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Acute exposure to ethanol potentiates human immunodeficiency virus type 1 Tat-induced Ca2+ overload and neuronal death in cultured rat cortical neurons

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Abstract

A significant number of human immunodeficiency virus type 1 (HIV-1)-infected patients are alcoholics. Either alcohol or HIV alone induces morphological and functional damage to the nervous system. HIV-1 Tat is a potent transcriptional activator of the viral promoter, with the ability to modulate a number of cellular regulatory circuits including apoptosis and to cause neuronal injury. To further evaluate the involvement of alcohol in neuronal injury, the authors examined the effect of ethanol on Tat-induced calcium responses in rat cerebral cortical neurons, using microfluorimetric calcium determination. HIV Tat protein (10 or 500 nM) elicited two types of calcium responses in cortical neurons: a fast-onset, short-lasting response and a slow-onset, sustained response. The responses were concentration-dependent and diminished in calcium-free saline. A short exposure to ethanol (50 mM) potentiated both types of calcium response, which was markedly decreased when the cells were pretreated with BAPTA-AM (20 μM). In addition, an increase in the neurotoxic effect of Tat, which was assessed by trypan blue exclusion assay, was observed. The result led the authors to conclude that alcohol exposure significantly potentiates Tat-induced calcium overload and neuronal death.

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References

  • Acheampong E, Mukhtar M, Parveen Z, Ngoubilly N, Ahmad N, Patel C, Pomerantz RJ (2002). Ethanol strongly potentiates apoptosis induced by HIV-1 proteins in primary human brain microvascular endothelial cells. Virology 304: 222–234.

    Article  PubMed  CAS  Google Scholar 

  • Amini S, Saunders M, Kelley K, Khalili K, Sawaya SE (2004). Interplay between HIV-1 Vpr and Spl modulates p21WAF1 gene expression in human astrocytes. J Biol Chem 279: 46046–46056.

    Article  PubMed  CAS  Google Scholar 

  • Belmadani A, Neafsey EJ, Collins MA (2003). Human immunodeficiency virus type 1 gp120 and ethanol coexposure in rat organotypic brain slice cultures: curtailment of gp120-induced neurotoxicity and neurotoxic mediators by moderate but not high ethanol concentrations. J NeuroVirol 9: 45–54.

    PubMed  CAS  Google Scholar 

  • Belmadani A, Zou JY, Schipma MJ, Neafsey EJ, Collins MA (2001). Ethanol pre-exposure suppresses HIV-1 glycoprotein 120-induced neuronal degeneration by abrogating endogenous glutamate/Ca2+-mediated neurotoxicity. Neuroscience 104: 769–781.

    Article  PubMed  CAS  Google Scholar 

  • Bonavia R, Bajetto A, Barbero S, Albini A, Noonan DM, Schettini G (2001). HIV-1 Tat causes apoptotic death and calcium homeostasis alterations in rat neurons. Biochem Biophys Res Commun 288: 301–308.

    Article  PubMed  CAS  Google Scholar 

  • Brailoiu E, Hoard JL, Filipeanu CM, Brailoiu GC, Dun SL, Patel S, Dun NJ (2005). NAADP potentiates neurite outgrowth. J Biol Chem 280: 5646–5650.

    Article  PubMed  CAS  Google Scholar 

  • Chen H, Zha J, Gowans RE, Camargo P, Nishitani J, McQuirter JL, Cole SW, Zack JA, Liu X (2004). Alcohol enhances HIV type 1 infection in normal human oral keratinocytes by up-regulating cell-surface CXCR4 coreceptor. AIDS Res Hum Retroviruses 20: 513–519.

    Article  PubMed  CAS  Google Scholar 

  • Chen W, Tang Z, Fortina P, Patel P, Addya S, Surrey S, Acheampong EA, Mukhtar M, Pomerantz RJ (2005). Ethanol potentiates HIV-1 gp120-induced apoptosis in human neurons via both the death receptor and NMDA receptor pathways. Virology 334: 59–73.

