title: IFN-Gamma Inhibits JC Virus Replication in Glial Cells by Suppressing T-Antigen Expression.
abstract: OBJECTIVE
  Patients 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.
  
  
  RESULTS
  Here, 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 3500 North Broad Street, 7th Floor, Philadelphia, PA, 19140, United States of America.
authors.forename: Francesca Isabella
authors.initials: FI
authors.lastname: De-Simone
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 3500 North Broad Street, 7th Floor, Philadelphia, PA, 19140, United States of America.
authors.forename: Rahsan
authors.initials: R
authors.lastname: Sariyer
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 3500 North Broad Street, 7th Floor, Philadelphia, PA, 19140, United States of America.
authors.forename: Yolanda-Lopez
authors.initials: YL
authors.lastname: Otalora
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 3500 North Broad Street, 7th Floor, Philadelphia, PA, 19140, United States of America.
authors.forename: Shadan
authors.initials: S
authors.lastname: Yarandi
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 3500 North Broad Street, 7th Floor, Philadelphia, PA, 19140, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Craigie
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 3500 North Broad Street, 7th Floor, Philadelphia, PA, 19140, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gordon
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 3500 North Broad Street, 7th Floor, Philadelphia, PA, 19140, United States of America.
authors.forename: Ilker Kudret
authors.initials: IK
authors.lastname: Sariyer
mesh_terms: D000957:Antigens, Viral, Tumor / Q000235:genetics / Q000378:metabolism*; D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007577:JC Virus / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D009457:Neuroglia / Q000821:virology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000957:Antigens, Viral, Tumor; D000998:Antiviral Agents; D007371:Interferon-gamma