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Role of Tat Protein in HIV Neuropathogenesis

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Abstract

The Tat protein of the human immunodeficiency virus (HIV) has been implicated in the pathophysiology of the neurocognitive deficits associated with HIV infection. This is the earliest protein to be produced by the proviral DNA in the infected cell. The protein not only drives the regulatory regions of the virus but may also be actively released from the cell and then interact with the cell surface receptors of other uninfected cells in the brain leading to cellular dysfunction. It may also be taken up by these cells and can then activate a number of host genes. The Tat protein is highly potent and has the unique ability to travel along neuronal pathways. Importantly, its production is not impacted by the use of antiretroviral drugs once the proviral DNA has been formed. This article reviews the pleomorphic actions of Tat protein and the evidence supporting its central role in the neuropathogenesis of the HIV infection.

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References

  • Aksenov MY, Hasselrot U, Bansal AK, Wu G, Nath A, Anderson C, Mactutus CF, Booze RM (2001) Oxidative damage induced by the injection of HIV-1 Tat protein in the rat striatum. Neurosci Lett 305:5–8

    Article  PubMed  CAS  Google Scholar 

  • Albini A, Ferrini S, Benelli R, Sforzini S, Giunciuglio D, Aluigi MG, Proudfoot AE, Alouani S, Wells TN, Mariani G, Rabin RL, Farber JM, Noonan DM (1998) HIV-1 Tat protein mimicry of chemokines. Proc Natl Acad Sci USA 95:13153–13158

    Article  PubMed  CAS  Google Scholar 

  • Amemiya K, Traub R, Durham L, Major EO (1989) Interaction of a nuclear factor-1-like protein with the regulatory region of the human polyomavirus JC virus. J Biol Chem 264:7025–7032

    PubMed  CAS  Google Scholar 

  • Amemiya K, Traub R, Durham L, Major EO (1992) Adjacent nuclear factor-1 and activator protein binding sites in the enhancer of the neurotropic JC virus. A common characteristic of many brain-specific genes. J Biol Chem 267:14204–14211

    PubMed  CAS  Google Scholar 

  • Andras IE, Rha G, Huang W, Eum S, Couraud PO, Romero IA, Hennig B, Toborek M (2008) Simvastatin protects against amyloid beta and HIV-1 Tat-induced promoter activities of inflammatory genes in brain endothelial cells. Mol Pharmacol 73:1424–1433

    Article  PubMed  CAS  Google Scholar 

  • Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J, Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69:1789–1799

    Article  PubMed  CAS  Google Scholar 

  • Arai M, Ohashi T, Tsukahara T, Murakami T, Hori T, Uchiyama T, Yamamoto N, Kannagi M, Fujii M (1998) Human T-cell leukemia virus type 1 Tax protein induces the expression of lymphocyte chemoattractant SDF-1/PBSF. Virology 241:298–303

    Article  PubMed  CAS  Google Scholar 

  • Atwood WJ, Wang L, Durham LC, Amemiya K, Traub RG, Major EO (1995) Evaluation of the role of cytokine activation in the multiplication of JC virus (JCV) in human fetal glial cells. J Neurovirol 1:40–49

    Article  PubMed  CAS  Google Scholar 

  • Banks WA, Robinson SM, Nath A (2005) Permeability of the blood-brain barrier to HIV-1 Tat. Exp Neurol 193:218–227

    Article  PubMed  CAS  Google Scholar 

  • Bansal AK, Mactutus CF, Nath A, Maragos W, Hauser KF, Booze RM (2000) Neurotoxicity of HIV-1 proteins gp120 and Tat in the rat striatum. Brain Res 879:42–49

    Article  PubMed  CAS  Google Scholar 

  • Barillari G, Gendelman R, Gallo RC, Ensoli B (1993) The Tat protein of HIV, a growth factor for AIDS Kaposi sarcoma and cytokine activated vascular cells, induces adhesion of the same cell types by using integrin receptors recognizing the RGD amino acid sequence. Proc Natl Acad Sci USA 90:7941–7945

    Article  PubMed  CAS  Google Scholar 

  • Bilodeau PS, Domsic JK, Stoltzfus CM (1999) Splicing regulatory elements within tat exon 2 of human immunodeficiency virus type 1 (HIV-1) are characteristic of group M but not group O HIV-1 strains. J Virol 73:9764–9772

    PubMed  CAS  Google Scholar 

  • Boess F, Ndikum-Moffor FM, Boelsterli UA, Roberts SM (2000) Effects of cocaine and its oxidative metabolites on mitochondrial respiration and generation of reactive oxygen species. Biochem Pharmacol 60:615–623

    Article  PubMed  CAS  Google Scholar 

  • Boven LA, Noorbakhsh F, Bouma G, van der Zee R, Vargas DL, Pardo C, McArthur JC, Nottet HS, Power C (2007) Brain-derived human immunodeficiency virus-1 Tat exerts differential effects on LTR transactivation and neuroimmune activation. J Neurovirol 13:173–184

    Article  PubMed  CAS  Google Scholar 

  • Brailoiu GC, Brailoiu E, Chang JK, Dun NJ (2008) Excitatory effects of human immunodeficiency virus 1 Tat on cultured rat cerebral cortical neurons. Neuroscience 151:701–710

    Article  PubMed  CAS  Google Scholar 

  • Bratanich AC, Liu C, McArthur JC, Fudyk T, Glass JD, Mittoo S, Klassen GA, Power C (1998) Brain-derived HIV-1 tat sequences from AIDS patients with dementia show increased molecular heterogeneity. J Neurovirol 4:387–393

    PubMed  CAS  Google Scholar 

  • Brorson JR, Manzolillo PA, Gibbons SJ, Miller RJ (1995) AMPA receptor desensitization predicts the selective vulnerability of cerebellar Purkinje cells to excitotoxicity. J Neurosci 15:4515–4524

    PubMed  CAS  Google Scholar 

  • Bruce-Keller AJ, Chauhan A, Dimayuga FO, Gee J, Keller JN, Nath A (2003) Synaptic transport of human immunodeficiency virus-Tat protein causes neurotoxicity and gliosis in rat brain. J Neurosci 23:8417–8422

    PubMed  CAS  Google Scholar 

  • Buscemi L, Ramonet D, Geiger JD (2007) Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-alpha-mediated neurotoxicity. Neurobiol Dis 26:661–670

    Article  PubMed  CAS  Google Scholar 

  • Cai NS, Cadet JL (2008) The combination of methamphetamine and of the HIV protein, Tat, induces death of the human neuroblastoma cell line, SH-SY5Y. Synapse 62:551–552

    Article  PubMed  CAS  Google Scholar 

  • Cass WA, Harned ME, Peters LE, Nath A, Maragos WF (2003) HIV-1 protein Tat potentiation of methamphetamine-induced decreases in evoked overflow of dopamine in the striatum of the rat. Brain Res 984:133–142

    Article  PubMed  CAS  Google Scholar 

  • Chang HC, Samaniego F, Nair BC, Buonaguro L, Ensoli B (1997) HIV-1 tat protein exits from cells via a leaderless secretory pathway and binds to extracellular matrix-associated heparan sulfate proteoglycan through its basic region. AIDS 11:1421–1431

