Abstract
ObjectivePatients undergoing immune modulatory therapies for the treatment of autoimmune diseases such as multiple sclerosis, and individuals with an impaired-immune system, most notably AIDS patients, are in the high risk group of developing progressive multifocal leukoencephalopathy (PML), an often lethal disease of the brain characterized by lytic infection of oligodendrocytes in the central nervous system (CNS) with JC virus (JCV). The immune system plays an important regulatory role in controlling JCV reactivation from latent sites by limiting viral gene expression and replication. However, little is known regarding the molecular mechanisms responsible for this regulation.Methods and ResultsHere, we investigated the impact of soluble immune mediators secreted by activated PBMCs on viral replication and gene expression by cell culture models and molecular virology techniques. Our data revealed that viral gene expression and viral replication were suppressed by soluble immune mediators. Further studies demonstrated that soluble immune mediators secreted by activated PBMCs inhibit viral replication induced by T-antigen, the major viral regulatory protein, by suppressing its expression in glial cells. This unexpected suppression of T-antigen was mainly associated with the suppression of translational initiation. Cytokine/chemokine array studies using conditioned media from activated PBMCs revealed several candidate cytokines with possible roles in this regulation. Among them, only IFN-γ showed a robust inhibition of T-antigen expression. While potential roles for IFN-β, and to a lesser extent IFN-α have been described for JCV, IFN-γ has not been previously implicated. Further analysis of IFN-γ signaling pathway revealed a novel role of Jak1 signaling in control of viral T-antigen expression. Furthermore, IFN-γ suppressed JCV replication and viral propagation in primary human fetal glial cells, and showed a strong anti-JCV activity.ConclusionsOur results suggest a novel role for IFN-γ in the regulation of JCV gene expression via downregulation of the major viral regulatory protein, T-antigen, and provide a new avenue of research to understand molecular mechanisms for downregulation of viral reactivation that may lead to development of novel strategies for the treatment of PML.
Highlights
Infection of glial cells by the neurotropic JC virus (JCV) causes the fatal central nervous system (CNS) demyelinating disease, progressive multifocal leukoencephalopathy (PML), which is primarily seen in patients with underlying immunocompromised conditions [1,2,3]
Our results suggest a novel role for IFN-γ in the regulation of JCV gene expression via downregulation of the major viral regulatory protein, T-antigen, and provide a new avenue of research to understand molecular mechanisms for downregulation of viral reactivation that may lead to development of novel strategies for the treatment of PML
Soluble immune mediators secreted by immune cells play important roles in neuroimmune communication which provides proper signaling for host response against intracellular CNS pathogens, including viruses [24]
Summary
Infection of glial cells by the neurotropic JC virus (JCV) causes the fatal CNS demyelinating disease, progressive multifocal leukoencephalopathy (PML), which is primarily seen in patients with underlying immunocompromised conditions [1,2,3]. PML has been reported as a risk factor in the context of auto-immune disorders treated with a variety of other monoclonal antibody therapies, suggesting that immunosuppression may lead to reactivation of JCV in the brain and can predispose patients to the development of PML. These include rituximab (trade named Rituxan) for the treatment of B cell lymphoma and rheumatoid arthritis which targets CD20 on circulating B cells causing their depletion from periphery [13], [14] and efalizumab (trade named Raptiva) for the treatment of plaque psoriasis which targets CD11a on T cells [15]
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