    Article  PubMed  CAS  Google Scholar 

  • Collins MA, Neafsey EJ, Zou JY (2000). HIV-I gpI20 neurotoxicity in brain cultures is prevented by moderate ethanol pretreatment. Neuroreport 11: 1219–1222.

    Article  PubMed  CAS  Google Scholar 

  • Cook RT, Stapleton JT, Dallas ZK, Klinzman D (1997). Effect of a single ethanol exposure on HIV replication in human lymphocytes. J Invest Med 45: 265–271.

    CAS  Google Scholar 

  • Dingle GA, Oei TP (1997). Is alcohol a cofactor of HIV and AIDS? Evidence from immunological and behavioral studies. Psychol Bull 122: 56–71.

    Article  PubMed  CAS  Google Scholar 

  • Daniell LC, Harris RA (1989). Ethanol and inositol 1,4,5-trisphosphate release calcium from separate stores of brain microsomes. J Pharmacol Exp Ther 250: 875–881.

    PubMed  CAS  Google Scholar 

  • Flora G, Pu H, Lee YW, Ravikumar R, Nath A, Hennig B, Toborek M (2005). Proinflammatory synergism of ethanol and HIV-1 Tat protein in brain tissue. Exp Neurol 191: 2–12.

    Article  PubMed  CAS  Google Scholar 

  • Ghosh A, Greenberg ME (1995). Calcium signaling in neurons: molecular mechanisms and cellular conseqences. Science 268: 239–247.

    Article  PubMed  CAS  Google Scholar 

  • Goodlett CR, Horn KH (2001). Mechanisms of alcoholinduced damage to the developing nervous system. Alcohol Res Health 25: 175–184.

    PubMed  CAS  Google Scholar 

  • Gonzalez-Scarano F, Martin-Garcia J (2005). The neuropathogenesis of AIDS. Nat Rev Immunol 5: 69–81.

    Article  PubMed  CAS  Google Scholar 

  • Green JT, Tran T, Steinmetz JE, Goodlett CR (2002). Neonatal ethanol produces cerebellar deep nuclear cell loss and correlated disruption of eyeblink conditioning in adult rats. Brain Res 956: 302–311.

    Article  PubMed  CAS  Google Scholar 

  • Grynkiewicz G, Poenie M, Tsien RY (1985). A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260: 3440–3450.

    PubMed  CAS  Google Scholar 

  • Haorah J, Heilman D, Diekmann C, Osna N, Donohue TM Jr, Ghorpade A, Persidsky Y (2004). Alcohol and HIV decrease proteasome and immunoproteasome function in macrophages: implications for impaired immune function during disease. Cell Immunol 229: 139–148.

    Article  PubMed  CAS  Google Scholar 

  • Haughey NJ, Holden CP, Nath A, Geiger JD (1999). Involvement of inositol 1,4,5-trisphosphate-regulated stores of intracellular calcium in calcium dysregulation and neuron cell death caused by HIV-1 protein tat. J Neurochem 73: 1363–1374.

    Article  PubMed  CAS  Google Scholar 

  • Haughey NJ, Mattson MP (2002). Calcium dysregulation and neuronal apoptosis by the HIV-1 proteins Tat and gp120. J Acquir Immune Defic Syndr 31: S55-S61.

    Article  PubMed  CAS  Google Scholar 

  • Haughey NJ, Nath A, Mattson MP, Slevin JT, Geiger JD (2001). HIV-1 Tat through phosphorylation of NMDA receptors potentiates glutamate excitotoxicity. J Neurochem 78: 457–467.

    Article  PubMed  CAS  Google Scholar 

  • Hoek JB, Thomas AP, Rubin R, Rubin E (1987). Ethanolinduced mobilization of calcium by activation of phosphoinositide-specific phospholipase C in intact hepatocytes. J Biol Chem 262: 682–691.

    PubMed  CAS  Google Scholar 

  • Ikegami Y, Goodenough S, Inoue Y, Dodd PR, Wilce PA, Matsumoto I (2003). Increased TUNEL positive cells in human alcoholic brains. Neurosci Lett 349: 201–205.

