Activation of the oxidative stress pathway by HIV-1 Vpr leads to induction of hypoxia-inducible factor 1alpha expression

The detection of biomarkers of oxidative stress in brain tissue and cerebrospinal fluid of patients with human immunodeficiency virus, type 1 (HIV)-associated dementia indicates the involvement of stress pathways in the neuropathogenesis of AIDS. Although the biological importance of oxidative stres...

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Bibliographic Details
Published in:The Journal of biological chemistry 2009-04, Vol.284 (17), p.11364
Main Authors: Deshmane, Satish L, Mukerjee, Ruma, Fan, Shongshan, Del Valle, Luis, Michiels, Carine, Sweet, Thersa, Rom, Inna, Khalili, Kamel, Rappaport, Jay, Amini, Shohreh, Sawaya, Bassel E
Format: Article
Language:English
Subjects:
Brain - metabolism
Cell Line
Dimerization
Gene Expression Regulation
HeLa Cells
Humans
Hydrogen Peroxide - metabolism
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Microglia - metabolism
Models, Biological
Oxidative Stress
Promoter Regions, Genetic
Reactive Oxygen Species
RNA Interference
vpr Gene Products, Human Immunodeficiency Virus - metabolism
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Summary:The detection of biomarkers of oxidative stress in brain tissue and cerebrospinal fluid of patients with human immunodeficiency virus, type 1 (HIV)-associated dementia indicates the involvement of stress pathways in the neuropathogenesis of AIDS. Although the biological importance of oxidative stress on events involved in AIDS neuropathogenesis and the HIV-1 proteins responsible for oxidative stress remain to be elucidated, our results point to the activation of hypoxia-inducible factor 1 (HIF-1) upon HIV-1 infection and its elevation in brain cells of AIDS patients with dementia. HIF-1 is a transcription factor that is responsive to oxygen. Under hypoxic conditions, HIF-1alpha becomes stable and translocates to the nucleus where it dimerizes with aryl hydrocarbon receptor nuclear translocator and modulates gene transcription. Activation of HIF-1 can also be mediated by the HIV-1 accessory protein Vpr. In addition, cellular components, including reactive oxygen species, contribute to the induction of HIF-1alpha. Our results show that Vpr induces reactive oxygen species by increasing H(2)O(2) production, which can contribute to HIF-1alpha accumulation. Interestingly, increased levels of HIF-1alpha stimulated HIV-1 gene transcription through HIF-1 association with HIV-1 long terminal repeat. These observations point to the existence of a positive feedback interplay between HIF-1alpha and Vpr and that, by inducing oxidative stress via activation of HIF-1, Vpr can induce HIV-1 gene expression and dysregulate multiple host cellular pathways.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M809266200