Noncoding control region of naturally occurring BK virus variants: Sequence comparison and functional analysis

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Abstract
The human polyomavirus BK (BKV) has a proven oncogenic potential, but its contribution to tumorigenesis under natural conditions remains undetermined. As for other primate polyomaviruses, the approximately 5.2 kbp double-stranded circular genome of BKV has three functional regions: the coding regions for the two early (T, t antigens) and four late (agno, capsid proteins; VP1-3) genes separated by a noncoding control region (NCCR). The NCCR contains the origin of replication as well as a promoter/enhancer with a mosaic ofcis-acting elements involved in the regulation of both early and late transcription. Since the original isolation of BKV in 1971, a number of other strains have been identified. Most strains reveal a strong sequence conservation in the protein coding regions of the genome, while the NCCR exhibits considerable variation between different BKV isolates. This variation is due to deletions, duplications, and rearrangements of a basic set of sequence blocks. Comparative studies have proven that the anatomy of the NCCR may determine the transcriptional activities governed by the promoter/enhancer, the host cell tropism and permissivity, as well as the oncogenic potential of a given BKV strain. In most cases, however, the NCCR sequence of new isolates was determined after the virus had been passaged several times in more or less arbitrarily chosen cell cultures, a process known to predispose for NCCR rearrangements. Following the development of the polymerase chain reaction (PCR), it has become feasible to obtain naturally occurring BKV NCCRs, and their sequences, in samples taken directly from infected human individuals. Hence, the biological significance of BKV NCCR variation may be studied without prior propagation of the virus in cell culture. Such variation has general interest, because the BKV NCCRs represent typical mammalian promoter/enhancers, with a large number of binding motifs for cellular transacting factors, which can be conveniently handled for experimental purposes. This communication reviews the naturally occurring BKV NCCR variants, isolated and sequenced directly from human samples, that have been reported so far. The sequences of the different NCCRs are compared and analyzed for the presence of proven and putative cellular transcription factor binding sites. Differences in biological properties between BKV variants are discussed in light of their aberrant NCCR anatomies and the potentially modifying influence of transacting factors.