Caocci, Maurizio (2018) IFNα-mediated suppression of JCV is mTOR pathway dependend. Doctoral Thesis.
The severe demyelinating disease progressive multifocal leukoencephalopathy (PML) is caused by the neurotropic polyomavirus JC (JCV), which replicates in oligodendrocytes and astrocytes in the brain. Infection by JCV is very common and is widespread worldwide, but PML occurs very rarely. Primary infection occurs early in life, usually in childhood, but the virus is contained by the action of immune system and subsequently persists asymptomatically. Initiation of PML occurs occasionally under conditions of immune dysfunction and results from the reactivation of persistent virus from an inactivate state to replicate lytically. Our earlier studies suggest that reactivation occurs within glial cells due to the action of cytokines, e.g. TNF-alpha, stimulating viral gene expression. In this study, we have now examined the cytokine interferon-alpha (IFN-alpha), which, in contrast, has a negative effect on JCV gene expression and replication. IFN-alpha and IFN-beta inhibited the replication of JCV in primary human fetal astrocytes and reduced transcription by JCV promoter reporter constructs in oligodendroglioma cells. We found that IFN-α treatment of glial cells induced expression of STAT1 and caused STAT1 phosphorylation and translocation to the nucleus. Other downstream signaling events were also examined including PI3K/Akt and mTOR and inhibition of PI3K with LY294002 was found to enhance JCV replication while rapamycin inhibition of mTOR affected STAT1 translocation to the nucleus. We conclude that pathways downstream of IFN-alpha negatively regulate JCV gene expression and replication and this may present new therapeutic opportunities for PML.
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