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

Satish L. Deshmane, Ruma Mukerjee, Shongshan Fan, Luis Del Valle, Carine Michiels, Thersa Sweet, Inna Rom, Kamel Khalili, Jay Rappaport, Shohreh Amini, Bassel E. Sawaya

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Abstract

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-1α 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-1α. Our results show that Vpr induces reactive oxygen species by increasing H2O2 production, which can contribute to HIF-1α accumulation. Interestingly, increased levels of HIF-1α 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-1α 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. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

Original languageEnglish
Pages (from-to)11364-11373
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number17
DOIs
Publication statusPublished - 2009

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Deshmane, S. L., Mukerjee, R., Fan, S., Del Valle, L., Michiels, C., Sweet, T., Rom, I., Khalili, K., Rappaport, J., Amini, S., & Sawaya, B. E. (2009). Activation of the oxidative stress pathway by HIV-1 Vpr leads to induction of hypoxia-inducible factor 1α expression. Journal of Biological Chemistry, 284(17), 11364-11373. https://doi.org/10.1074/jbc.M809266200