (RPTEC) allowed efficient replication only of BKPyV strains with rearranged (rr) non‐coding control regions (NCCR), which may develop at later disease stages, but not of ww‐BKPyV. Here, we optimized culture conditions allowing robust replication of patient‐derived ww‐BKPyV, while efficiently preserving their ww‐NCCR. TNF‐α promoted rr‐BKPyV replication, while the TH1 cytokine IFN‐γ suppressed it, also in the presence of TNF‐α. Surprisingly, TNF‐α alone was sufficient to suppress all ww‐BKPyV strains tested. Comprehensive analysis using siRNAs, and chimeric or mutated BKPyV‐ strains revealed that the response to TNF‐α depends on the NCCR type, and that the NF‐κB p65 pathway but not the conserved NF‐κB binding site is essential for the TNF‐α‐induced enhancement of rr‐BKPyV replication. Our data suggest that in immunosuppressed patients with archetype‐dominated infections, TNF‐α blockade could interfere with natural TNF‐α‐mediated anti‐BKPyviral control, and this could be detrimental when IFN‐γ‐driven TH1 responses are impaired. Ongoing inflammation, however, could lead to the selection of rearrangements responding to NCCR‐activating pathways downstream of NF‐κB p65 signaling, that may overcome the initial TNF‐α‐mediated suppression. Our findings also highlight the importance of using clinically relevant BKPyV isolates for drug testing and discovery, for which this new assay paves the way.