title: 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 x 10(4)/ml vs. 4.4 x 10(5)/ml; P < 0.001). Emergence of rr-NCCR in plasma correlated with duration and peak BKV load (R(2) = 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.
authors.affiliation: Transplantation Virology and Molecular Diagnostic Laboratory, Institute for Medical Microbiology, Department of Biomedicine, University of Basel, CH-4003 Basel, Switzerland.
authors.forename: Rainer
authors.initials: R
authors.lastname: Gosert
authors.forename: Christine H
authors.initials: CH
authors.lastname: Rinaldo
authors.forename: Georg A
authors.initials: GA
authors.lastname: Funk
authors.forename: Adrian
authors.initials: A
authors.lastname: Egli
authors.forename: Emilio
authors.initials: E
authors.lastname: Ramos
authors.forename: Cinthia B
authors.initials: CB
authors.lastname: Drachenberg
authors.forename: Hans H
authors.initials: HH
authors.lastname: Hirsch
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001739:BK Virus / Q000235:genetics* / Q000502:physiology*; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral; D004279:DNA, Viral / Q000097:blood / Q000235:genetics* / Q000652:urine; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D027601:Polyomavirus Infections / Q000473:pathology / Q000821:virology; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D014412:Tumor Virus Infections / Q000473:pathology / Q000821:virology; D014760:Viral Fusion Proteins / Q000378:metabolism; D019562:Viral Load; D014766:Viremia; D014779:Virus Replication
chemical_list: D004279:DNA, Viral; D014760:Viral Fusion Proteins