    Article  PubMed  CAS  Google Scholar 

  • Chauhan A, Turchan J, Pocernich C, Bruce-Keller A, Roth S, Butterfield DA, Major EO, Nath A (2003) Intracellular human immunodeficiency virus Tat expression in astrocytes promotes astrocyte survival but induces potent neurotoxicity at distant sites via axonal transport. J Biol Chem 278:13512–13519

    Article  PubMed  CAS  Google Scholar 

  • Chauhan A, Hahn S, Gartner S, Pardo CA, Netesan SK, McArthur J, Nath A (2007) Molecular programming of endothelin-1 in HIV-infected brain: role of Tat in up-regulation of ET-1 and its inhibition by statins. FASEB J 21:777–789

    Article  PubMed  CAS  Google Scholar 

  • Chen P, Mayne M, Power C, Nath A (1997) The Tat protein of HIV-1 induces tumor necrosis factor-a production: implications for HIV associated neurological diseases. J Biol Chem 272:22385–22388

    Article  PubMed  CAS  Google Scholar 

  • Cheng J, Nath A, Knudsen B, Hochman S, Geiger JDMM, Magnuson DSK (1998) Neuronal excitatory properties of human immunodeficiency virus type 1 tat protein. Neuroscience 82:97–106

    Article  PubMed  CAS  Google Scholar 

  • Chowdhury M, Taylor JP, Tada H, Rappaport J, Wong-Staal F, Amini S, Khalili K (1990) Regulation of the human neurotropic virus promoter by JCV-T antigen and HIV-1 tat protein. Oncogene 5:1737–1742

    PubMed  CAS  Google Scholar 

  • Chowdhury M, Taylor JP, Chang CF, Rappaport J, Khalili K (1992) Evidence that a sequence similar to TAR is important for induction of the JC virus late promoter by human immunodeficiency virus type 1 Tat. J Virol 66:7355–7361

    PubMed  CAS  Google Scholar 

  • Conant K, Ma M, Nath A, Major EO (1996) Extracellular HIV-1 Tat protein is associated with an increase in both NF-kappa B binding and protein kinase C activity in primary human astrocytes. J Virol 70:1384–1389

    PubMed  CAS  Google Scholar 

  • Conant K, Garzino-Demo A, Nath A, McArthur JC, Halliday W, Power C, Gallo RC, Major EO (1998) Induction of monocyte chemotactic protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia. Proc Natl Acad Sci USA 95:3117–3121

    Article  PubMed  CAS  Google Scholar 

  • Coyle-Rink J, Sweet T, Abraham S, Sawaya B, Batuman O, Khalili K, Amini S (2002) Interaction between TGFbeta signaling proteins and C/EBP controls basal and Tat-mediated transcription of HIV-1 LTR in astrocytes. Virology 299:240–247

    Article  PubMed  CAS  Google Scholar 

  • D’Aversa TG, Yu KO, Berman JW (2004) Expression of chemokines by human fetal microglia after treatment with the human immunodeficiency virus type 1 protein Tat. J Neurovirol 10:86–97

    Article  PubMed  CAS  Google Scholar 

  • D’Orso I, Frankel AD (2009) Tat acetylation modulates assembly of a viral-host RNA-protein transcription complex. Proc Natl Acad Sci USA 106:3101–3106

    Article  PubMed  Google Scholar 

  • Darbinian N, Sawaya BE, Khalili K, Jaffe N, Wortman B, Giordano A, Amini S (2001) Functional interaction between cyclin T1/cdk9 and Puralpha determines the level of TNFalpha promoter activation by Tat in glial cells. J Neuroimmunol 121:3–11

    Article  PubMed  CAS  Google Scholar 

  • Deng L, Ammosova T, Pumfery A, Kashanchi F, Nekhai S (2002) HIV-1 Tat interaction with RNA polymerase II C-terminal domain (CTD) and a dynamic association with CDK2 induce CTD phosphorylation and transcription from HIV-1 promoter. J Biol Chem 277:33922–33929

    Article  PubMed  CAS  Google Scholar 

  • Dhillon N, Zhu X, Peng F, Yao H, Williams R, Callen S, Ladner AO, Buch S, Qiu J (2008) Molecular mechanism(s) involved in the synergistic induction of CXCL10 by human immunodeficiency virus type 1 Tat and interferon-gamma in macrophages. J Neurovirol 14:196–204

    PubMed  CAS  Google Scholar 

  • Eletto D, Russo G, Passiatore G, Del Valle L, Giordano A, Khalili K, Gualco E, Peruzzi F (2008) Inhibition of SNAP25 expression by HIV-1 Tat involves the activity of mir-128a. J Cell Physiol 216:764–770

    Article  PubMed  CAS  Google Scholar 

  • El-Hage N, Gurwell JA, Singh IN, Knapp PE, Nath A, Hauser KF (2005) Synergistic increases in intracellular Ca2+, and the release of MCP-1, RANTES, and IL-6 by astrocytes treated with opiates and HIV-1 Tat. Glia 50:91–106

    Article  PubMed  Google Scholar 

  • Ensoli B, Buonaguro L, Barillari G, Fiorelli V, Gendelman R, Morgan R, Wingfield P, Gallo R (1993) Release, uptake, and effects of extracellular human immunodeficiency virus type-1 Tat protein on cell growth and viral replication. J Virol 67:277–287

    PubMed  CAS  Google Scholar 

  • Eugenin EA, D’Aversa TG, Lopez L, Calderon TM, Berman JW (2003) MCP-1 (CCL2) protects human neurons and astrocytes from NMDA or HIV-tat-induced apoptosis. J Neurochem 85:1299–1311

    Article  PubMed  CAS  Google Scholar 

  • Eugenin EA, Dyer G, Calderon TM, Berman JW (2005) HIV-1 tat protein induces a migratory phenotype in human fetal microglia by a CCL2 (MCP-1)-dependent mechanism: possible role in NeuroAIDS. Glia 49:501–510

    Article  PubMed  Google Scholar 

  • Eugenin EA, King JE, Nath A, Calderon TM, Zukin RS, Bennett MV, Berman JW (2007) HIV-tat induces formation of an LRP-PSD-95-NMDAR-nNOS complex that promotes apoptosis in neurons and astrocytes. Proc Natl Acad Sci USA 104:3438–3443

    Article  PubMed  CAS  Google Scholar 

  • Everall I, Barnes H, Spargo E, Lantos P (1995) Assessment of neuronal density in the putamen in human immunodeficiency virus (HIV) infection. Application of stereology and spatial analysis of quadrats. J Neurovirol 1:126–129

    Article  PubMed  CAS  Google Scholar 

  • Ferris MJ, Frederick-Duus D, Fadel J, Mactutus CF, Booze RM (2009) In vivo microdialysis in awake, freely moving rats demonstrates HIV-1 Tat-induced alterations in dopamine transmission. Synapse 63:181–185

    Article  PubMed  CAS  Google Scholar 

  • Fitting S, Booze RM, Mactutus CF (2008) Neonatal intrahippocampal injection of the HIV-1 proteins gp120 and Tat: differential effects on behavior and the relationship to stereological hippocampal measures. Brain Res 1232:139–154

