Inhibition of Nuclear Factor Erythroid 2-Related Factor 2 Exacerbates HIV-1 gp120-Induced Oxidative and Inflammatory Response: Role in HIV Associated Neurocognitive Disorder

The HIV epidemic continues to be the most severe public health problem and concern within USA and across the globe. In spite of the highly active antiretroviral therapy, HIV infected subjects experience major neurological complications that range from HIV associated dementia to moderate neurocogniti...

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Bibliographic Details
Published in:Neurochemical research 2012-08, Vol.37 (8), p.1697-1706
Main Authors: Reddy, Pichili Vijaya Bhaskar, Agudelo, Marisela, Atluri, Venkata S. R., Nair, Madhavan P.
Format: Article
Language:English
Subjects:
AIDS Dementia Complex - physiopathology
Antioxidants
Astrocytes
Astrocytes - drug effects
Astrocytes - metabolism
Biochemistry
Biomedical and Life Sciences
Biomedicine
Cell Biology
Cell survival
Chromium
Cognition
CYBB protein
Gelatinase B
Glycoprotein gp120
Hand
highly active antiretroviral therapy
HIV Envelope Protein gp120 - pharmacology
Human immunodeficiency virus 1
Humans
Inflammation
Inflammation - physiopathology
Leucine zipper proteins
Matrix Metalloproteinase 9 - biosynthesis
Membrane Glycoproteins - biosynthesis
NAD(P)H oxidase
NADPH Oxidase 2
NADPH Oxidases - biosynthesis
Neurochemistry
Neurological diseases
Neurology
Neuropathogenesis
Neurosciences
NF-E2-Related Factor 2 - antagonists & inhibitors
NF-E2-Related Factor 2 - genetics
NF-kappa B - biosynthesis
Original Paper
Oxidative stress
Oxidative Stress - drug effects
Reactive Oxygen Species - antagonists & inhibitors
siRNA
Transcription factors
Tumor necrosis factor- alpha
Tumor Necrosis Factor-alpha - metabolism
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Summary:The HIV epidemic continues to be the most severe public health problem and concern within USA and across the globe. In spite of the highly active antiretroviral therapy, HIV infected subjects experience major neurological complications that range from HIV associated dementia to moderate neurocognitive and motor impairments collectively termed as HIV associated neurocognitive disorders (HAND). Astrocytes play an important role in the neuropathogenesis of HAND. Further, in the recent years it has been shown that oxidative stress plays a major role in the neuropathogenesis of HAND. Nuclear factor erythroid 2-related factor 2 (Nrf2), a leucine zipper redox-sensitive transcription factor, is an important regulator of cell survival and adaptive mechanisms and has been shown to possess a protective role in a variety of neurological and inflammatory disorders. Earlier we have shown that Nrf2 is upregulated in response to HIV-1 gp120 and such upregulation of Nrf2 may be a protective mechanism against the HIV-induced oxidative stress. We hypothesize that Nrf2-mediated antioxidant pathways are important in regulating the HIV-induced oxidative stress and that the disruption of Nrf2 makes the cells more susceptible to HIV gp120-induced deleterious effects. Our results indicate that when astrocytes are exposed to gp120 there is an increase in the expression of NOX2, a subunit of NADPH oxidase, and also an upregulated expression of nuclear factor kappa B, tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-9 (MMP-9). However, the degree of expression was significantly higher in those cells where Nrf2 was silenced by siRNA. Taken together, these results suggest a possible protective role of Nrf2 in regulating the levels of pro-oxidative and pro-inflammatory molecules in HAND.
ISSN:0364-3190
1573-6903
DOI:10.1007/s11064-012-0779-0