BK Polyomavirus Genetic Diversity and Evolution in Kidney Transplant Recipients with Viral Nephropathy Using Whole Genome Sequencing.

Abstract

Among kidney transplant recipients (KTR) with BKPyV associated nephropathy (BKPyVN), the dynamics of BKPyV replication are not well established. We aim to investigate BKPyV genetic diversity and evolution following kidney transplantation. We retrospectively analyzed 32 KTR with a biopsy-proven diagnosis of BKPyVN. Stored plasma and kidney biopsies were tested for BKPyV viral load, and BKPyV whole genome sequencing (WGS) performed on BKPyV-positive samples. A total of 104 samples positive for BKPyV DNA detection were sequenced, among which 83 were included in the analysis. BKPyV-I was the most frequent genotype detected, followed by BKPyV-IVc2 and BKPyV-II. At BKPyVN diagnosis (median time: 12 [8-17] months post-transplant), WGS identified the same BKPyV-subtype in the plasma and kidney biopsy for all patients but one. Alignment of BKPyV consensus sequences between the two compartments at the time of BKPyVN showed similarity > 99%, but identified single nucleotide polymorphisms in 13/23 of the cases, including 25% APOBEC-associated mutations. Among the 16 KTR with ≥ 2 consecutive BKPyV-positive samples available for analysis, consensus sequence showed a different BKPyV subtype in pre-BKPyVN kidney biopsies compared to BKPyVN in 9 patients. Before BKPyVN diagnosis, minority variants on VP1 sequence were identified in 10/11 kidney biopsy and 5/10 plasma samples. Among KTR with BKPyVN, we show that BKPyV viral populations change over time, with the coexistence of several viral populations in early samples compared to BKPyVN, as a result of both APOBEC-mediated editing and replication-driven diversification within the kidney allograft.