Abstract
BackgroundPolyomavirus JC (JCV) causes the CNS demyelinating disease progressive multifocal leukoencephalopathy (PML), which occurs almost exclusively in people with immune deficiencies, such as HIV-1/AIDS patients. JCV infection is very common and usually occurs early in life. After primary infection, virus is controlled by the immune system but, rarely when immune function is impaired, it can re-emerge and multiply in the astrocytes and oligodendrocytes in the brain and cause PML. Thus a central question in PML pathogenesis is the nature of the molecular mechanisms maintaining JCV in a latent state and then allowing reactivation.MethodsSince transcription can be regulated by epigenetic mechanisms including DNA methylation and histone acetylation, we investigated their role in JCV regulation by employing inhibitors of epigenetic events.ResultsThe histone deacetylase inhibitors trichostatin A (TSA) and sodium butyrate powerfully stimulated JCV early and late transcription while the DNA methylation inhibitor 5-azacytidine had no effect. Analysis of JCV mutants showed that this effect was mediated by the KB element of the JCV control region, which binds transcription factors NF-κB p65, NFAT4 and C/EBPβ and mediates stimulation by TNF-α. Stimulation of transcription by p65 was additive with TSA as was cotransfection with transcriptional coactivators/acetyltransferase p300 whereas depletion of endogenous p65 by RNA interference inhibited the effect of TSA. EMSA with a KB oligonucleotide showed p65 expression, TNF-α stimulation or TSA treatment each caused a gel shift that was further shifted by antibody to p65.ConclusionsWe conclude that JCV is regulated epigenetically by protein acetylation events and that these involve the NF-κB p65 binding site in the JCV control region.
Highlights
Polyomavirus JC (JCV) causes the CNS demyelinating disease progressive multifocal leukoencephalopathy (PML), which occurs almost exclusively in people with immune deficiencies, such as HIV-1/AIDS patients
Since these transcription factors are regulated by signal transduction pathways that are controlled by extracellular cytokines, we have suggested that control of the latency/reactivation of JC virus (JCV) may be regulated by cytokines acting through the KB element
We have found that cytokines including TNF-α and IL-1β stimulate JCV early and late transcription and that this is mediated through the KB element [9]
Summary
Polyomavirus JC (JCV) causes the CNS demyelinating disease progressive multifocal leukoencephalopathy (PML), which occurs almost exclusively in people with immune deficiencies, such as HIV-1/AIDS patients. JC virus (JCV) is a human neurotropic polyomavirus and is the causative agent of progressive multifocal leukoencephalopathy, PML, which is a fatal demyelinating disease of the brain that involves the cytolytic destruction of oligodendrocytes by JCV replication. After the primary infection virus persists in a latent state and further sequelae only occur in people with severe immunosuppression where viral reactivation leads to PML. Many important aspects of the JCV life cycle and the pathogenesis of PML remain unclear including the nature of the latent state, the mechanisms whereby it is maintained and the regulation of restoration of viral transcription/replication when virus reactivates and causes PML
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