    Article  PubMed  CAS  Google Scholar 

  • Fittipaldi A, Ferrari A, Zoppe M, Arcangeli C, Pellegrini V, Beltram F, Giacca M (2003) Cell membrane lipid rafts mediate caveolar endocytosis of HIV-1 Tat fusion proteins. J Biol Chem 278:34141–34149

    Article  PubMed  CAS  Google Scholar 

  • Flora G, Lee YW, Nath A, Hennig B, Maragos W, Toborek M (2003) Methamphetamine potentiates HIV-1 Tat protein-mediated activation of redox-sensitive pathways in discrete regions of the brain. Exp Neurol 179:60–70

    Article  PubMed  CAS  Google Scholar 

  • Ford KG, Darling D, Souberbielle B, Farzaneh F (2000) Protein transduction: a new tool for the study of cellular ageing and senescence. Mech Ageing Dev 121:113–121

    Article  PubMed  CAS  Google Scholar 

  • Frankel AD, Pabo CO (1988) Cellular uptake of the tat protein from human immunodeficiency virus. Cell 55:1189–1193

    Article  PubMed  CAS  Google Scholar 

  • Frankel A, Bredt D, Pabo C (1988) Tat protein from immunodeficiency virus forms a metal-linked dimer. Science 240:70–73

    Article  PubMed  CAS  Google Scholar 

  • Garthwaite J (1991) Glutamate, nitric oxide and cell–cell signalling in the nervous system. Trends Neurosci 14:60–67

    Article  PubMed  CAS  Google Scholar 

  • Gourdou I, Mabrouk K, Harkiss G, Marchot P, Watt N, Hery F, Vigne R (1990) Neurotoxicity in mice due to cysteine-rich parts of visna virus and HIV-1 Tat proteins. C R Acad Sci III 311:149–155

    PubMed  CAS  Google Scholar 

  • Gregoire C, Peloponese JM Jr, Esquieu D, Opi S, Campbell G, Solomiac M, Lebrun E, Lebreton J, Loret EP (2001) Homonuclear (1)H-NMR assignment and structural characterization of human immunodeficiency virus type 1 Tat Mal protein. Biopolymers 62:324–335

    Article  PubMed  CAS  Google Scholar 

  • Hamy F, Brondani V, Florsheimer A, Stark W, Blommers MJ, Klimkait T (1998) A new class of HIV-1 Tat antagonist acting through Tat-TAR inhibition. Biochemistry 37:5086–5095

    Article  PubMed  CAS  Google Scholar 

  • Hamy F, Gelus N, Zeller M, Lazdins JL, Bailly C, Klimkait T (2000) Blocking HIV replication by targeting Tat protein. Chem Biol 7:669–676

    Article  PubMed  CAS  Google Scholar 

  • Harrich D, Ulich C, Garcia-Martinez LF, Gaynor RB (1997) Tat is required for efficient HIV-1 reverse transcription. EMBO J 16:1224–1235

    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, 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 

  • Hauser KF, Hahn YK, Adjan VV, Zou S, Buch SK, Nath A, Bruce-Keller AJ, Knapp PE (2009) HIV-1 Tat and morphine have interactive effects on oligodendrocyte survival and morphology. Glia 57:194–206

    Article  PubMed  Google Scholar 

  • Hayashi K, Pu H, Tian J, Andras IE, Lee YW, Hennig B, Toborek M (2005) HIV-Tat protein induces P-glycoprotein expression in brain microvascular endothelial cells. J Neurochem 93:1231–1241

    Article  PubMed  CAS  Google Scholar 

  • Hayashi K, Pu H, Andras IE, Eum SY, Yamauchi A, Hennig B, Toborek M (2006) HIV-TAT protein upregulates expression of multidrug resistance protein 1 in the blood-brain barrier. J Cereb Blood Flow Metab 26:1052–1065

    Article  PubMed  CAS  Google Scholar 

  • Hayman M, Arbuthnott G, Harkiss G, Brace H, Filippi P, Philippon V, Thomson D, Vigne R, Wright A (1993) Neurotoxicity of peptide analogues of the transactivating protein tat from Maedi-Visna virus and human immunodeficiency virus. Neuroscience 53:1–6

    Article  PubMed  CAS  Google Scholar 

  • Hofman FM, Dohadwala MM, Wright AD, Hinton DR, Walker SM (1994) Exogenous tat protein activates central nervous system-derived endothelial cells. J Neuroimmunol 54:19–28

    Article  PubMed  CAS  Google Scholar 

  • Hofman FM, Chen P, Incardona F, Zidovetzki R, Hinton DR (1999) HIV-1 tat protein induces the production of interleukin-8 by human brain-derived endothelial cells. J Neuroimmunol 94:28–39

    Article  PubMed  CAS  Google Scholar 

  • Hsu MC, Schutt AD, Holly M, Slice LW, Sherman MI, Richman DD, Potash MJ, Volsky DJ (1991) Inhibition of HIV replication in acute and chronic infections in vitro by a Tat antagonist. Science 254:1799–1802

    Article  PubMed  CAS  Google Scholar 

  • Hsu MC, Schutt AD, Holly M, Slice LW, Sherman MI, Richman DD, Potash MJ, Volsky DJ (1992) Discovery and characterization of an HIV-1 Tat antagonist. Biochem Soc Trans 20:525–531

    PubMed  CAS  Google Scholar 

  • Hsu MC, Dhingra U, Earley JV, Holly M, Keith D, Nalin CM, Richou AR, Schutt AD, Tam SY, Potash MJ et al (1993) Inhibition of type 1 human immunodeficiency virus replication by a tat antagonist to which the virus remains sensitive after prolonged exposure in vitro. Proc Natl Acad Sci USA 90:6395–6399

    Article  PubMed  CAS  Google Scholar 

  • Huang L, Bosch I, Hofmann W, Sodroski J, Pardee AB (1998) Tat protein induces human immunodeficiency virus type 1 (HIV-1) co-receptors and promotes infection with both macrophage-tropic and T-lymphotropic HIV-1 strains. J Virol 72:8952–8960

    PubMed  CAS  Google Scholar 

  • Huang X, Seifert U, Salzmann U, Henklein P, Preissner R, Henke W, Sijts AJ, Kloetzel PM, Dubiel W (2002) The RTP site shared by the HIV-1 Tat protein and the 11S regulator subunit alpha is crucial for their effects on proteasome function including antigen processing. J Mol Biol 323:771–782

    Article  PubMed  CAS  Google Scholar 

  • Huang W, Rha GB, Han MJ, Eum SY, Andras IE, Zhong Y, Hennig B, Toborek M (2008) PPARalpha and PPARgamma effectively protect against HIV-induced inflammatory responses in brain endothelial cells. J Neurochem 107:497–509

    Article  PubMed  CAS  Google Scholar 

  • Hudson L, Liu J, Nath A, Narayan O, Male D, Jones M, Everall I (2000) Detection of human immunodeficiency virus regulatory protein Tat in CNS tissues. J Neurovirol 6:145–155

