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.
Piña-Oviedo
Sergio
S
Department of Neuroscience, Center for Neurovirology and Neuropathology Core, Temple University School of Medicine, 1900 N. 12th Street, Philadelphia, PA 19122, USA.
Khalili
Kamel
K
Del Valle
Luis
L
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