NDT Advance Access originally published online on September 9, 2008
Nephrology Dialysis Transplantation 2008 23(12):3752-3761; doi:10.1093/ndt/gfn470
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BK virus large T and VP-1 expression in infected human renal allografts
1 Institute for Pathology, University Hospital Basel, Schönbeinstrasse 40, CH-4003 Basel, Switzerland 2 Institute of Virology, University Hospital Essen, Hufelandstrasse 55, D-45122 Essen, Germany 3 Clinic for Transplantation Immunology and Nephrology, University Hospital Baseland 4 Transplantation Virology, Medical Microbiology, University of Basel, CH-4003 Basel, Switzerland
Correspondence and offprint requests to: Michael J. Mihatsch, Institute for Pathology, University Hospital Basel, Schönbeinstrasse 40, CH-4003 Basel, Switzerland. Tel: +41-61-265-2872; Fax: +41-61-265-3194; E-mail: mjmihatsch{at}uhbs.ch
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Abstract |
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Objective. We investigated the expression of early and late phase BK virus (BKV) proteins and their interactions with host cell proteins in renal allografts, with ongoing polyomavirus associated nephropathy (PVAN), and correlated this with the nuclear and cell morphology.
Methods. Frozen sections from three patients with renal allografts (two biopsies, one explant) with PVAN were analysed by indirect immunofluorescence using BKV specific anti-polyoma large T-antigen and anti-VP-1 antibodies, as well as anti-p53, anti-Ki67, anti-caspase-3, anti-bcl2 and anti-cytokeratin 22 antibodies. Nuclear morphology and size were estimated by DNA Hoechst staining.
Results. In infected tubular cells the early and late phases of infection could be distinguished according to expression of large T-antigen or VP-1. The early phase revealed almost normal nuclear proportions, whereas in later phases nuclear size increased about 2 to 3 fold. Expression of large T-antigen was strongly associated with accumulation of p53 in the nucleus, accompanied by the activation of the cell cycle associated cell protein Ki67. In contrast, expression of BKV VP1 correlated only weakly with p53. Virus dependent cell lysis was due to necrosis, since neither caspase 3 nor nuclear nor cytoskeleton changes indicated apoptosis.
Conclusion. In our selected patients with PVAN a clear distinction between early and late phases was possible, according to the protein expression patterns of BKV markers. Striking nuclear enlargement is only present in the late phase of infection. In the inflammatory setting of PVAN, BKV dependent effects appear to be mediated by the inhibition of p53, resulting in the activation of the cell cycle. We assume that in PVAN similar BKV mechanisms are operative as in certain in vitro systems.
Keywords: BK virus nephropathy; renal transplantation
Received for publication: 2. 7.08
Accepted in revised form: 25. 7.08
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