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BK virus and neoplasia: An emerging role

BK, JC, and SV40 viruses are three closely related members of the polyomavirus family. These viruses have been found in a number of species, including humans, monkeys, and rodents. The first of these viruses to be identified were mouse polyomavirus and SV40, more than 40 yr ago in the 1960s, followed by JCV and BKV in the 1970s (1). Recently two new human members of polyomavirus, named WU and KI virus, have also been discovered. These were isolated from patients with respiratory symptoms (2, 3). BKV is turning out to be one of the most important members of the polyomavirus family with relevance to the transplant community. In fact, it was first isolated from the urine of a renal transplant patient (1). Several studies have shown a worldwide seroprevalence rate of approximately 80–90% in adults (4, 5). It causes an initial respiratory infection, which is usually followed by viral latency in the urogenital tract. It can subsequently reactivate in immunosuppressed transplant patients and lead to allograft nephropathy. BKV reactivation is thought to occur in 10–60% of renal transplant recipients (6). Besides its propensity to cause both acute and chronic allograft nephropathy in renal transplant recipients, BKV is also thought to have oncogenic properties. Indeed the word polyoma is derived from the virus ability to cause multiple tumors in rodents. BKV has been shown to transform rodent cells in culture (7) and cause kidney tumors in transgenic mice (8). SV40, a closely related polyomavirus, is routinely used to transform and immortalize a variety of cell lines in culture. Despite these observations, a possible role for BKV in human cancers has so far remained controversial. One possible reason for this controversy could be that a very high proportion of the adults are already exposed to the virus at a very early age in childhood, which makes it difficult to use epidemiologic methods to test its association with a cancer. Additionally, there have only been a few and inconsistent reports of identification of BKV genome or protein(s) in human cancers. However, this may be changing, and lately several reports documenting association of BKV with renal and urinary tract cancers have been published (9– 12). In this issue of the journal a well conducted study on association of BKV with CDC is reported by Emerson et al. (13). These reports are beginning to give further credence to proposed role for BK (and other polyomaviruses) in human malignancy. The BKV genome has several unique features that give it oncogenic potential. The BKV genome is small, circular, double stranded and consists of approximately 5000 bases that are packed with host cell histones (Fig. 1). The genome can be divided into three functional domains: (i) the early region that encodes regulatory proteins, including the TAg and tAg, (ii) the late region that codes for the capsid proteins VP1, VP2, VP3, and the agnoprotein, and (iii) the NCCR (14, 15). The NCCR region controls transcription of early and late regions in a divergent fashion (Fig. 1a). The early region of the BKV genome appears to be most relevant for its potential to cause tumors. The BKV TAg/tAg (which stands for tumor antigens) are coded by this region and show similarity with oncogenes found in other small DNA tumor viruses, like HPV. These early proteins are the first to be expressed during infection. After TAg accumulates to a high level, it initiates viral DNA replication in the cell nucleus by recruiting DNA polymerase complex, and stimulates expression of the late genes (VP1, VP2, VP3, and agnoprotein). In a non-productive infection, which usually occurs as a result of a cellular environment Abbreviations: BKV, BK virus; CDC, collecting duct carcinoma; Hsc, heat shock class; JCV, JC virus; NCCR, noncoding control region; PP2A, protein phosphatase 2A; RCC, renal cell carcinoma; TAg, large T-antigen; tAg, small t-antigen. Pediatr Transplantation 2008: 12: 499–502 Copyright 2008 Blackwell Munksgaard