Title:Expression of Signaling Molecules in Progressive Multifocal Leukoencephalopathy
Volume: 14
Issue: 1
Author(s): Hassen S. Wollebo, Bianca Cotto, Radhika Adiga, Dianne Langford and Martyn K. White
Affiliation:
Keywords:
Human polyomavirus JC, NF-κB, NFAT4, progressive multifocal leukoencephalopathy, proinflammatory
cytokines, tumor necrosis factor-α, viral reactivation.
Abstract: Introduction: 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.
Objectives: 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.
Conclusion: 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.
