We have compared the promoter/enhancer structure of human polyomavirus JC (JCV) isolates from 11 progressive multifocal leukoencephalopathy brains. The duplications and deletions of the regulatory region were different in each patient, and usually only one sequence was found in each. The sites of strand breakage in the promoter were not random; four or five preferred sites or areas exist. Alignment of the JCV prototype Mad-1 regulatory region with the unduplicated archetypal structure defines six blocks of sequence, A to F. The preferred sites of strand breaks delineate these regions, although Mad-1 is an unusual promoter containing a break site not observed in other isolates, and an additional site is targeted in several promoters. Region A, containing the TATA box, and the first half of region C, containing several enhancer elements, and region E are consistently retained. Region B, the 23 bp insertion in the archetypal structure (relative to Mad-1) was also retained in all 11 isolates. Region D, the 66 bp insertion, was retained in isolates from three patients. Regions A and D were never duplicated, whereas regions C and E usually were duplicated or triplicated. Variation in the exact point of breakage within the preferred sites, alternative use of the sites in individual promoters and occasional short deletions at other sites result in sequences that are unique in each case. At the same time, the limited choice of break sites and the characteristic fates of the regions themselves result in three broad patterns of repeat sequences. The patterns do not correspond to the viral genotypes 1 and 2 defined by coding region base changes, and do not appear to be a stable feature of the virus. Rather, rearrangements appear to be generated in the host from a basic archetypal sequence.

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Sequence variations are seen in the JC virus promoter/enhancer in virus taken from progressive multifocal leukoencephalopathy (PML) brains and it has been hypothesized that the variations arise in the host at some point in the development of PML. These rearrangements may be adaptations for enhanced growth in glial cells ; if so, transcription or replication levels should differ between archetypal and rearranged PML-type promoters. The archetype and four PML-type promoters were analysed in human glial cells for early and late transcriptional activity in the absence or presence of virus T antigen,