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 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.
Deshmane
Satish L
SL
Department of Neuroscience and Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania 19122, USA.
Mukerjee
Ruma
R
Fan
Shongshan
S
Del Valle
Luis
L
Michiels
Carine
C
Sweet
Thersa
T
Rom
Inna
I
Khalili
Kamel
K
Rappaport
Jay
J
Amini
Shohreh
S
Sawaya
Bassel E
BE
D001921:Brain / Q000378:metabolism; D002460:Cell Line; D019281:Dimerization; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism; D008954:Models, Biological; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D017382:Reactive Oxygen Species; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D054325:vpr Gene Products, Human Immunodeficiency Virus; D006861:Hydrogen Peroxide