Hypoxia inducible factor-1 alpha activation of the JCV promoter: role in the pathogenesis of progressive multifocal leukoencephalopathy.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Piña-Oviedo, S; Khalili, K; Del Valle, L

Published Date

  • August 2009

Published In

Volume / Issue

  • 118 / 2

Start / End Page

  • 235 - 247

PubMed ID

  • 19360424

Pubmed Central ID

  • PMC2856344

Electronic International Standard Serial Number (EISSN)

  • 1432-0533

Digital Object Identifier (DOI)

  • 10.1007/s00401-009-0533-0

Language

  • eng

Conference Location

  • Germany