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Neurotoxicity of Human Immunodeficiency Virus-1: Viral Proteins and Axonal Transport

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Abstract

Human immunodeficiency virus-1 (HIV) infection of the central nervous system may cause a neurological syndrome termed HIV-associated neurocognitive disorder (HAND) which includes minor neurocognitive disorders or a more severe form of motor and cognitive impairments. Although treatment with highly active antiretroviral agents decreases the load of HIV in the brain, the prevalence of mild forms of HAND is actually increased due to longer life. Therefore, adjunctive and combined therapies must be developed to prevent and perhaps reverse the neurologic deficits observed in individuals with HAND. Key to developing effective therapies is a better understanding of the molecular and cellular mechanisms by which the virus causes this disorder. A number of HIV proteins has been shown to be released from HIV-infected cells. Moreover, these proteins have been shown to possess neurotoxic properties. This review describes new evidence of a direct interaction of the HIV protein gp120 with neurons, which might play a role in the etiopathology of HAND.

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References

  • Acquas E, Bachis A, Nosheny RL, Cernak I, Mocchetti I (2004) Human immunodeficiency virus type 1 protein gp120 causes neuronal cell death in the rat brain by activating caspases. Neurotox Res 5:605–615

    Article  PubMed  Google Scholar 

  • Ahmed F, Tessarollo L, Thiele C, Mocchetti I (2008) Brain-derived neurotrophic factor modulates expression of chemokine receptors in the brain. Brain Res 1227:1–11

    Article  PubMed  CAS  Google Scholar 

  • Albini A, Soldi R, Giunciuglio D, Giraudo E, Benelli R, Primo L, Noonan D, Salio M, Camussi G, Rockl W, Bussolino F (1996) The angiogenesis induced by HIV-1 tat protein is mediated by the Flk-1/KDR receptor on vascular endothelial cells. Nat Med 2:1371–1375

    Article  PubMed  CAS  Google Scholar 

  • Albright AV, Shieh JT, Itoh T, Lee B, Pleasure D, O’Connor MJ, Doms RW, Gonzalez-Scarano F (1999) Microglia express CCR5, CXCR4, and CCR3, but of these, CCR5 is the principal coreceptor for human immunodeficiency virus type 1 dementia isolates. J Virol 73:205–213

    PubMed  CAS  Google Scholar 

  • Albright AV, Soldan SS, Gonzalez-Scarano F (2003) Pathogenesis of human immunodeficiency virus-induced neurological disease. J Neurovirol 9:222–227

    PubMed  CAS  Google Scholar 

  • Altar CA, Cai N, Bliven T, Juhasz M, Conner JM, Acheson AL, Lindsay RM, Wiegand SJ (1997) Anterograde transport of brain-derived neurotrophic factor and its role in the brain. Nature 389:856–860

    Article  PubMed  CAS  Google Scholar 

  • Avdoshina V, Biggio F, Palchik G, Campbell LA, Mocchetti I (2010) Morphine induces the release of CCL5 from astrocytes: potential neuroprotective mechanism against the HIV protein gp120. Glia 58:1630–1639

    PubMed  Google Scholar 

  • Avdoshina V, Becker J, Campbell L, Parsadanian M, Mhyre T, Tessarollo L, Mocchetti I (2011) Neurotrophins modulate the expression of chemokine receptors in the brain. J NeuroVirol 17:58–62

    Article  PubMed  CAS  Google Scholar 

  • Bachis A, Mocchetti I (2004) The chemokine receptor CXCR4 and not the N-methyl-d-aspartate receptor mediates gp120 neurotoxicity in cerebellar granule cells. J Neurosci Res 75:75–82

    Article  PubMed  CAS  Google Scholar 

  • Bachis A, Mocchetti I (2005) Brain-derived neurotrophic factor is neuroprotective against human immunodeficiency virus-1 envelope proteins. Ann NY Acad Sci 1053:247–257

    Article  PubMed  CAS  Google Scholar 

  • Bachis A, Major EO, Mocchetti I (2003) Brain-derived neurotrophic factor inhibits human immunodeficiency virus-1/gp120-mediated cerebellar granule cell death by preventing gp120 internalization. J Neurosci 23:5715–5722

    PubMed  CAS  Google Scholar 

  • Bachis A, Aden SA, Nosheny RL, Andrews PM, Mocchetti I (2006) Axonal transport of human immunodeficiency virus type 1 envelope glycoprotein 120 is found in association with neuronal apoptosis. J Neurosci 26:6771–6780

    Article  PubMed  CAS  Google Scholar 

  • Bachis A, Cruz MI, Mocchetti I (2010) M-tropic HIV envelope protein gp120 exhibits a different neuropathological profile than T-tropic gp120 in rat striatum. Eur J Neurosci 32:570–578

    Article  PubMed  Google Scholar 

  • Bagetta G, Corasaniti MT, Aloe L, Berliocchi L, Costa N, Finazzi-Agro A, Nistico G (1996) Intracerebral injection of human immunodeficiency virus type 1 coat protein gp120 differentially affects the expression of nerve growth factor and nitric oxide synthase in the hippocampus of rat. Proc Natl Acad Sci USA 93:928–933

    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 

  • Beggs HE, Schahin-Reed D, Zang K, Goebbels S, Nave KA, Gorski J, Jones KR, Sretavan D, Reichardt LF (2003) FAK deficiency in cells contributing to the basal lamina results in cortical abnormalities resembling congenital muscular dystrophies. Neuron 40:501–514

    Article  PubMed  CAS  Google Scholar 

  • Berger JR, Arendt G (2000) HIV dementia: The role of the basal ganglia and dopaminergic systems. J Psychopharmacol 14:214–221

    Article  PubMed  CAS  Google Scholar 

  • Berger EA, Murphy PM, Farber JM (1999) Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol 17:657–700

    Article  PubMed  CAS  Google Scholar 

  • Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E, Vescovi A, Bagetta G, Kollias G, Meldolesi J, Volterra A (2001) CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci 4:702–710

    Article  PubMed  CAS  Google Scholar 

  • Biard-Piechaczyk M, Robert-Hebmann V, Richard V, Roland J, Hipskind RA, Devaux C (2000) Caspase-dependent apoptosis of cells expressing the chemokine receptor CXCR4 is induced by cell membrane-associated human immunodeficiency virus type 1 envelope glycoprotein (gp120). Virology 268:329–344

    Article  PubMed  CAS  Google Scholar 

  • Bodner A, Toth PT, Miller RJ (2004) Activation of c-Jun N-terminal kinase mediates gp120IIIB- and nucleoside analogue-induced sensory neuron toxicity. Exp Neurol 188:246–253

    Article  PubMed  CAS  Google Scholar 

  • Boldogh IR, Pon LA (2007) Mitochondria on the move. Trends Cell Biol 17:502–510

    Article  PubMed  CAS  Google Scholar 

  • Brack-Werner R (1999) Astrocytes: HIV cellular reservoirs and important participants in neuropathogenesis. AIDS 13:1–22

    Article  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 

  • Cavallaro U, Dejana E (2011) Adhesion molecule signalling: not always a sticky business. Nat Rev Mol Cell Biol 12:189–197

    Article  PubMed  CAS  Google Scholar 

  • Chen H, Chan DC (2009) Mitochondrial dynamics—fusion, fission, movement, and mitophagy—in neurodegenerative diseases. Hum Mol Genet 18:R169–R176

    Article  PubMed  CAS  Google Scholar 

  • Cysique LA, Brew BJ (2009) Neuropsychological functioning and antiretroviral treatment in HIV/AIDS: a review. Neuropsychol Rev 19:169–185

    Article  PubMed  Google Scholar 

  • Darbinian N, Darbinyan A, Czernik M, Peruzzi F, Khalili K, Reiss K, Gordon J, Amini S (2008) HIV-1 Tat inhibits NGF-induced Egr-1 transcriptional activity and consequent p35 expression in neural cells. J Cell Physiol 216:128–134

    Article  PubMed  CAS  Google Scholar 

  • Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, Di Marzio P, Marmon S, Sutton RE, Hill CM, Davis CB, Peiper SC, Schall TJ, Littman DR, Landau NR (1996) Identification of a major co-receptor for primary isolates of HIV-1. Nature 381:661–666

    Article  PubMed  CAS  Google Scholar 

  • Ditaranto-Desimone K, Saito M, Tekirian TL, Saito M, Berg M, Dubowchik G, Soreghan B, Thomas S, Marks N, Yang AJ (2003) Neuronal endosomal/lysosomal membrane destabilization activates caspases and induces abnormal accumulation of the lipid secondary messenger ceramide. Brain Res Bull 59:523–531

    Article  PubMed  CAS  Google Scholar 

  • Dittmar MT, McKnight A, Simmons G, Clapham PR, Weiss RA, Simmonds P (1997) HIV-1 tropism and co-receptor use. Nature 385:495–496

    Article  PubMed  CAS  Google Scholar 

  • Donzella GA, Schols D, Lin SW, Este JA, Nagashima KA, Maddon PJ, Allaway GP, Sakmar TP, Henson G, De Clercq E, Moore JP (1998) AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nat Med 4:72–77

    Article  PubMed  CAS  Google Scholar 

  • Ellis R, Langford D, Masliah E (2007) HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci 8:33–44

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Erickson KI, Prakash RS, Voss MW, Chaddock L, Heo S, McLaren M, Pence BD, Martin SA, Vieira VJ, Woods JA, McAuley E, Kramer AF (2011) Brain-derived neurotrophic factor is associated with age-related decline in hippocampal volume. J Neurosci 30:5368–5375

    Article  CAS  Google Scholar 

  • Estanislao L, Carter K, McArthur J, Olney R, Simpson D (2004) A randomized controlled trial of 5% lidocaine gel for HIV-associated distal symmetric polyneuropathy. J Acquir Immune Defic Syndr 37:1584–1586

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

    Article  PubMed  CAS  Google Scholar 

  • Eugenin EA, Clements JE, Zink MC, Berman JW (2011) Human immunodeficiency virus infection of human astrocytes disrupts blood-brain barrier integrity by a gap junction-dependent mechanism. J Neurosci 31:9456–9465

    Article  PubMed  CAS  Google Scholar 

  • Everall IP, Hudson L, al-Sarraj S, Honavar M, Lantos P, Kerwin R (1995) Decreased expression of AMPA receptor messenger RNA and protein in AIDS: a model for HIV-associated neurotoxicity. Nat Med 1:1174–1178

    Article  PubMed  CAS  Google Scholar 

  • Everall IP, Bell C, Mallory M, Langford D, Adame A, Rockestein E, Masliah E (2002) Lithium ameliorates HIV-gp120-mediated neurotoxicity. Mol Cell Neurosci 21:493–501

    Article  PubMed  CAS  Google Scholar 

  • Everall IP, Hansen LA, Masliah E (2005) The shifting patterns of HIV encephalitis neuropathology. Neurotox Res 8:51–61

    Article  PubMed  CAS  Google Scholar 

  • Figurov A, Pozzo-Miller LD, Olafsson P, Wang T, Lu B (1996) Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381:706–709

    Article  PubMed  CAS  Google Scholar 

  • Fox L, Alford M, Achim C, Mallory M, Masliah E (1997) Neurodegeneration of somatostatin-immunoreactive neurons in HIV encephalitis. J Neuropathol Exp Neurol 56:360–368

    Article  PubMed  CAS  Google Scholar 

  • Fu W-Y, Chen Y, Sahin M, Zhao X-S, Shi L, Bikoff JB, Lai K-O, Yung W-H, Fu AKY, Greenberg ME, Ip NY (2007) Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nat Neurosci 10:67–76

    Article  PubMed  CAS  Google Scholar 

  • Garden GA, Budd SL, Tsai E, Hanson L, Kaul M, D’Emilia DM, Friedlander RM, Yuan J, Masliah E, Lipton SA (2002) Caspase cascades in human immunodeficiency virus-associated neurodegeneration. J Neurosci 22:4015–4024

    PubMed  CAS  Google Scholar 

  • Garden GA, Guo W, Jayadev S, Tun C, Balcaitis S, Choi J, Montine TJ, Moller T, Morrison RS (2004) HIV associated neurodegeneration requires p53 in neurons and microglia. FASEB J 18:1141–1143

    PubMed  CAS  Google Scholar 

  • Gelman BB, Soukup VM, Holzer CEI, Fabian RH, Schuenke KW, Keherly MJ, Richey FJ, Lahart CJ (2005) Potential role for white matter lysosome expansion in HIV-associated dementia. JAIDS 39:422–425

    Article  PubMed  CAS  Google Scholar 

  • Ghorpade A, Nukuna A, Che M, Haggerty S, Persidsky Y, Carter E, Carhart L, Shafer L, Gendelman HE (1998) Human immunodeficiency virus neurotropism: an analysis of viral replication and cytopathicity for divergent strains in monocytes and microglia. J Virol 72:3340–3350

    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 

  • Haughey NJ, Cutler RG, Tamara A, McArthur JC, Vargas DL, Pardo CA, Turchan J, Nath A, Mattson MP (2004) Perturbation of sphingolipid metabolism and ceramide production in HIV-dementia. Ann Neurol 55:257–267

    Article  PubMed  CAS  Google Scholar 

  • He J, Chen Y, Farzan M, Choe H, Ohagen A, Gartner S, Busciglio J, Yang X, Hofmann W, Newman W, Mackay CR, Sodroski J, Gabuzda D (1997) CCR3 and CCR5 are co-receptors for HIV-1 infection of microglia. Nature 385:645–649

    Article  PubMed  CAS  Google Scholar 

  • Hesselgesser J, Taub D, Baskar P, Greenberg M, Hoxie J, Kolson DL, Horuk R (1998) Neuronal apoptosis induced by HIV-1 gp120 and the chemokine SDF-1 alpha is mediated by the chemokine receptor CXCR4. Curr Biol 8:595–598

    Article  PubMed  CAS  Google Scholar 

  • Hickey WF (2001) Basic principles of immunological surveillance of the normal central nervous system. Glia 36:118–124

    Article  PubMed  CAS  Google Scholar 

  • Holden CP, Haughey NJ, Nath A, Geiger JD (1999) Role of Na+/H+ exchangers, excitatory amino acid receptors and voltage-operated Ca2+ channels in human immunodeficiency virus type 1 gp120-mediated increases in intracellular Ca2 + in human neurons and astrocytes. Neuroscience 91:1369–1378

    Article  PubMed  CAS  Google Scholar 

  • Horch HW, Katz LC (2002) BDNF release from single cells elicits local dendritic growth in nearby neurons. Nat Neurosci 5:1177–1184

    Article  PubMed  CAS  Google Scholar 

  • Iskander S, Walsh KA, Hammond RR (2004) Human CNS cultures exposed to HIV-1 gp120 reproduce dendritic injuries of HIV-1-associated dementia. J Neuroinflamm 1:7

    Article  Google Scholar 

  • Itoh K, Mehraein P, Weis S (2000) Neuronal damage of the substantia nigra in HIV-1 infected brains. Acta Neuropathol (Berl) 99:376–384

    Article  CAS  Google Scholar 

  • Ivankovic-Dikic I, Gronroos E, Blaukat A, Barth BU, Dikic I (2000) Pyk2 and FAK regulate neurite outgrowth induced by growth factors and integrins. Nat Cell Biol 2:574–581

    Article  PubMed  CAS  Google Scholar 

  • James KAC, Bray JJ, Morgan IG, Austin L (1970) The effect of colchicine on the transport of axonal protein in the chicken. Biochem J 117:767–771

    PubMed  CAS  Google Scholar 

  • James HJ, Sharer LR, Zhang Q, Wang HG, Epstein LG, Reed JC, Gelbard HA (1999) Expression of caspase-3 in brains from paediatric patients with HIV-1 encephalitis. Neuropathol Appl Neurobiol 25:380–386

    Article  PubMed  CAS  Google Scholar 

  • Jana A, Pahan K (2004) Human Immunodeficiency Virus Type 1 gp120 induces apoptosis in human primary neurons through redox-regulated activation of neutral sphingomyelinase. J Neurosci 24:9531–9540

    Article  PubMed  CAS  Google Scholar 

  • Jones GJ, Barsby NL, Cohen EA, Holden J, Harris K, Dickie P, Jhamandas J, Power C (2007) HIV-1 Vpr causes neuronal apoptosis and in vivo neurodegeneration. J Neurosci 27:3703–3711

    Article  PubMed  CAS  Google Scholar 

  • Joska JA, Gouse H, Paul RH, Stein DJ, Flisher AJ (2010) Does highly active antiretroviral therapy improve neurocognitive function? A systematic review. J Neurovirol 16:101–114

    Article  PubMed  CAS  Google Scholar 

  • Kaul M, Lipton SA (1999) Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis. Proc Natl Acad Sci USA 96:8212–8216

    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 

  • Kim E, Sheng M (2004) PDZ domain proteins of synapses. Nat Rev Neurosci 5:771–781

    Article  PubMed  CAS  Google Scholar 

  • Kim PK, Hailey DW, Mullen RT, Lippincott-Schwartz J (2008) Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes. Proc Natl Acad Sci USA 105:20567–20574

    Article  PubMed  CAS  Google Scholar 

  • Klein RS, Williams KC, Alvarez-Hernandez X, Westmoreland S, Force T, Lackner AA, Luster AD (1999) Chemokine receptor expression and signaling in macaque and human fetal neurons and astrocytes: implications for the neuropathogenesis of AIDS. J Immunol 163:1636–1646

    PubMed  CAS  Google Scholar 

  • Koot M, van ‘t Wout AlB, Kootstra NA, de Goede REY, Tersmette M, Schuitemaker H (1996) Relation between changes in cellular load, evolution of viral phenotype, and the clonal composition of virus populations in the course of human immunodeficiency virus type 1 infection. J Infect Dis 173:349–354

    Article  PubMed  CAS  Google Scholar 

  • Koutsilieri E, Sopper S, Scheller C, ter Meulen V, Riederer P (2002) Parkinsonism in HIV dementia. J Neural Transm 109:767–775

    Article  PubMed  CAS  Google Scholar 

  • Kraft-Terry SD, Stothert AR, Buch S, Gendelman HE (2010) HIV-1 neuroimmunity in the era of antiretroviral therapy. Neurobiol Dis 37:542–548

    Article  PubMed  CAS  Google Scholar 

  • Kramer-Hammerle S, Rothenaigner I, Wolff H, Bell JE, Brack-Werner R (2005) Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus. Virus Res 111:194–213

    Article  PubMed  CAS  Google Scholar 

  • Kundu M, Thompson CB (2008) Autophagy: basic principles and relevance to disease. Annu Rev Pathol 3:427–455

    Article  PubMed  CAS  Google Scholar 

  • Lazarini F, Casanova P, Tham TN, De Clercq E, Arenzana-Seisdedos F, Baleux F, Dubois-Dalcq M (2000) Differential signalling of the chemokine receptor CXCR4 by stromal cell-derived factor 1 and the HIV glycoprotein in rat neurons and astrocytes. Eur J Neurosci 12:117–125

    Article  PubMed  CAS  Google Scholar 

  • Li Y, Luikart BW, Birnbaum S, Chen J, Kwon C-H, Kernie SG, Bassel-Duby R, Parada LF (2008) TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron 59:399–412

    Article  PubMed  CAS  Google Scholar 

  • Li W, Li G, Steiner J, Nath A (2009) Role of Tat protein in HIV neuropathogenesis. Neurotox Res 16:205–220

    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 Y, Liu H, Kim BO, Gattone VH, Li J, Nath A, Blum J, He JJ (2004) CD4-independent infection of astrocytes by human immunodeficiency virus type 1: requirement for the human mannose receptor. J Virol 78:4120–4133

    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 

  • Masliah E, Heaton RK, Marcotte TD, Ellis RJ, Wiley CA, Mallory M, Achim CL, McCutchan JA, Nelson JA, Atkinson JH, Grant I (1997) Dendritic injury is a pathological substrate for human immunodeficiency virus-related cognitive disorders. HNRC group. The HIV neurobehavioral research center. Ann Neurol 42:963–972

    Article  PubMed  CAS  Google Scholar 

  • Mattson MP (1997) Neuroprotective signal transduction: relevance to stroke. Neurosci Biobehav Rev 21:193–206

    Article  PubMed  CAS  Google Scholar 

  • Mattson MP, Haughey NJ, Nath A (2005) Cell death in HIV dementia. Cell Death Differ 12(Suppl 1):893–904

    Article  PubMed  CAS  Google Scholar 

  • Maxfield FR, McGraw TE (2004) Endocytic recycling. Nat Rev Mol Cell Biol 5:121–132

    Article  PubMed  CAS  Google Scholar 

  • McArthur JC (2004) HIV dementia: an evolving disease. J Neuroimmunol 157:3–10

    Article  PubMed  CAS  Google Scholar 

  • McArthur JC, Steiner JP, Sacktor N, Nath A (2010) Human immunodeficiency virus-associated neurocognitive disorders: mind the gap. Ann Neurol 67:699–714

    Article  PubMed  CAS  Google Scholar 

  • Melli G, Keswani SC, Fischer A, Chen W, Hoke A (2006) Spatially distinct and functionally independent mechanisms of axonal degeneration in a model of HIV-associated sensory neuropathy. Brain 129:1330–1338

    Article  PubMed  Google Scholar 

  • Meucci O, Fatatis A, Simen AA, Bushell TJ, Gray PW, Miller RJ (1998) Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity. Proc Natl Acad Sci USA 95:14500–14505

    Article  PubMed  CAS  Google Scholar 

  • Milani D, Mazzoni M, Zauli G, Mischiati C, Gibellini D, Giacca M, Capitani S (1998) HIV-1 Tat induces tyrosine phosphorylation of p125FAK and its association with phosphoinositide 3-kinase in PC12 cells. AIDS 12:1275–1284

    Article  PubMed  CAS  Google Scholar 

  • Nagatsu T, Mogi M, Ichinose H, Togari A (2000) Changes in cytokines and neurotrophins in Parkinson’s disease. J Neural Transm Suppl 60:277–290

    PubMed  Google Scholar 

  • Naska S, Park KJ, Hannigan GE, Dedhar S, Miller FD, Kaplan DR (2006) An essential role for the integrin-linked kinase-glycogen synthase kinase-3 beta pathway during dendrite initiation and growth. J Neurosci 26:13344–13356

    Article  PubMed  CAS  Google Scholar 

  • Nath A (2002) Human immunodeficiency virus (HIV) proteins in neuropathogenesis of HIV dementia. J Infect Dis 186:S193–S198

    Article  PubMed  CAS  Google Scholar 

  • Nath A, Berger J (2004) HIV dementia. Curr Treat Options Neurol 6:139–151

    Article  PubMed  Google Scholar 

  • Nath A, Conant K, Chen P, Scott C, Major EO (1999) Transient exposure to HIV-1 Tat protein results in cytokine production in macrophages and astrocytes. A hit and run phenomenon. J Biol Chem 274:17098–17102

    Article  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 

  • Nguyen TP, Soukup VM, Gelman BB (2010) Persistent hijacking of brain proteasomes in HIV-associated dementia. Am J Pathol 176:893–902

    Article  PubMed  CAS  Google Scholar 

  • Nosheny RL, Bachis A, Acquas E, Mocchetti I (2004) Human immunodeficiency virus type 1 glycoprotein gp120 reduces the levels of brain-derived neurotrophic factor in vivo: potential implication for neuronal cell death. Eur J Neurosci 20:2857–2864

    Article  PubMed  Google Scholar 

  • Nosheny RL, Bachis A, Aden SA, De Bernardi MA, Mocchetti I (2006) Intrastriatal administration of human immunodeficiency virus-1 glycoprotein 120 reduces glial cell-line derived neurotrophic factor levels and causes apoptosis in the substantia nigra. J Neurobiol 66:1311–1321

    Article  PubMed  CAS  Google Scholar 

  • Nosheny RL, Amhed F, Yakovlev AG, Meyer EM, Ren K, Tessarollo L, Mocchetti I (2007) Brain-derived neurotrophic factor prevents the nigrostriatal degeneration induced by human immunodeficiency virus-1 glycoprotein 120 in vivo. Eur J Neurosci 25:2275–2284

    Article  PubMed  Google Scholar 

  • Orsini MJ, Parent J-L, Mundell SJ, Benovic JL (1999) Trafficking of the HIV coreceptor CXCR4. Role of arrestins and identificaton of residues in the C-terminals tail that mediate receptor internalization. J Biol Chem 274:31076–31086

    Article  PubMed  CAS  Google Scholar 

  • Patel CA, Mukhtar M, Pomerantz RJ (2000) Human immunodeficiency virus type 1 Vpr induces apoptosis in human neuronal cells. J Virol 74:9717–9726

    Article  PubMed  CAS  Google Scholar 

  • Petito CK, Kerza-Kwiatecki AP, Gendelman HE, McCarthy M, Nath A, Podack ER, Shapshak P, Wiley CA (1999) Review: neuronal injury in HIV infection. J Neurovirol 5:327–341

    Article  PubMed  CAS  Google Scholar 

  • Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA, Winslow JW (1991) BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease. Neuron 7:695–702

    Article  PubMed  CAS  Google Scholar 

  • Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, Small S, Spencer B, Rockenstein E, Levine B, Wyss-Coray T (2008) The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest 118:2190–2199

    PubMed  CAS  Google Scholar 

  • Polianova MT, Ruscetti FW, Pert CB, Ruff MR (2005) Chemokine receptor-5 (CCR5) is a receptor for the HIV entry inhibitor peptide T (DAPTA). Antiviral Res 67:83–92

    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 

  • Price RW, Spudich S (2008) Antiretroviral therapy and central nervous system HIV type 1 infection. J Infect Dis 197(Suppl 3):S294–S306

    Article  PubMed  Google Scholar 

  • Pu H, Tian J, Flora G, Lee YW, Nath A, Hennig B, Toborek M (2003) HIV-1 Tat protein upregulates inflammatory mediators and induces monocyte invasion into the brain. Mol Cell Neurosci 24:224–237

    Article  PubMed  CAS  Google Scholar 

  • Pumpradit W, Ananworanich J, Lolak S, Shikuma C, Paul R, Siangphoe U, Chaoniti N, Kaew-On P, Paris R, Ruxrungtham K, Valcour V (2010) Neurocognitive impairment and psychiatric comorbidity in well-controlled human immunodeficiency virus-infected Thais from the 2NN cohort study. J Neurovirol 16:76–82

    Article  PubMed  Google Scholar 

  • Radja F, Kay DG, Albrecht S, Jolicoeur P (2003) Oligodendrocyte-specific expression of human immunodeficiency virus type 1 Nef in transgenic mice leads to vacuolar myelopathy and alters oligodendrocyte phenotype in vitro. J Virol 77:11745–11753

    Article  PubMed  CAS  Google Scholar 

  • Raff MC, Whitmore AV, Finn JT (2002) Axonal self-destruction and neurodegeneration. Science 296:868–871

    Article  PubMed  CAS  Google Scholar 

  • Reyes MG, Faraldi F, Senseng CS, Flowers C, Fariello R (1991) Nigral degeneration in acquired immune deficiency syndrome (AIDS). Acta Neuropathol (Berl) 82:39–44

    Article  CAS  Google Scholar 

  • Ryan LA, Peng H, Erichsen DA, Huang Y, Persidsky Y, Zhou Y, Gendelman HE, Zheng J (2004) TNF-related apoptosis-inducing ligand mediates human neuronal apoptosis: links to HIV-1-associated dementia. J Neuroimmunol 148:127–139

    Article  PubMed  CAS  Google Scholar 

  • Samson F, Donoso JA, Heller-Bettinger I, Watson D, Himes RH (1979) Nocodazole action on tubulin assembly, axonal ultrastructure and fast axoplasmic transport. J Pharmacol Exp Ther 208:411–417

    PubMed  CAS  Google Scholar 

  • Signoret N, Pelchen-Matthews A, Mack M, Proudfoot AE, Marsh M (2000) Endocytosis and recycling of the HIV coreceptor CCR5. J Cell Biol 151:1281–1294

    Article  PubMed  CAS  Google Scholar 

  • Singh IN, Goody RJ, Dean C, Ahmad NM, Lutz SE, Knapp PE, Nath A, Hauser KF (2004) Apoptotic death of striatal neurons induced by human immunodeficiency virus-1 Tat and gp120: Differential involvement of caspase-3 and endonuclease G. J Neurovirol 10:141–151

    Article  PubMed  CAS  Google Scholar 

  • Singh IN, El-Hage N, Campbell ME, Lutz SE, Knapp PE, Nath A, Hauser KF (2005) Differential involvement of p38 and JNK MAP kinases in HIV-1 Tat and gp120-induced apoptosis and neurite degeneration in striatal neurons. Neuroscience 135:781–790

    Article  PubMed  CAS  Google Scholar 

  • Song L, Nath A, Geiger JD, Moore A, Hochman S (2003) Human immunodeficiency virus type 1 Tat protein directly activates neuronal N-methyl-d-aspartate receptors at an allosteric zinc-sensitive site. J Neurovirol 9:399–403

    PubMed  CAS  Google Scholar 

  • Song JH, Wang CX, Song DK, Wang P, Shuaib A, Hao C (2005) Interferon gamma induces neurite outgrowth by up-regulation of p35 neuron-specific cyclin-dependent kinase 5 activator via activation of ERK1/2 pathway. J Biol Chem 280:12896–12901

    Article  PubMed  CAS  Google Scholar 

  • Stevenson M, Gendelman HE (1994) Cellular and viral determinants that regulate HIV-1 infection in macrophages. J Leukoc Biol 56:278–288

    PubMed  CAS  Google Scholar 

  • Sui Y, Potula R, Dhillon N, Pinson D, Li S, Nath A, Anderson C, Turchan J, Kolson D, Narayan O, Buch S (2004) Neuronal apoptosis is mediated by CXCL10 overexpression in simian human immunodeficiency virus Encephalitis. Am J Pathol 164:1557–1566

    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 

  • Toggas SM, Masliah E, Rockenstein EM, Rall GF, Abraham CR, Mucke L (1994) Central nervous system damage produced by expression of the HIV-1 coat protein gp120 in transgenic mice. Nature 367:188–193

    Article  PubMed  CAS  Google Scholar 

  • Tornatore C, Chandra R, Berger JR, Major EO (1994a) HIV-1 infection of subcortical astrocytes in the pediatric central nervous system. Neurology 44:481–487

    PubMed  CAS  Google Scholar 

  • Tornatore C, Meyers K, Atwood W, Conant K, Major E (1994b) Temporal patterns of human immunodeficiency virus type 1 transcripts in human fetal astrocytes. J Virol 68:93–102

    PubMed  CAS  Google Scholar 

  • Tran PB, Banisadr G, Ren D, Chenn A, Miller RJ (2007) Chemokine receptor expression by neural progenitor cells in neurogenic regions of mouse brain. J Comp Neurol 500:1007–1034

    Article  PubMed  CAS  Google Scholar 

  • Trecki J, Brailoiu GC, Unterwald EM (2010) Localization of CXCR4 in the forebrain of the adult rat. Brain Res 1315:53–62

    Article  PubMed  CAS  Google Scholar 

  • Ungewickell EJ, Hinrichsen L (2007) Endocytosis: clathrin-mediated membrane budding. Curr Opin Cell Biol 19:417–425

    Article  PubMed  CAS  Google Scholar 

  • Valcour V, Shikuma C, Shiramizu B, Watters M, Poff P, Selnes O, Holck P, Grove J, Sacktor N (2004) Higher frequency of dementia in older HIV-1 individuals: The Hawaii aging with HIV-1 cohort. Neurology 63:822–827

    PubMed  CAS  Google Scholar 

  • van der Meer P, Ulrich AM, Gonzalez-Scarano F, Lavi E (2000) Immunohistochemical analysis of CCR2, CCR3, CCR5, and CXCR4 in the human brain: potential mechanisms for HIV dementia. Exp Mol Pathol 69:192–201

    Article  PubMed  CAS  Google Scholar 

  • van Marle G, Henry S, Todoruk T, Sullivan A, Silva C, Rourke SB, Holden J, McArthur JC, Gill MJ, Power C (2004) Human immunodeficiency virus type 1 Nef protein mediates neural cell death: a neurotoxic role for IP-10. Virology 329:302–318

    PubMed  Google Scholar 

  • Venkatesan A, Nath A, Ming Gl, Song H (2007) Adult hippocampal neurogenesis: regulation by HIV and drugs of abuse. Cell Mol Life Sci 64:2120–2132

    Article  PubMed  CAS  Google Scholar 

  • Vivithanaporn P, Heo G, Gamble J, Krentz HB, Hoke A, Gill MJ, Power C (2010) Neurologic disease burden in treated HIV/AIDS predicts survival: a population-based study. Neurology 75:1150–1158

    Article  PubMed  CAS  Google Scholar 

  • Volosin M, Song W, Almeida RD, Kaplan DR, Hempstead BL, Friedman WJ (2006) Interaction of survival and death signaling in basal forebrain neurons: roles of neurotrophins and proneurotrophins. J Neurosci 26:7756–7766

    Article  PubMed  CAS  Google Scholar 

  • Wang G-J, Chang L, Volkow ND, Telang F, Logan J, Ernst T, Fowler JS (2004) Decreased brain dopaminergic transporters in HIV-associated dementia patients. Brain 127:2452–2458

    Article  PubMed  Google Scholar 

  • Wang QJ, Ding Y, Kohtz DS, Mizushima N, Cristea IM, Rout MP, Chait BT, Zhong Y, Heintz N, Yue Z (2006) Induction of autophagy in axonal dystrophy and degeneration. J Neurosci 26:8057–8068

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Dong XX, Cao Y, Liang ZQ, Han R, Wu JC, Gu ZL, Qin ZH (2009) p53 induction contributes to excitotoxic neuronal death in rat striatum through apoptotic and autophagic mechanisms. Eur J Neurosci 30:2258–2270

    Article  PubMed  Google Scholar 

  • Wei J, Fujita M, Nakai M, Waragai M, Watabe K, Akatsu H, Rockenstein E, Masliah E, Hashimoto M (2007) Enhanced lysosomal pathology caused by beta-synuclein mutants linked to dementia with Lewy bodies. J Biol Chem 282:28904–28914

    Article  PubMed  CAS  Google Scholar 

  • Xie Y, Hayden MR, Xu B (2010) BDNF overexpression in the forebrain rescues Huntington’s disease phenotypes in YAC128 mice. J Neurosci 30:14708–14718

    Article  PubMed  CAS  Google Scholar 

  • Xu B, Zang K, Ruff NL, Zhang YA, McConnell SK, Stryker MP, Reichardt LF (2000) Cortical degeneration in the absence of neurotrophin signaling: dendritic retraction and neuronal loss after removal of the receptor TrkB. Neuron 26:233–245

    Article  PubMed  CAS  Google Scholar 

  • Zakharenko SS, Patterson SL, Dragatsis I, Zeitlin SO, Siegelbaum SA, Kandel ER, Morozov A (2003) Presynaptic BDNF required for a presynaptic but not postsynaptic component of LTP at hippocampal CA1-CA3 synapses. Neuron 39:975–990

    Article  PubMed  CAS  Google Scholar 

  • Zhang Z, Butler JD, Levin SW, Wisniewski KE, Brooks SS, Mukherjee AB (2001) Lysosomal ceroid depletion by drugs: therapeutic implications for a hereditary neurodegenerative disease of childhood. Nat Med 7:478

    Article  PubMed  CAS  Google Scholar 

  • Zheng J, Thylin MR, Ghorpade A, Xiong H, Persidsky Y, Cotter R, Niemann D, Che M, Zeng YC, Gelbard HA, Shepard RB, Swartz JM, Gendelman HE (1999) Intracellular CXCR4 signaling, neuronal apoptosis and neuropathogenic mechanisms of HIV-1-associated dementia. J Neuroimmunol 98:185–200

    Article  PubMed  CAS  Google Scholar 

  • Zhou M, Deng L, Lacoste V, Park HU, Pumfery A, Kashanchi F, Brady JN, Kumar A (2004) Coordination of transcription factor phosphorylation and histone methylation by the P-TEFb kinase during human immunodeficiency virus type 1 transcription. J Virol 78:13522–13533

    Article  PubMed  CAS  Google Scholar 

  • Zuccato C, Cattaneo E (2007) Role of brain-derived neurotrophic factor in Huntington’s disease. Prog Neurobiol 81:294–330

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by National Institute of Health Grants DA026174 and NS040670.

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  1. Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road, NW, New Research Building WP13, Washington, DC, 20057, USA

    Italo Mocchetti, Alessia Bachis & Valeriya Avdoshina

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  1. Italo Mocchetti
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  2. Alessia Bachis
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Correspondence to Italo Mocchetti.

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Mocchetti, I., Bachis, A. & Avdoshina, V. Neurotoxicity of Human Immunodeficiency Virus-1: Viral Proteins and Axonal Transport. Neurotox Res 21, 79–89 (2012). https://doi.org/10.1007/s12640-011-9279-2

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