Polyomavirus BK with rearranged noncoding control region emerge in vivo in renal transplant patients and increase viral replication and cytopathology

Abstract

Immunosuppression is required for BK viremia and polyomavirus BK–associated nephropathy (PVAN) in kidney transplants (KTs), but the role of viral determinants is unclear. We examined BKV noncoding control regions (NCCR), which coordinate viral gene expression and replication. In 286 day–matched plasma and urine samples from 129 KT patients with BKV viremia, including 70 with PVAN, the majority of viruses contained archetypal (ww-) NCCRs. However, rearranged (rr-) NCCRs were more frequent in plasma than in urine samples (22 vs. 4%; P < 0.001), and were associated with 20-fold higher plasma BKV loads (2.0 × 104/ml vs. 4.4 × 105/ml; P < 0.001). Emergence of rr-NCCR in plasma correlated with duration and peak BKV load (R2 = 0.64; P < 0.001). This was confirmed in a prospective cohort of 733 plasma samples from 227 patients. For 39 PVAN patients with available biopsies, rr-NCCRs were associated with more extensive viral replication and inflammation. Cloning of 10 rr-NCCRs revealed diverse duplications or deletions in different NCCR subregions, but all were sufficient to increase early gene expression, replication capacity, and cytopathology of recombinant BKV in vitro. Thus, rr-NCCR BKV emergence in plasma is linked to increased replication capacity and disease in KTs.

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

“…This suggests that the susceptibility to BKPyV might be enhanced by the transformed phenotype of cancer host cells, which often involve altered signal transduction and metabolic pathways 54, 55. For our study, we used the well‐characterized BKPyV(Dun) strain, which is derived from the original Gardner strain 56, and replicates similarly to natural variants found in KT patients 16. Also, different donor sources of RPTECs were used with indistinguishable results, suggesting that our results would apply to most KT recipients.…”

Mutations in the BC‐loop of the BKV VP1 region do not influence viral load in renal transplant patients

“…The variation of NCCRs has been described in renal transplant patients and is associated with an increased replication and the onset of BKVAN [Gosert et al, 2008;Olsen et al, 2006]. In contrast to the architectural rearrangement of NCCRs, the consequences of mutations within the VP1-loop have not been examined in vivo.…”

“…The reasons for the reactivation of BKV are not well understood. Among various other discussed risk factors, virus-specific determinants were investigated as well [Smith et al, 1998;Boldorini et al, 2001;Chen et al, 2001;Randhawa et al, 2003;Carr et al, 2006;Gosert et al, 2008]. The polyomavirus genome encodes for the agnoprotein, the capsid proteins VP1-3 and the small and large T-antigen.…”

The human JC polyomavirus (JCPyV): virological background and clinical implications

“…The NCCR sequence showed no rearrangements indicating that the pathology of JCPyVAN occurs without rr-NCCR. This is similar to BKPyVAN, which arises with at-NCCR BKPyV that are, however, subsequently replaced by rr-NCCR BKPyV variants as majority species if uncontrolled virus replication has been ongoing for some time (243). The factors permitting relatively high-level replication of the JCPyV archetype in the urinary tract of immunocompetent individuals and causing invasive renal disease in some kidney transplant and HIV patients are currently undefined.…”