Abstract
ObjectivePML is a rare and fatal demyelinating disease of the CNS caused by the human polyomavirus, JC virus (JCV), which occurs in AIDS patients and those on immunosuppressive monoclonal antibody therapies (mAbs). We sought to identify mechanisms that could stimulate reactivation of JCV in a cell culture model system and targeted pathways which could affect early gene transcription and JCV T-antigen production, which are key steps of the viral life cycle for blocking reactivation of JCV. Two important regulatory partners we have previously identified for T-antigen include Pur-alpha and SRSF1 (SF2/ASF). SRSF1, an alternative splicing factor, is a potential regulator of JCV whose overexpression in glial cells strongly suppresses viral gene expression and replication. Pur-alpha has been most extensively characterized as a sequence-specific DNA- and RNA-binding protein which directs both viral gene transcription and mRNA translation, and is a potent inducer of the JCV early promoter through binding to T-antigen.Methods and ResultsPur-alpha and SRSF1 both act directly as transcriptional regulators of the JCV promoter and here we have observed that Pur-alpha is capable of ameliorating SRSF1-mediated suppression of JCV gene expression and viral replication. Interestingly, Pur-alpha exerted its effect by suppressing SRSF1 at both the protein and mRNA levels in glial cells suggesting this effect can occur independent of T-antigen. Pur-alpha and SRSF1 were both localized to oligodendrocyte inclusion bodies by immunohistochemistry in brain sections from patients with HIV-1 associated PML. Interestingly, inclusion bodies were typically positive for either Pur-alpha or SRSF1, though some cells appeared to be positive for both proteins.ConclusionsTaken together, these results indicate the presence of an antagonistic interaction between these two proteins in regulating of JCV gene expression and viral replication and suggests that they play an important role during viral reactivation leading to development of PML.
Highlights
Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the brain caused by the reactivation of JC virus from a low level persistent state
Pur-alpha and SRSF1 both act directly as transcriptional regulators of the JC virus (JCV) promoter and here we have observed that Pur-alpha is capable of ameliorating SRSF1-mediated suppression of JCV gene expression and viral replication
Pur-alpha exerted its effect by suppressing SRSF1 at both the protein and mRNA levels in glial cells suggesting this effect can occur independent of T-antigen
Summary
Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the brain caused by the reactivation of JC virus from a low level persistent state. PML has been reported as an adverse event in the context of treatment of other auto-immune disorders with a variety of monoclonal antibody therapies, suggesting that immunosuppression can predispose these patients to the development of PML as well. These include efalizumab (Raptiva) for the treatment of plaque psoriasis, which targets CD11a on T cells [4] and three monoclonal antibodies targeting TNF-alpha, adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade) for the treatment of psoriasis, rheumatoid arthritis, and Crohn's disease. The only option for PML patients is reduction in immunosuppression or restoration of underlying immune impairment. A broad range of drugs, some with potential anti-viral mechanisms of action have been tested and have failed at controlling JC virus replication and halting its progression in PML patients
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