    Article  PubMed  CAS  Google Scholar 

  • Ikonomidou C, Bittigau P, Ishimaru MJ, Wozniak DF, Koch C, Genz K, Price MT, Stefovska V, Horster F, Tenkova T, Dikranian K, Olney JW (2000). Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 287: 1056–1060.

    Article  PubMed  CAS  Google Scholar 

  • Kaul M, Garden GA, Lipton SA (2001). Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410: 988–994.

    Article  PubMed  CAS  Google Scholar 

  • Koller H, Schaal H, Freund M, Garrido SR, von Giesen HJ, Ott M, Rosenbaum C, Arendt G (2001). HIV-1 protein Tat reduces the glutamate-induced intracellular Ca2+ increase in cultured cortical astrocytes. Eur J Neurosci 14: 1793–1799.

    Article  PubMed  CAS  Google Scholar 

  • Kruman II, Nath A, Mattson MP (1998). HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress. Exp Neurol 154: 276–288.

    Article  PubMed  CAS  Google Scholar 

  • Liu X, Zha J, Nishitani J, Chen H, Zack JA (2003). HIV-1 infection in peripheral blood lymphocytes (PBLs) exposed to alcohol. Virology 307: 37–44.

    Article  PubMed  CAS  Google Scholar 

  • Meyerhoff DJ (2001). Effects of alcohol and HIV infection on the central nervous system. Alcohol Res Health 25: 288–298

    PubMed  CAS  Google Scholar 

  • Mattson MP, Chan SL (2003). Calcium orchestrates apoptosis. Nat Cell Biol 5: 1041–1043.

    Article  PubMed  CAS  Google Scholar 

  • Mattson MP, Haughey NJ, Nath A (2005). Cell death in HIV dementia. Cell Death Differ 12: 893–904.

    Article  PubMed  CAS  Google Scholar 

  • Mayne M, Holden CP, Nath A, Geiger JD (2000). Release of calcium from inositol 1,4,5-trisphosphate receptorregulated stores by HIV-1 Tat regulates TNF-alpha production in human macrophages. J Immunol 164: 6538–6542.

    PubMed  CAS  Google Scholar 

  • Nagy J, Muller F, Laszlo L (2001). Cytotoxic effect of alcohol-withdrawal on primary cultures of cortical neurones. Drug Alcohol Depend 61: 155–162.

    Article  PubMed  CAS  Google Scholar 

  • Nath A, Geiger J (1998). Neurobiological aspects of human immunodeficiency virus infection: Neurotoxic mechanisms. Prog Neurobiol 54: 19–33.

    Article  PubMed  CAS  Google Scholar 

  • Nath A, Psooy K, Martin C, Knudsen B, Magnuson DS, Haughey N, Geiger JD (1996). Identification of a human immunodeficiency virus type 1 Tat epitope that is neuroexcitatory and neurotoxic. J Virol 70: 1475–1480.

    PubMed  CAS  Google Scholar 

  • New DR, Ma M, Epstein LG, Nath A, Gelbard HA (1997). Human immunodeficiency virus type 1 Tat protein induces death by apoptosis in primary human neuron cultures. J NeuroVirol 3: 168–173.

    Article  PubMed  CAS  Google Scholar 

  • Pandey SC (1996). Acute and chronic ethanol consumption effects on the immunolabeling of Gq/11 alpha subunit protein and phospholipase C isozymes in the rat brain. J Neurochem 67: 2355–2361.

    Article  PubMed  CAS  Google Scholar 

  • Pawlak R, Skrzypiec A, Sulkowski S, Buczko W (2002). Ethanol-induced neurotoxicity is counterbalanced by increased cell proliferation in mouse dentate gyrus. Neurosci Lett 327: 83–86.

    Article  PubMed  CAS  Google Scholar 

  • Pfefferbaum A, Adalsteinsson E, Sullivan EV (2005). Cortical NAA deficits in HIV infection without dementia: influence of alcoholism comorbidity. Neuropsychopharmacology 30: 1392–1399.

    Article  PubMed  CAS  Google Scholar 

  • Popp RL, Lickteig RL, Lovinger DM (1999). Factors that enhance ethanol inhibition of N-methyl-d-aspartate receptors in cerebellar granule cells. J Pharmacol Exp Ther 289: 1564–1574.

