Hypoxia inducible factor-1 alpha activation of the JCV promoter: role in the pathogenesis of Progressive Multifocal Leukoencephalopathy

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Abstract
Activation of viral promoter transcription is a crucial event in the life cycle of several viruses. Hypoxia inducible factor-1 alpha (HIF-1α) is an inducible transcription factor whose activity is dependent on environmental conditions, most notably oxygen levels and cellular stress. HIF-1α has been implicated in the pathogenesis of several viruses, including HIV-1, HHV-8 and RSV. Under hypoxic conditions or oxidative stress, HIF-1α 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-1α in the activation of JCV. Glial cell cultures infected with JCV demonstrated a significant increase in the levels of HIF-1α, in where it is located to the nucleus. Immunohistochemical studies corroborated upregulation of HIF-1α in JCV infected oligodendrocytes and astrocytes in clinical samples of PML compared with normal glial cells from the same samples in which HIF-1α expression is weak. CAT assays performed in co-transfected glial cells demonstrated activation of the JCV early promoter in the presence of HIF-1α. This activation was potentiated in the presence of Smad3 and Smad4. Finally, chromatin immunoprecipitation assays demonstrated the binding of HIF-1α to the JCV control region. These results suggest a role for HIF-1α 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.