    Article  PubMed  CAS  Google Scholar 

  • Hwang S, Tamilarasu N, Kibler K, Cao H, Ali A, Ping YH, Jeang KT, Rana TM (2003) Discovery of a small molecule Tat-transactivation-responsive RNA antagonist that potently inhibits human immunodeficiency virus-1 replication. J Biol Chem 278:39092–39103

    Article  PubMed  CAS  Google Scholar 

  • Jayasuriya H, Lingham RB, Graham P, Quamina D, Herranz L, Genilloud O, Gagliardi M, Danzeisen R, Tomassini JE, Zink DL, Guan Z, Singh SB (2002) Durhamycin A, a potent inhibitor of HIV Tat transactivation. J Nat Prod 65:1091–1095

    Article  PubMed  CAS  Google Scholar 

  • Jeang KT, Xiao H, Rich EA (1999) Multifaceted activities of the HIV-1 transactivator of transcription, Tat. J Biol Chem 274:28837–28840

    Article  PubMed  CAS  Google Scholar 

  • Johnston JB, Zhang K, Silva C, Shalinsky DR, Conant K, Ni W, Corbett D, Yong VW, Power C (2001) HIV-1 Tat neurotoxicity is prevented by matrix metalloproteinase inhibitors. Ann Neurol 49:230–241

    Article  PubMed  CAS  Google Scholar 

  • Jonas P, Sakmann B (1992) Glutamate receptor channels in isolated patches from CA1 and CA3 pyramidal cells of rat hippocampal slices. J Physiol (Lond) 455:143–171

    CAS  Google Scholar 

  • Jones M, Olafson K, Del Bigio MR, Peeling J, Nath A (1998) Intraventricular injection of human immunodeficiency virus type 1 (HIV-1) Tat protein causes inflammation, gliosis, apoptosis, and ventricular enlargement. J Neuropathol Exp Neurol 57:563–570

    Article  PubMed  CAS  Google Scholar 

  • Kaniowska D, Kaminski R, Amini S, Radhakrishnan S, Rappaport J, Johnson E, Khalili K, Del Valle L, Darbinyan A (2006) Cross-interaction between JC virus agnoprotein and human immunodeficiency virus type 1 (HIV-1) Tat modulates transcription of the HIV-1 long terminal repeat in glial cells. J Virol 80:9288–9299

    Article  PubMed  CAS  Google Scholar 

  • Kaplan IM, Wadia JS, Dowdy SF (2005) Cationic TAT peptide transduction domain enters cells by macropinocytosis. J Control Release 102:247–253

    Article  PubMed  CAS  Google Scholar 

  • Khurdayan VK, Buch S, El-Hage N, Lutz SE, Goebel SM, Singh IN, Knapp PE, Turchan-Cholewo J, Nath A, Hauser KF (2004) Preferential vulnerability of astroglia and glial precursors to combined opioid and HIV-1 Tat exposure in vitro. Eur J Neurosci 19:3171–3182

    Article  PubMed  Google Scholar 

  • Kim BO, Liu Y, Ruan Y, Xu ZC, Schantz L, He JJ (2003a) Neuropathologies in transgenic mice expressing human immunodeficiency virus type 1 Tat protein under the regulation of the astrocyte-specific glial fibrillary acidic protein promoter and doxycycline. Am J Pathol 162:1693–1707

    PubMed  CAS  Google Scholar 

  • Kim TA, Avraham HK, Koh YH, Jiang S, Park IW, Avraham S (2003b) HIV-1 Tat-mediated apoptosis in human brain microvascular endothelial cells. J Immunol 170:2629–2637

    PubMed  CAS  Google Scholar 

  • Klimkait T, Felder ER, Albrecht G, Hamy F (1998) Rational optimization of a HIV-1 Tat inhibitor: rapid progress on combinatorial lead structures. Biotechnol Bioeng 61:155–168

    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 

  • Kolson DL, Buchhalter J, Collman R, Hellmig B, Farrell CF, Debouck C, Gonzalez-Scarano F (1993) HIV-1 Tat alters normal organization of neurons and astrocytes in primary rodent brain cell cultures: RGD sequence dependence. AIDS Res Hum Retroviruses 9:677–685

    Article  PubMed  CAS  Google Scholar 

  • Kruman I, Nath A, Mattson MP (1998) HIV protein Tat induces apoptosis by a mechanism involving mitochondrial calcium overload and caspase activation. Exp Neurol 154:276–288

    Article  PubMed  CAS  Google Scholar 

  • Kruman II, Nath A, Maragos WF, Chan SL, Jones M, Rangnekar VM, Jakel RJ, Mattson MP (1999) Evidence that Par-4 participates in the pathogenesis of AIDS dementia. Am J Pathol 155:39–46

    PubMed  CAS  Google Scholar 

  • Kuppuswamy M, Subramanian T, Srinivasan A, Chinnadurai G (1989) Multiple functional domains of Tat, the trans-activator of HIV-1, defined by mutational analysis. Nucleic Acids Res 17:3551–3561

    Article  PubMed  CAS  Google Scholar 

  • Kutsch O, Oh J, Nath A, Benveniste EN (2000) Induction of the chemokines interleukin-8 and IP-10 by human immunodeficiency virus type 1 tat in astrocytes. J Virol 74:9214–9221

    Article  PubMed  CAS  Google Scholar 

  • Kutsch O, Levy DN, Bates PJ, Decker J, Kosloff BR, Shaw GM, Priebe W, Benveniste EN (2004) Bis-anthracycline antibiotics inhibit human immunodeficiency virus type 1 transcription. Antimicrob Agents Chemother 48:1652–1663

    Article  PubMed  CAS  Google Scholar 

  • Langford D, Sanders VJ, Mallory M, Kaul M, Masliah E (2002) Expression of stromal cell-derived factor 1alpha protein in HIV encephalitis. J Neuroimmunol 127:115–126

    Article  PubMed  CAS  Google Scholar 

  • Langford D, Grigorian A, Hurford R, Adame A, Crews L, Masliah E (2004) The role of mitochondrial alterations in the combined toxic effects of human immunodeficiency virus Tat protein and methamphetamine on calbindin positive-neurons. J Neurovirol 10:327–337

    Article  PubMed  CAS  Google Scholar 

  • Lapidot A, Ben-Asher E, Eisenstein M (1995) Tetrahydropyrimidine derivatives inhibit binding of a Tat-like, arginine-containing peptide, to HIV TAR RNA in vitro. FEBS Lett 367:33–38

    Article  PubMed  CAS  Google Scholar 

  • Lee CW, Cao H, Ichiyama K, Rana TM (2005) Design and synthesis of a novel peptidomimetic inhibitor of HIV-1 Tat-TAR interactions: squaryldiamide as a new potential bioisostere of unsubstituted guanidine. Bioorg Med Chem Lett 15:4243–4246

    Article  PubMed  CAS  Google Scholar 

  • Li ST, Matsushita M, Moriwaki A, Saheki Y, Lu YF, Tomizawa K, Wu HY, Terada H, Matsui H (2004) HIV-1 inhibits long-term potentiation and attenuates spatial learning. Ann Neurol 55:362–371

    Article  PubMed  CAS  Google Scholar 

  • Li W, Huang Y, Reid R, Steiner J, Malpica-Llanos T, Darden TA, Shankar SK, Mahadevan A, Satishchandra P, Nath A (2008) NMDA receptor activation by HIV-Tat protein is clade dependent. J Neurosci 28:12190–12198

    Article  PubMed  CAS  Google Scholar 

  • Lind KE, Du Z, Fujinaga K, Peterlin BM, James TL (2002) Structure-based computational database screening, in vitro assay, and NMR assessment of compounds that target TAR RNA. Chem Biol 9:185–193

    Article  PubMed  CAS  Google Scholar 

  • Liu Y, Jones M, Hingtgen CM, Bu G, Laribee N, Tanzi RE, Moir RD, Nath A, He JJ (2000) Uptake of HIV-1 tat protein mediated by low-density lipoprotein receptor-related protein disrupts the neuronal metabolic balance of the receptor ligands. Nat Med 6:1380–1387

    Article  PubMed  CAS  Google Scholar 

  • Liu X, Jana M, Dasgupta S, Koka S, He J, Wood C, Pahan K (2002) Human immunodeficiency virus type-1 (HIV-1) Tat induces nitric oxide synthase in human astroglia. J Biol Chem 277(42):39312–39319

    Article  PubMed  CAS  Google Scholar 

  • Lusti-Narasimhan M, Power CA, Allet B, Alouani S, Bacon KB, Mermod JJ, Proudfoot AE, Wells TN (1995) Mutation of Leu25 and Val27 introduces CC chemokine activity into interleukin-8. J Biol Chem 270:2716–2721

    Article  PubMed  CAS  Google Scholar 

  • Ma M, Nath A (1997) Molecular determinants for cellular uptake of Tat protein of human immunodeficiency virus type 1 in brain cells. J Virol 71:2495–2499

    PubMed  CAS  Google Scholar 

  • Maggirwar SB, Tong N, Ramirez S, Gelbard HA, Dewhurst S (1999) HIV-1 Tat-mediated activation of glycogen synthase kinase-3beta contributes to Tat-mediated neurotoxicity. J Neurochem 73:578–586

    Article  PubMed  CAS  Google Scholar 

  • Magnuson DS, Knudsen BE, Geiger JD, Brownstone RM, Nath A (1995) Human immunodeficiency virus type 1 tat activates non-N-methyl-d-aspartate excitatory amino acid receptors and causes neurotoxicity. Ann Neurol 37:373–380

    Article  PubMed  CAS  Google Scholar 

  • Malim MH, Cullen BR (1991) HIV-1 structural gene expression requires the binding of multiple Rev monomers to the viral RRE: implications for HIV-1 latency. Cell 65:241–248

    Article  PubMed  CAS  Google Scholar 

  • Malva JO, Carvalho AP, Carvalho CM (1998) Kainate receptors in hippocampal CA3 subregion: evidence for a role in regulating neurotransmitter release. Neurochem Int 32:1–6

    Article  PubMed  CAS  Google Scholar 

  • Maragos WF, Young KL, Turchan JT, Guseva M, Pauly JR, Nath A, Cass WA (2002) Human immunodeficiency virus-1 Tat protein and methamphetamine interact synergistically to impair striatal dopaminergic function. J Neurochem 83:955–963

    Article  PubMed  CAS  Google Scholar 

  • Maragos WF, Tillman P, Jones M, Bruce-Keller AJ, Roth S, Bell JE, Nath A (2003) Neuronal injury in hippocampus with human immunodeficiency virus transactivating protein, Tat. Neuroscience 117:43–53

    Article  PubMed  CAS  Google Scholar 

  • Marcello A, Zoppe M, Giacca M (2001) Multiple modes of transcriptional regulation by the HIV-1 Tat transactivator. IUBMB Life 51:175–181

    Article  PubMed  CAS  Google Scholar 

  • Mayne M, Bratanich AC, Chen P, Rana F, Nath A, Power C (1998) HIV-1 tat molecular diversity and induction of TNF-alpha: implications for HIV-induced neurological disease. Neuroimmunomodulation 5:184–192

    Article  PubMed  CAS  Google Scholar 

  • McCarthy M, Auger D, He J, Wood C (1998) Cytomegalovirus and human herpesvirus-6 transactivate the HIV-1 long terminal repeat via multiple response regions in human fetal astrocytes. J Neurovirol 4:495–511

    PubMed  CAS  Google Scholar 

  • McManus CM, Weidenheim K, Woodman SE, Nunez J, Hesselgesser J, Nath A, Berman JW (2000) Chemokine and chemokine-receptor expression in human glial elements: induction by the HIV protein, Tat, and chemokine autoregulation. Am J Pathol 156:1441–1453

    PubMed  CAS  Google Scholar 

  • McMillan NA, Chun RF, Siderovski DP, Galabru J, Toone WM, Samuel CE, Mak TW, Hovanessian AG, Jeang KT, Williams BR (1995) HIV-1 Tat directly interacts with the interferon-induced, double-stranded RNA-dependent kinase, PKR. Virology 213:413–424

    Article  PubMed  CAS  Google Scholar 

  • Michne WF, Schroeder JD, Bailey TR, Neumann HC, Cooke D, Young DC, Hughes JV, Kingsley SD, Ryan KA, Putz HS et al (1995) Keto/enol epoxy steroids as HIV-1 Tat inhibitors: structure-activity relationships and pharmacophore localization. J Med Chem 38:3197–3206

    Article  PubMed  CAS  Google Scholar 

  • Mishra M, Vetrivel S, Siddappa NB, Ranga U, Seth P (2008) Clade-specific differences in neurotoxicity of human immunodeficiency virus-1 B and C Tat of human neurons: significance of dicysteine C30C31 motif. Ann Neurol 63:366–376

    Article  PubMed  CAS  Google Scholar 

  • Montembault M, Vo-Thanh G, Deyine A, Fargeas V, Villieras M, Adjou A, Dubreuil D, Esquieu D, Gregoire C, Opi S, Peloponese JM, Campbell G, Watkins J, de Mareuil J, Aubertin AM, Bailly C, Loret E, Lebreton J (2004) A possible improvement for structure-based drug design illustrated by the discovery of a Tat HIV-1 inhibitor. Bioorg Med Chem Lett 14:1543–1546

    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 

  • Nath A, Haughey NJ, Jones M, Anderson C, Bell JE, Geiger JD (2000) Synergistic neurotoxicity by human immunodeficiency virus proteins Tat and gp120: protection by memantine. Ann Neurol 47:186–194

    Article  PubMed  CAS  Google Scholar 

  • Nath A, Hauser KF, Wojna V, Booze RM, Maragos W, Prendergast M, Cass W, Turchan JT (2002) Molecular basis for interactions of HIV and drugs of abuse. J Acquir Immune Defic Syndr 31(suppl 2):S62–S69

    PubMed  CAS  Google Scholar 

  • Nelbock P, Dillon PJ, Perkins A, Rosen CA (1990) A cDNA for a protein that interacts with the human immunodeficiency virus Tat transactivator. Science 248:1650–1653

    Article  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

    PubMed  CAS  Google Scholar 

  • New DR, Maggirwar SB, Epstein LG, Dewhurst S, Gelbard HA (1998) HIV-1 Tat induces neuronal death via tumor necrosis factor-alpha and activation of non-N-methyl-d-aspartate receptors by a NFkappaB-independent mechanism. J Biol Chem 273:17852–17858

    Article  PubMed  CAS  Google Scholar 

  • Norman JP, Perry SW, Kasischke KA, Volsky DJ, Gelbard HA (2007) HIV-1 trans activator of transcription protein elicits mitochondrial hyperpolarization and respiratory deficit, with dysregulation of complex IV and nicotinamide adenine dinucleotide homeostasis in cortical neurons. J Immunol 178:869–876

    PubMed  CAS  Google Scholar 

  • Norman JP, Perry SW, Reynolds HM, Kiebala M, De Mesy Bentley KL, Trejo M, Volsky DJ, Maggirwar SB, Dewhurst S, Masliah E, Gelbard HA (2008) HIV-1 Tat activates neuronal ryanodine receptors with rapid induction of the unfolded protein response and mitochondrial hyperpolarization. PLoS ONE 3:e3731

    Article  PubMed  CAS  Google Scholar 

  • Ohya O, Tomaru U, Yamashita I, Kasai T, Morita K, Ikeda H, Wakisaka A, Yoshiki T (1997) HTLV-I induced myeloneuropathy in WKAH rats: apoptosis and local activation of the HTLV-I pX and TNF-alpha genes implicated in the pathogenesis. Leukemia 11(suppl 3):255–257

    PubMed  Google Scholar 

  • Patrizio M, Colucci M, Levi G (2001) Human immunodeficiency virus type 1 Tat protein decreases cyclic AMP synthesis in rat microglia cultures. J Neurochem 77:399–407

    Article  PubMed  CAS  Google Scholar 

  • Peloponese JM Jr, Collette Y, Gregoire C, Bailly C, Campese D, Meurs EF, Olive D, Loret EP (1999) Full peptide synthesis, purification, and characterization of six Tat variants. Differences observed between HIV-1 isolates from Africa and other continents. J Biol Chem 274:11473–11478

    Article  PubMed  CAS  Google Scholar 

  • Perez A, Probert AW, Wang KK, Sharmeen L (2001) Evaluation of HIV-1 Tat induced neurotoxicity in rat cortical cell culture. J Neurovirol 7:1–10

    Article  PubMed  CAS  Google Scholar 

  • Perry SW, Norman JP, Litzburg A, Zhang D, Dewhurst S, Gelbard HA (2005) HIV-1 transactivator of transcription protein induces mitochondrial hyperpolarization and synaptic stress leading to apoptosis. J Immunol 174:4333–4344

    PubMed  CAS  Google Scholar 

  • Polazzi E, Levi G, Minghetti L (1999) Human immunodeficiency virus type 1 Tat protein stimulates inducible nitric oxide synthase expression and nitric oxide production in microglial cultures. J Neuropathol Exp Neurol 58:825–831

    Article  PubMed  CAS  Google Scholar 

  • Pragani R, Roush WR (2008) Studies on the synthesis of durhamycin A: stereoselective synthesis of a model aglycone. Org Lett 10:4613–4616

    Article  PubMed  CAS  Google Scholar 

  • Prendergast MA, Rogers DT, Mulholland PJ, Littleton JM, Wilkins LH Jr, Self RL, Nath A (2002) Neurotoxic effects of the human immunodeficiency virus type-1 transcription factor Tat require function of a polyamine sensitive-site on the N-methyl-d-aspartate receptor. Brain Res 954:300–307

    Article  PubMed  CAS  Google Scholar 

  • Pu H, Hayashi K, Andras IE, Eum SY, Hennig B, Toborek M (2007) Limited role of COX-2 in HIV Tat-induced alterations of tight junction protein expression and disruption of the blood-brain barrier. Brain Res 1184:333–344

    Article  PubMed  CAS  Google Scholar 

  • Pulliam L, Sun B, Rempel H, Martinez PM, Hoekman JD, Rao RJ, Frey WHII, Hanson LR (2007) Intranasal tat alters gene expression in the mouse brain. J Neuroimmune Pharmacol 2:87–92

    Article  PubMed  Google Scholar 

  • Ramirez SH, Sanchez JF, Dimitri CA, Gelbard HA, Dewhurst S, Maggirwar SB (2001) Neurotrophins prevent HIV Tat-induced neuronal apoptosis via a nuclear factor-kappaB (NF-kappaB)-dependent mechanism. J Neurochem 78:874–889

    Article  PubMed  CAS  Google Scholar 

  • Ranga U, Shankarappa R, Siddappa NB, Ramakrishna L, Nagendran R, Mahalingam M, Mahadevan A, Jayasuryan N, Satishchandra P, Shankar SK, Prasad VR (2004) Tat protein of human immunodeficiency virus type 1 subtype C strains is a defective chemokine. J Virol 78:2586–2590

    Article  PubMed  CAS  Google Scholar 

  • Rao VR, Sas AR, Eugenin EA, Siddappa NB, Bimonte-Nelson H, Berman JW, Ranga U, Tyor WR, Prasad VR (2008) HIV-1 clade-specific differences in the induction of neuropathogenesis. J Neurosci 28:10010–10016

    Article  PubMed  CAS  Google Scholar 

  • Richard JP, Melikov K, Brooks H, Prevot P, Lebleu B, Chernomordik LV (2005) Cellular uptake of unconjugated TAT peptide involves clathrin-dependent endocytosis and heparan sulfate receptors. J Biol Chem 280:15300–15306

    Article  PubMed  CAS  Google Scholar 

  • Robert-Guroff M, Popovic M, Gartner S, Markham P, Gallo RC, Reitz MS (1990) Structure and expression of tat-, rev-, and nef-specific transcripts of human immunodeficiency virus type 1 in infected lymphocytes and macrophages. J Virol 64:3391–3398

    PubMed  CAS  Google Scholar 

  • Rodman TC, Pruslin FH, To SE, Winston R (1992) Human immunodeficiency virus (HIV) Tat-reactive antibodies present in normal HIV-negative sera and depleted in HIV-positive sera. Identification of the epitope. J Exp Med 175:1247–1253

    Article  PubMed  CAS  Google Scholar 

  • Rosen CA, Terwilliger E, Dayton A, Sodroski JG, Haseltine WA (1988) Intragenic cis-acting art gene-responsive sequences of the human immunodeficiency virus. Proc Natl Acad Sci USA 85:2071–2075

    Article  PubMed  CAS  Google Scholar 

  • Rott O, Tontsch U, Fleischer B, Cash E (1993) Interleukin-6 production in “normal” and HTLV-1 tax-expressing brain-specific endothelial cells. Eur J Immunol 23:1987–1991

    Article  PubMed  CAS  Google Scholar 

  • Ruben S, Perkins A, Purcell R, Joung K, Sia R, Burghoff R, Haseltine WA, Rosen CA (1989) Structural and functional characterization of human immunodeficiency virus tat protein. J Virol 63:1–8

    PubMed  CAS  Google Scholar 

  • Sabatier JM, Vives E, Marbrouk K et al (1991) Evidence for neurotoxicity of tat from HIV. J Virol 65:961–967

    PubMed  CAS  Google Scholar 

  • Schwarze SR, Ho A, Vocero-Akbani A, Dowdy SF (1999) In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285:1569–1572

    Article  PubMed  CAS  Google Scholar 

  • Secchiero P, Zella D, Capitani S, Gallo RC, Zauli G (1999) Extracellular HIV-1 tat protein up-regulates the expression of surface CXC-chemokine receptor 4 in resting CD4+ T cells. J Immunol 162:2427–2431

    PubMed  CAS  Google Scholar 

  • Seeger M, Ferrell K, Frank R, Dubiel W (1997) HIV-1 tat inhibits the 20S proteasome and its 11S regulator-mediated activation. J Biol Chem 272:8145–8148

    Article  PubMed  CAS  Google Scholar 

  • Sheng WS, Hu S, Lokensgard JR, Peterson PK (2003) U50, 488 inhibits HIV-1 Tat-induced monocyte chemoattractant protein-1 (CCL2) production by human astrocytes. Biochem Pharmacol 65:9–14

    Article  PubMed  CAS  Google Scholar 

  • Shi B, Raina J, Lorenzo A, Busciglio J, Gabuzda D (1998) Neuronal apoptosis induced by HIV-1 Tat protein and TNF-alpha: potentiation of neurotoxicity mediated by oxidative stress and implications for HIV-1 dementia. J Neurovirol 4:281–290

    Article  PubMed  CAS  Google Scholar 

  • Silvers JM, Aksenova MV, Aksenov MY, Mactutus CF, Booze RM (2007) Neurotoxicity of HIV-1 Tat protein: involvement of D1 dopamine receptor. Neurotoxicology 28:1184–1190

    Article  PubMed  CAS  Google Scholar 

  • Smith DG, Guillemin GJ, Pemberton L, Kerr S, Nath A, Smythe GA, Brew BJ (2001) Quinolinic acid is produced by macrophages stimulated by platelet activating factor, Nef and Tat. J Neurovirol 7:56–60

    Article  PubMed  CAS  Google Scholar 

  • Snyder EL, Dowdy SF (2001) Protein/peptide transduction domains: potential to deliver large DNA molecules into cells. Curr Opin Mol Ther 3:147–152

    PubMed  CAS  Google Scholar 

  • Spitere K, Toulouse A, O’Sullivan DB, Sullivan AM (2008) TAT-PAX6 protein transduction in neural progenitor cells: a novel approach for generation of dopaminergic neurones in vitro. Brain Res 1208:25–34

    Article  PubMed  CAS  Google Scholar 

  • Starling I, Wright A, Arbuthnott G, Harkiss G (1999) Acute in vivo neurotoxicity of peptides from Maedi Visna virus transactivating protein Tat. Brain Res 830:285–291

    Article  PubMed  CAS  Google Scholar 

  • Stauber RH, Pavlakis GN (1998) Intracellular trafficking and interactions of the HIV-1 Tat protein. Virology 252:126–136

    Article  PubMed  CAS  Google Scholar 

  • Strijbos PJ, Zamani MR, Rothwell NJ, Arbuthnott G, Harkiss G (1995) Neurotoxic mechanisms of transactivating protein Tat of Maedi-Visna virus. Neurosci Lett 197:215–218

    Article  PubMed  CAS  Google Scholar 

  • Sui Z, Sniderhan LF, Fan S, Kazmierczak K, Reisinger E, Kovacs AD, Potash MJ, Dewhurst S, Gelbard HA, Maggirwar SB (2006) Human immunodeficiency virus-encoded Tat activates glycogen synthase kinase-3beta to antagonize nuclear factor-kappaB survival pathway in neurons. Eur J Neurosci 23:2623–2634

    Article  PubMed  Google Scholar 

  • Sui Z, Sniderhan LF, Schifitto G, Phipps RP, Gelbard HA, Dewhurst S, Maggirwar SB (2007) Functional synergy between CD40 ligand and HIV-1 Tat contributes to inflammation: implications in HIV type 1 dementia. J Immunol 178:3226–3236

    PubMed  CAS  Google Scholar 

  • Szymocha R, Brisson C, Bernard A, Akaoka H, Belin MF, Giraudon P (2000) Long-term effects of HTLV-1 on brain astrocytes: sustained expression of Tax-1 associated with synthesis of inflammatory mediators. J Neurovirol 6:350–357

    Article  PubMed  CAS  Google Scholar 

  • Tada H, Rappaport J, Lashgari M, Amini S, Wong-Staal F, Khalili K (1990) Trans-activation of the JC virus late promoter by the tat protein of type 1 human immunodeficiency virus in glial cells. Proc Natl Acad Sci USA 87:3479–3483

    Article  PubMed  CAS  Google Scholar 

  • Tanaka T, Nakamura T, Takagi H, Sato M (1997) Molecular cloning and characterization of a novel TBP-1 interacting protein (TBPIP): enhancement of TBP-1 action on Tat by TBPIP. Biochem Biophys Res Commun 239:176–181

    Article  PubMed  CAS  Google Scholar 

  • Tardieu M, Hery C, Peudenier S, Boespflug O, Montagnier L (1992) Human immunodeficiency virus type 1-infected monocytic cells can destroy human neural cells after cell-to-cell adhesion. Ann Neurol 32:11–17

    Article  PubMed  CAS  Google Scholar 

  • Taylor JP, Pomerantz R, Bagasra O, Chowdhury M, Rappaport J, Khalili K, Amini S (1992) TAR-independent transactivation by Tat in cells derived from the CNS: a novel mechanism of HIV-1 gene regulation. EMBO J 11:3395–3403

    PubMed  CAS  Google Scholar 

  • Theodore S, Cass WA, Nath A, Steiner J, Young K, Maragos WF (2006a) Inhibition of tumor necrosis factor-alpha signaling prevents human immunodeficiency virus-1 protein Tat and methamphetamine interaction. Neurobiol Dis 23:663–668

    Article  PubMed  CAS  Google Scholar 

  • Theodore S, Stolberg S, Cass WA, Maragos WF (2006b) Human immunodeficiency virus-1 protein tat and methamphetamine interactions. Ann N Y Acad Sci 1074:178–190

    Article  PubMed  CAS  Google Scholar 

  • Theodore S, Cass WA, Nath A, Maragos WF (2007) Progress in understanding basal ganglia dysfunction as a common target for methamphetamine abuse and HIV-1 neurodegeneration. Curr HIV Res 5:301–313

    Article  PubMed  CAS  Google Scholar 

  • Thomas ER, Dunfee RL, Stanton J, Bogdan D, Kunstman K, Wolinsky SM, Gabuzda D (2007) High frequency of defective vpu compared with tat and rev genes in brain from patients with HIV type 1-associated dementia. AIDS Res Hum Retroviruses 23:575–580

    Article  PubMed  CAS  Google Scholar 

  • Toborek M, Lee YW, Pu H, Malecki A, Flora G, Garrido R, Hennig B, Bauer HC, Nath A (2003) HIV-Tat protein induces oxidative and inflammatory pathways in brain endothelium. J Neurochem 84:169–179

    Article  PubMed  CAS  Google Scholar 

  • Turchan J, Anderson C, Hauser KF, Sun Q, Zhang J, Liu Y, Wise PM, Kruman I, Maragos W, Mattson MP, Booze R, Nath A (2001) Estrogen protects against the synergistic toxicity by HIV proteins, methamphetamine and cocaine. BMC Neurosci 2:3

    Article  PubMed  CAS  Google Scholar 

  • Tyagi M, Rusnati M, Presta M, Giacca M (2001) Internalization of HIV-1 tat requires cell surface heparan sulfate proteoglycans. J Biol Chem 276:3254–3261

    Article  PubMed  CAS  Google Scholar 

  • Valle LD, Croul S, Morgello S, Amini S, Rappaport J, Khalili K (2000) Detection of HIV-1 Tat and JCV capsid protein, VP1, in AIDS brain with progressive multifocal leukoencephalopathy. J Neurovirol 6:221–228

    Article  PubMed  Google Scholar 

  • Vendeville A, Rayne F, Bonhoure A, Bettache N, Montcourrier P, Beaumelle B (2004) HIV-1 Tat enters T cells using coated pits before translocating from acidified endosomes and eliciting biological responses. Mol Biol Cell 15:2347–2360

    Article  PubMed  CAS  Google Scholar 

  • Vives E, Brodin P, Lebleu B (1997) A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J Biol Chem 272:16010–16017

    Article  PubMed  CAS  Google Scholar 

  • Wang P, Barks JD, Silverstein FS (1999) Tat, a human immunodeficiency virus-1-derived protein, augments excitotoxic hippocampal injury in neonatal rats. Neuroscience 88:585–597

    Article  PubMed  CAS  Google Scholar 

  • Weeks BS, Lieberman DM, Johnson B, Roque E, Green M, Lowenstein P, Oldfield EH, Kleinman HK (1995) Neurotoxicity of the human immunodeficiency virus type 1 Tat transactivator to PC12 cells requires the Tat amino acid 49–58 basic domain. J Neurosci Res 42:34–40

    Article  PubMed  CAS  Google Scholar 

  • Wei X, Miou Z, Baudry M (2008) Neuroprotection by cell permeable TAT-mGluR1 peptide in ischemia: synergy between carrier and cargo sequences. Neuroscientist 14:409–414

    Article  CAS  Google Scholar 

  • Weiss JM, Nath A, Major EO, Berman JW (1999) HIV-Tat induces MCP-1 mediated monocyte transmigration and upregulates CCR5 expression on human monocytes. J Immunol 163:2953–2959

    PubMed  CAS  Google Scholar 

  • Wesselingh SL, Power C, Glass JD, Tyor WR, McArthur JC, Farber JM, Griffin JW, Griffin DE (1993) Intracerebral cytokine messenger RNA expression in acquired immunodeficiency syndrome dementia. Ann Neurol 33:576–582

    Article  PubMed  CAS  Google Scholar 

  • Westendorp MO, Frank R, Ochsenbauer C, Stricker K, Dhein J, Walczak H, Debatin KM, Krammer PH (1995) Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature 375:497–500

    Article  PubMed  CAS  Google Scholar 

  • Wiley CA, Baldwin M, Achim CL (1996) Expression of regulatory and structural mRNA in the central nervous system. AIDS 10:943–947

    Article  Google Scholar 

  • Woodman SE, Benveniste EN, Nath A, Berman JW (1999) Human immunodeficiency virus type 1 TAT protein induces adhesion molecule expression in astrocytes. J Neurovirol 5:678–684

    Article  PubMed  CAS  Google Scholar 

  • Wortman MJ, Krachmarov CP, Kim JH, Gordon RG, Chepenik LG, Brady JN, Gallia GL, Khalili K, Johnson EM (2000) Interaction of HIV-1 Tat with Puralpha in nuclei of human glial cells: characterization of RNA-mediated protein–protein binding. J Cell Biochem 77:65–74

    Article  PubMed  CAS  Google Scholar 

  • Xiao H, Neuveut C, Tiffany HL, Benkirane M, Rich EA, Murphy PM, Jeang KT (2000) Selective CXCR4 antagonism by Tat: implications for in vivo expansion of coreceptor use by HIV-1. Proc Natl Acad Sci USA 97:11466–11471

    Article  PubMed  CAS  Google Scholar 

  • Yedavalli VS, Benkirane M, Jeang KT (2003) Tat and trans-activation-responsive (TAR) RNA-independent induction of HIV-1 long terminal repeat by human and murine cyclin T1 requires Sp1. J Biol Chem 278:6404–6410

    Article  PubMed  CAS  Google Scholar 

  • Zagury JF, Sill A, Blattner W, Lachgar A, Le Buanec H, Richardson M, Rappaport J, Hendel H, Bizzini B, Gringeri A, Carcagno M, Criscuolo M, Burny A, Gallo RC, Zagury D (1998) Antibodies to the HIV-1 Tat protein correlated with nonprogression to AIDS: a rationale for the use of Tat toxoid as an HIV-1 vaccine [see comments]. J Hum Virol 1:282–292

    PubMed  CAS  Google Scholar 

  • Zhao T, Adams MH, Zou SP, El-Hage N, Hauser KF, Knapp PE (2007) Silencing the PTEN gene is protective against neuronal death induced by human immunodeficiency virus type 1 Tat. J Neurovirol 13:97–106

    Article  PubMed  CAS  Google Scholar 

  • Zhong Y, Smart EJ, Weksler B, Couraud PO, Hennig B, Toborek M (2008) Caveolin-1 regulates human immunodeficiency virus-1 Tat-induced alterations of tight junction protein expression via modulation of the Ras signaling. J Neurosci 28:7788–7796

    Article  PubMed  CAS  Google Scholar 

  • Zidovetzki R, Wang JL, Chen P, Jeyaseelan R, Hofman F (1998) Human immunodeficiency virus Tat protein induces interleukin 6 mRNA expression in human brain endothelial cells via protein kinase C- and cAMP-dependent protein kinase pathways. AIDS Res Hum Retroviruses 14:825–833

    Article  PubMed  CAS  Google Scholar 

  • Zou W, Kim BO, Zhou BY, Liu Y, Messing A, He JJ (2007) Protection against human immunodeficiency virus type 1 Tat neurotoxicity by Ginkgo biloba extract EGb 761 involving glial fibrillary acidic protein. Am J Pathol 171:1923–1935

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Neurology, Johns Hopkins University, 509 Pathology, 600 North Wolfe Street, Baltimore, MD, 21287, USA

    Wenxue Li, Guanhan Li, Joseph Steiner & Avindra Nath

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Li, W., Li, G., Steiner, J. et al. Role of Tat Protein in HIV Neuropathogenesis. Neurotox Res 16, 205–220 (2009). https://doi.org/10.1007/s12640-009-9047-8

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