    PubMed  CAS  Google Scholar 

  • Resnick L, Berger JR, Shapshak P, Tourtellotte WW (1988). Early penetration of the blood-brain barrier by HTLV-III/LAV. Neurology 38: 9–15.

    PubMed  CAS  Google Scholar 

  • Rothlind JC, Greenfield TM, Bruce AV, Meyerhoff DJ, Flenniken DL, Lindgren JA, Weiner MW (2005). Heavy alcohol consumption in individuals with HIV infection: effects on neuropsychological performance. J Int Neuropsychol Soc 11: 70–83.

    Article  PubMed  Google Scholar 

  • Sabatier JM, Vives E, Mabrouk K, Benjouad A, Rochat H, Duval A, Hue B, Bahraoui E (1991). Evidence for neurotoxic activity of tat from human immunodeficiency virus type 1. J Virol 65: 961–967.

    PubMed  CAS  Google Scholar 

  • Samet JH, Phillips SJ, Morton NJ, Traphagen ET, Freedberg KA (2004). Detecting alcohol problems in HIV-infected patients: use of the CAGE questionnaire. AIDS Res Hum Retroviruses 20: 151–155.

    Article  PubMed  Google Scholar 

  • Schulte T, Mueller-Oehring EM, Rosenbloom MJ, Pfefferbaum A, Sullivan EV (2005). Differential effect of HIV infection and alcoholism on conflict processing, attentional allocation, and perceptual load: evidence from a Stroop Match-to-Sample task. Biol Psychol 57: 67–75.

    Article  Google Scholar 

  • Self RL, Mulholland PJ, Harris BR, Nath A, Prendergast MA (2004). Cytotoxic effects of exposure to the human immunodeficiency virus type 1 protein Tat in the hippocampus are enhanced by prior ethanol treatment. Alcohol Clin Exp Res 28: 1916–1924.

    Article  PubMed  CAS  Google Scholar 

  • Strayer DS, Hoek JB, Thomas AP, White MK (1999). Cellular activation by Ca2+ release from stores in the endoplasmic reticulum but not by increased free Ca2+ in the cytosol. Biochem J 344: 39–46.

    Article  PubMed  CAS  Google Scholar 

  • Wang MY, Rampil IJ, Kendig JJ (1999). Ethanol directly depresses AMPA and NMDA glutamate currents in spinal cord motor neurons independent of actions on GABAA or glycine receptors. J Pharmacol Exp Ther 290: 362–367.

    PubMed  CAS  Google Scholar 

  • Winsauer PJ, Moerschbaecher JM, Brauner IN, Purcell JE, Lancaster JR Jr, Bagby GJ, Nelson S (2002). Alcohol unmasks simian immunodeficiency virus-induced cognitive impairments in rhesus monkeys. Alcohol Clin Exp Res 26: 1846–1857.

    Article  PubMed  CAS  Google Scholar 

  • Yang Z, Wang J, Zheng T, Altura BT, Altura BM (2001). Importance of extracellular Ca2+ and intacellular Ca2+ release in ethanol-induced contraction of cerebral arterial smooth muscle. Alcohol 24: 145–153.

    Article  PubMed  CAS  Google Scholar 

  • Zheng J, Yang OO, Xie Y, Campbell R, Chen IS, Pang S (2004). Ethanol stimulation of HIV infection of oral epithelial cells. J Acquir Immune Defic Syndr 37: 1445–1453.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Eugen Brailoiu.

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This study was supported by NIH Grants NS18710 and HL51314 from the Department of Health and Human Services.

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Brailoiu, E., Brailoiu, G.C., Mameli, G. et al. Acute exposure to ethanol potentiates human immunodeficiency virus type 1 Tat-induced Ca2+ overload and neuronal death in cultured rat cortical neurons. Journal of NeuroVirology 12, 17–24 (2006). https://doi.org/10.1080/13550280500516427

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  • DOI: https://doi.org/10.1080/13550280500516427

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