NONCODING CONTROL REGION OF NATURALLY-OCCURRING BK VIRUS VARIANTS - SEQUENCE COMPARISON AND FUNCTIONAL-ANALYSIS

The human polyomavirus BK (BKV) has a proven oncogenic potential, but its contribution to tumorigenesis under natural conditions remains und etermined. As for other primate polyomaviruses, the approximately 5.2 kbp double-stranded circular genome of BKV has three functional region s: 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 of cis-acting elements involved in t he regulation of both early and late transcription. Since the original isolation of BKV in 1971, a number of other strains have been identif ied. Most strains reveal a strong sequence conservation in the protein coding regions of the genome, while the NCCR exhibits considerable va riation between different BKV isolates. This variation is due to delet ions, duplications, and rearrangements of a basic set of sequence bloc ks. Comparative studies have proven that the anatomy of the NCCR may d etermine the transcriptional activities governed by the promoter/enhan cer, the host cell tropism and permissivity, as well as the oncogenic potential of a given BKV strain. In most cases, however, the NCCR sequ ence of new isolates was determined after the virus had been passaged several times in more or less arbitrarily chosen cell cultures, a proc ess known to predispose for NCCR rearrangements. Following the develop ment 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 propa gation of the virus in cell culture. Such variation has general intere st, because the BKV NCCRs represent typical mammalian promoter/enhance rs, with a large number of binding motifs for cellular transacting fac tors, which can be conveniently handled for experimental purposes. Thi s communication reviews the naturally occurring BKV NCCR variants, iso lated and sequenced directly from human samples, that have been report ed so far. The sequences of the different NCCRs are compared and analy zed for the presence of proven and putative cellular transcription fac tor binding sites. Differences in biological properties between BKV va riants are discussed in light of their aberrant NCCR anatomies and the potentially modifying influence of transacting factors.