Antioxidants and Dipyridamole Inhibit HIV-1 gp120-Induced Free Radical-Based Oxidative Damage to Human Monocytoid Cells

Abstract

Reactive oxygen species (ROS) may play an important role in HIV-1 pathogenesis and HIV-1 gp120-induced neurotoxicity. Our studies determined the extent to which gp120 increased ROS production in human monocytic U937 cells and the effectiveness of various agents, including dipyridamole (DPR), in blocking these responses. The thiobarbituric acid-reactive substances (TBARS) assay was used as a measure of recombinant gp120 (HIV-1[3B])-induced oxidative damage to U937 cells. As a control, TBARS production was measured using a hypoxanthine/xanthine superoxide generating system. There was gp120-induced oxidative damage in U937 cells with a concentration that produces 50% of maximal effect (apparent EC50 value) of 11 pM. Polyclonal antiserum to gp120 significantly (p < 0.05) inhibited gp120-induced oxidative damage. gp120-induced oxidative damage was significantly inhibited 81% (p < 0.01) by catalase/superoxide dismutase, 53% (p < 0.05) by (+/-)-alpha-tocopherol, 78% (p < 0.01) by desferrioxamine, and 82% (p < 0.01) by ethylene diamine tetraacetic acid (EDTA). These results indicate that gp120 is capable of promoting iron-based oxygen free radical damage to U937 cells. DPR potently (p < 0.05) inhibited both hypoxanthine/xanthine- and gp120-induced oxidative damage with concentrations that produce 50% inhibition (apparent IC50 values) of 1.3 microM for hypoxanthine/xanthine and 1.0 microM for gp120. Therapeutic intervention against ROS production may prevent HIV-1 neurotoxicity.

Activation of the Oxidative Stress Pathway by HIV-1 Vpr Leads to Induction of Hypoxia-inducible Factor 1α Expression

“…In this regard, gp120 has been shown to induce ROS secretion in monocytic cells that can produce neuronal damage (49). ROS produced in glial cells by gp120 exposure has been shown to cause neurodegeneration by inducing the synthesis of interleukin-1␤ (50).…”

Cell death in HIV dementia

“…37,38 The activation of monocyte/ macrophages by gp120 can promote oxidative damage and increase the release of neurotoxic cytokines, including TNF-a, IL-1b and prostaglandin E2 (PGE2; an arachidonic acid metabolite from the cyclooxygenase and lipoxygenase pathway). [39][40][41][42] The transmembrane protein gp41 that links gp120 to the envelope of the virion has been shown to be elevated in patients with severe HIV dementia. In vitro, gp41 is lethal to neurons in the low nanomolar range and requires the presence of glia, suggesting an indirect mechanism of cell death.…”

“…137 The combined mechanisms of an increased pool of extracellular glutamate and deregulated NMDA receptor function can result in neuronal calcium overload and cellular dysfunction or death by mechanisms involving disruptions of redox balance and sphingolipid metabolism. 39,93,138 The glutamate receptor antagonist memantine has been shown to inhibit gp120-evoked calcium changes in neurons and astrocytes and protects neurons from gp120-induced cell death. [139][140][141][142] A clinical trial using this drug is currently under way in patients with HIV dementia.…”

Intracellular Human Immunodeficiency Virus Tat Expression in Astrocytes Promotes Astrocyte Survival but Induces Potent Neurotoxicity at Distant Sites via Axonal Transport

“…Tat can produce oxidative stress in microglia cells (12), monocytes (13), and T lymphocytes. In the latter, intracellular expression of Tat leads to down-regulation of mitochondrial superoxide dismutase, thereby causing impaired mitochondrial membrane potential (14,15).…”