Cholesterol-dependent modulation of the toxicity of HIV-1 coat protein gp120 in human neuroblastoma cells.
The human immunodeficiency virus type 1 (HIV-1) coat glycoprotein gp120 binds to its (co)receptors and orchestrates cell entry by the direct fusion of viral and target cell membranes. Here, we modulated membrane fluidity of human neuroblastoma CHP100 cells by modulating their cholesterol content, and investigated the ability of gp120 to induce cell death in comparison with the untreated cells. We show that in normal CHP100 cells gp120 induces necrosis by: (i) increased cyclooxygenase and 5-lipoxygenase activity, and metabolites generated thereof (prostaglandin E2 and leukotriene B4, respectively); (ii) increased membrane lipoperoxidation; and (iii) increased mitochondrial uncoupling. These events were triggered by a rapid increase in intracellular calcium, and in cholesterol-depleted cells engaged CXCR4 chemokine receptors. The intracellular calcium chelator EGTA-AM protected CHP100 cells almost completely against the toxic effects of gp120. However, gp120-induced necrosis and related biochemical changes were negligible in cholesterol-enriched, and significantly enhanced in cholesterol-depleted, CHP100 cells exposed to the viral glycoprotein under the same experimental conditions. Taken together, these results suggest that membrane fluidity may control the neurotoxic effects of HIV-1 glycoprotein gp120.
D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002784:Cholesterol / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D015497:HIV-1; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D008560:Membrane Fluidity / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D015699:HIV Envelope Protein gp120; D019718:Receptors, CXCR4; D016718:Arachidonic Acid; D002784:Cholesterol; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D002118:Calcium