Summary auto-generated
JC virus (JCV) is a human polyomavirus that causes progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease in immunosuppressed patients. The viral regulatory region controlling early and late gene transcription exists in two forms: an archetype found in urine and kidneys, and rearranged PML-type variants found in brain tissue from PML patients. This study investigated whether regulatory region rearrangements enhance viral activity in glial cells, the primary target tissue. Using reporter gene assays in human glioblastoma cells, the archetype promoter was compared with four PML-type promoters for early and late transcriptional activity, with and without viral T antigen protein. Transcriptional activity varied within a fivefold range, with the archetype showing intermediate strength compared to PML-type promoters. A key functional difference emerged: the archetype's late promoter was less responsive to T antigen stimulation than rearranged promoters, and the shift from early to late transcription upon T antigen presence was less pronounced in the archetype. DNA replication levels were similar across all regulatory regions. These findings suggest that promoter rearrangement is not required for glial cell activity, but may specifically enhance late gene regulation during the viral lytic cycle.
Key findings
- The archetype JCV promoter is transcriptionally active in glial cells and equally or more active than some PML-type rearranged promoters
- The archetype late promoter shows reduced responsiveness to T antigen stimulation compared to all four PML-type promoters, which showed 140-240% increases versus 59% for archetype
- All five regulatory regions demonstrated similar DNA replication levels, indicating rearrangement does not enhance replication capability
- Promoter rearrangement creates a functional shift in the ratio of early to late transcription activity, particularly in response to T antigen presence
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Abstract
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, and for DNA replication. CAT reporter expression differed within a fivefold range and the archetype was intermediate in strength to the PML-type regulatory regions. The archetype differed from rearranged promoters in that the late promoter was less responsive to T antigen and the shift from early to late activity with T antigen was less pronounced. All five regulatory regions demonstrated similar levels of DNA replicating activity. Rearrangement of the archetype was not required for activity in glial cells, but the potential for differences in the regulation of the late capsid genes was found.