Journal article
Extracellular human immunodeficiency virus type 1 viral protein R causes reductions in astrocytic ATP and glutathione levels compromising the antioxidant reservoir
Virus research, v 167(2), pp 358-369
Aug 2012
PMID: 22691542
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
► Extracellular HIV-1 Vpr induces a decline in astrocytic ATP and GSH levels. ► Exogenous HIV-1 Vpr promotes accumulation of reactive oxygen species. ► N-acetyl-cysteine treatment ameliorates HIV-1 Vpr-induced oxidative stress. ► Exposure of astrocytes to HIV-1 Vpr increases levels of oxidized glutathione. ► Treatment with HIV-1 Vpr disrupts primary astrocytes architectural structure.
Patients infected with human immunodeficiency virus type 1 (HIV-1) often display neurological complications in late stage disease and increased viral loads directly correlated with higher concentrations of extracellular HIV-1 viral protein r (Vpr) in the blood serum and cerebrospinal fluid. Additionally, HIV-1-infected patients with a low CD4+ T-lymphocyte count displayed lower concentrations of reduced glutathione (GSH), the main intracellular antioxidant molecule, and lower level of survival. To establish a correlation between increased concentrations of extracellular Vpr and an oxidative stress-induced phenotype, the U-87 MG astroglioma cell line has been used to determine the downstream effects induced by Vpr. Conditioned media obtained from the human endothelial kidney (HEK) 293 T cell line transfected either in the absence or presence of HIV-1 Vpr contained free Vpr. Exposure of U-87 MG to this conditioned media decreased intracellular levels of both adenosine triphosphate (ATP) and GSH. These observations were recapitulated using purified recombinant HIV-1 Vpr both in U-87 MG and primary human fetal astrocytes in a dose- and time-dependent manner. Vpr-induced oxidative stress could be partly restored by co-treatment with the antioxidant molecule N-acetyl-cysteine (NAC). In addition, free Vpr augmented production of reactive oxygen species due to an increase in the level of oxidized glutathione (GSSG). This event was almost entirely suppressed by treatment with an anti-Vpr antibody or co-treatment with NAC. These studies confirm a role of extracellular Vpr in impairing astrocytic levels of intracellular ATP and GSH. Studies are underway to better understand the intricate correlation between reductions in ATP and GSH metabolites and how they affect neuronal survival in end-stage disease.
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Details
- Title
- Extracellular human immunodeficiency virus type 1 viral protein R causes reductions in astrocytic ATP and glutathione levels compromising the antioxidant reservoir
- Creators
- Adriano Ferrucci - School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USAMichael R Nonnemacher - Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USAÉric A Cohen - Laboratory of Human Retrovirology, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, CanadaBrian Wigdahl - Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
- Publication Details
- Virus research, v 167(2), pp 358-369
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000306889100028
- Scopus ID
- 2-s2.0-84863872696
- Other Identifier
- 991014877785404721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Virology