Hypoxia inducible factor-1 alpha activation of the JCV promoter: role in the pathogenesis of progressive multifocal leukoencephalopathy.
Activation of viral promoter transcription is a crucial event in the life cycle of several viruses. Hypoxia inducible factor-1 alpha (HIF-1alpha) is an inducible transcription factor whose activity is dependent on environmental conditions, most notably oxygen levels and cellular stress. HIF-1alpha has been implicated in the pathogenesis of several viruses, including HIV-1, HHV-8 and RSV. Under hypoxic conditions or oxidative stress, HIF-1alpha becomes stable and translocates to the nucleus, where it modulates gene transcription. The objective of the present study was to investigate a possible role for HIF-1alpha in the activation of JCV. Glial cell cultures infected with JCV demonstrated a significant increase in the levels of HIF-1alpha, in where it is located to the nucleus. Immunohistochemical studies corroborated upregulation of HIF-1alpha in JCV infected oligodendrocytes and astrocytes in clinical samples of PML compared with normal glial cells from the same samples in which HIF-1alpha expression is weak. CAT assays performed in co-transfected glial cells demonstrated activation of the JCV early promoter in the presence of HIF-1alpha. This activation was potentiated in the presence of Smad3 and Smad4. Finally, chromatin immunoprecipitation assays demonstrated the binding of HIF-1alpha to the JCV control region. These results suggest a role for HIF-1alpha in the activation of JCV; understanding of this pathway may lead to the development of more effective therapies for PML, thus far an incurable disease.
Department of Neuroscience, Center for Neurovirology and Neuropathology Core, Temple University School of Medicine, 1900 N. 12th Street, Philadelphia, PA 19122, USA.
Sergio
S
Piña-Oviedo
Kamel
K
Khalili
Luis
L
Del Valle
D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D007577:JC Virus / Q000235:genetics* / Q000378:metabolism; D007968:Leukoencephalopathy, Progressive Multifocal / Q000209:etiology / Q000378:metabolism* / Q000821:virology; D008297:Male; D008875:Middle Aged; D009836:Oligodendroglia / Q000378:metabolism / Q000821:virology; D015533:Transcriptional Activation
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit