The Journal of Experimental Medicine
StemCell Technologies
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Published online March 17, 2008
doi:10.1084/jem.20072097
The Journal of Experimental Medicine, Vol. 205, No. 4, 841-852
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Gosert et al.
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ARTICLE

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

Rainer Gosert1, Christine H. Rinaldo2, Georg A. Funk1, Adrian Egli1, Emilio Ramos3, Cinthia B. Drachenberg4, and Hans H. Hirsch1,5

1 Transplantation Virology and Molecular Diagnostic Laboratory, Institute for Medical Microbiology, Department of Biomedicine, University of Basel, CH-4003 Basel, Switzerland
2 Microbiology and Infection Control, University Hospital of North Norway, 9038 Tromsø, Norway
3 Department of Medicine and 4 Department of Pathology, University of Maryland Transplant Center, Baltimore, MD 21201
5 Infectious Diseases and Hospital Epidemiology, University Hospital Basel, 4031 Basel, Switzerland

CORRESPONDENCE Hans H. Hirsch: Hans.Hirsch{at}unibas.ch

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 104/ml vs. 4.4 x 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.

Abbreviations used: dat, days after transfection; geq, genome equivalent; HEK, human embryonic kidney; KT, kidney transplant; LTag, large T-antigen; NCCR, noncoding control region; PVAN, polyomavirus BK–associated nephropathy; RFP, red fluorescent protein; RPTEC, renal proximal tubular epithelial cell.


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