title: Extracellular HIV-1 viral protein R affects astrocytic glyceraldehyde 3-phosphate dehydrogenase activity and neuronal survival.
abstract: Extracellular human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) is a pleiotropic protein accomplishing several functions within the viral life cycle. While Vpr has been described extensively as an intracellular protein, very little is known about its role as an extracellular protein. In fact, HIV-1 Vpr has been detected in the blood, serum, and cerebrospinal fluid of HIV-1-infected patients, with concentrations increasingly higher in late-stage disease. To determine the role exogenous Vpr plays in HIV-associated central nervous system dysfunction, primary human fetal astrocytes were exposed to recombinant Vpr and a time- and dose-dependent decrease was demonstrated in two fundamental intracellular metabolites (adenosine-5'-triphosphate (ATP) and glutathione (GSH)). Additionally, exposure to exogenous Vpr led to increased caspase activity and secretion of proinflammatory cytokines IL-6 and IL-8 and chemoattractants, monocyte chemotactic protein-1, and migration inhibition factor. Extracellular Vpr also dampened the glycolytic pathway through impairment of glyceraldehyde 3-phosphate dehydrogenase activity, causing a decline in the levels of ATP. The reduction in intracellular ATP increased reactive oxygen species buildup, decreasing GSH concentrations, which affected several genes in the oxidative stress pathway. In addition, exposure of the SK-N-SH neuroblastoma cell line to conditioned medium from exogenous Vpr-treated astrocytes decreased synthesis of GSH, leading to their apoptosis. These observations point to a role that Vpr plays in altering astrocytic metabolism and indirectly affecting neuronal survival. We propose a model that may explain some of the neurological damage and therefore neurocognitive impairment observed during the course of HIV-1 disease.
authors.affiliation: School of Biomedical Engineering, Science and Health Systems, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
authors.forename: Adriano
authors.initials: A
authors.lastname: Ferrucci
authors.forename: Michael R
authors.initials: MR
authors.lastname: Nonnemacher
authors.forename: Brian
authors.initials: B
authors.lastname: Wigdahl
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005333:Fetus; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000821:virology; D018384:Oxidative Stress; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000494:pharmacology*
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D017077:Culture Media, Conditioned; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D020169:Caspases; D005978:Glutathione