Polyomavirus BK with rearranged noncoding control region emerge in vivo in renal transplant patients and increase viral replication and cytopathology
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 plas...
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Published in | The Journal of experimental medicine Vol. 205; no. 4; pp. 841 - 852 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
The Rockefeller University Press
14.04.2008
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 CORRESPONDENCE Hans H. Hirsch: Hans.Hirsch@unibas.ch 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. |
ISSN: | 0022-1007 1540-9538 1892-1007 |
DOI: | 10.1084/jem.20072097 |