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Activity of JC virus archetype and PML-type regulatory regions in glial cells
1Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. ga5k@nih.gov.
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.
Insights
JC virus promoter variations in progressive multifocal leukoencephalopathy (PML) may enhance glial cell growth. Studies show differences in transcriptional activity but not DNA replication between archetypal and rearranged JC virus promoters.
Area of Science:
- Virology
- Neuroscience
- Molecular Biology
Background:
- JC virus (JCV) promoter/enhancer sequence variations are observed in progressive multifocal leukoencephalopathy (PML) brains.
- These variations are hypothesized to arise during PML development and potentially enhance viral growth in glial cells.
Purpose of the Study:
- To investigate whether sequence rearrangements in the JCV promoter/enhancer influence transcriptional activity and DNA replication in glial cells.
- To compare the regulatory properties of archetypal JCV promoters with those found in PML.
Main Methods:
- Analysis of archetypal and four PML-type JCV promoters in human glial cells.
- Assessment of early and late transcriptional activity using CAT reporter gene expression, with and without JCV T antigen.
- Evaluation of DNA replication activity for all promoter types.
Main Results:
- Transcriptional activity varied within a fivefold range, with PML-type promoters generally showing higher activity than the archetype.
- The archetype promoter exhibited less responsiveness to T antigen for late promoter activity compared to rearranged promoters.
- All analyzed regulatory regions demonstrated similar DNA replicating activity.
Conclusions:
- JCV promoter rearrangement is not essential for activity in glial cells.
- Sequence variations in PML-type JCV promoters can alter transcriptional regulation, particularly affecting late gene expression in response to T antigen.
- These findings suggest potential differences in the regulation of late capsid genes, which may contribute to JCV pathogenesis in PML.