title: Expression of Signaling Molecules in Progressive Multifocal Leukoencephalopathy.
abstract: BACKGROUND
  Progressive multifocal leukoencephalopathy (PML) is a debilitating demyelinating disease of the CNS caused by the infection and destruction of glial cells by JC virus (JCV) and is an AIDS-defining disease. Infection with JCV is common and most people acquire antibodies early in life. After initial infection, JCV remains in an asymptomatic persistent state and can be detected by PCR in many tissues including brain. A major question in PML pathogenesis is how the virus reactivates from persistence in HIV-1/AIDS. Our studies with primary cultures of glial cells have implicated transcription factors NF-κB and NFAT4, which bind to a unique site in the JCV noncoding control region and stimulate viral gene expression. Furthermore, these transcription factors are controlled by pathways downstream of proinflammatory cytokines, e.g., TNF-α activates NF-κB and stimulates JCV transcription.
  
  
  OBJECTIVE
  We hypothesize that HIV-1/PML initiation may involve reactivation of JCV by cytokine disturbances in the brain such as occur in HIV-1/AIDS. In this study, the objective was to evaluate HIV-1/PML clinical samples for expression of TNF-α and its receptors and subcellular localization of NF-κB p65 and NFAT4 compared to non-PML controls.
  
  
  METHODS
  We evaluated HIV-1/PML clinical samples and non-PML controls for expression of TNF-α and its receptors and subcellular localization of NF-κB p65 and NFAT4 using Western blot and immunohistochemistry.
  
  
  RESULTS
  Consistent with our hypothesis, compared to non-PML controls, HIV-1/PML tissue has high levels of TNF-α and TNFR1 expression and NF-κB and NFAT4 were preferentially localized to the nucleus.
  
  
  CONCLUSIONS
  The involvement of TNF-α/NF-κB/NFAT4 signaling in JCV regulation that we reported from experiments in cultured human glial cells may be clinically relevant in PML.
authors.forename: Hassen S
authors.initials: HS
authors.lastname: Wollebo
authors.forename: Bianca
authors.initials: B
authors.lastname: Cotto
authors.forename: Radhika
authors.initials: R
authors.lastname: Adiga
authors.forename: Dianne
authors.initials: D
authors.lastname: Langford
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA. martyn.white@temple.edu.
authors.forename: Martyn K
authors.initials: MK
authors.lastname: White
mesh_terms: D000328:Adult; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000378:metabolism*; D015497:HIV-1; D006801:Humans; D007150:Immunohistochemistry; D007968:Leukoencephalopathy, Progressive Multifocal / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014775:Virus Activation / Q000502:physiology
chemical_list: D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494008:NFATC3 protein, human; D021122:Protein Subunits; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha