Abstract
HIV infection of the central nervous system (CNS) can result in neurologic dysfunction with devastating consequences in a significant number of individuals with AIDS. Two main CNS complications in individuals with HIV are encephalitis and dementia, which are characterized by leukocyte infiltration into the CNS, microglia activation, aberrant chemokine expression, blood–brain barrier (BBB) disruption, and eventual damage and/or loss of neurons. One of the major mediators of NeuroAIDS is the transmigration of HIV-infected leukocytes across the BBB into the CNS. This review summarizes new key findings that support a critical role of the BBB in regulating leukocyte transmigration. In addition, we discuss studies on communication among cells of the immune system, BBB, and the CNS parenchyma, and suggest how these interactions contribute to the pathogenesis of NeuroAIDS. We also describe some of the animal models that have been used to study and characterize important mechanisms that have been proposed to be involved in HIV-induced CNS dysfunction. Finally, we review the pharmacologic interventions that address neuroinflammation, and the effect of substance abuse on HIV-1 related neuroimmunity.
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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
Anderson ER, Gendelman HE, Xiong H (2004) Memantine protects hippocampal neuronal function in murine human immunodeficiency virus type 1 encephalitis. J Neurosci 24:7194–7198
Andras IE, Pu H, Deli MA, Nath A, Hennig B, Toboreck M (2003) HIV-1 Tat protein alters tight junction protein expresion and distribution in cultured brain endothelial cells. J Neurosci Res 72:255–265
Annunziata P, Cioni C, Toneatto S, Paccagnini E (1998) HIV-1 gp120 increases the permeability of rat brain endothelium cultures by a mechanism involving substance P. Aids 12:2377–2385
Annunziata P, Cioni C, Santonini R, Paccagnini E (2002) Substance P antagonist blocks leakage and reduces activation of cytokine-stimulated rat brain endothelium. J Neuroimmunol 131:41–49
Anthony IC, Ramage SN, Carnie FW, Simmonds P, Bell JE (2005) Influence of HAART on HIV-related CNS disease and neuroinflammation. J Neuropathol Exp Neurol 64:529–536
Apetrei C, Robertson DL, Marx PA (2004) The history of SIVS and AIDS: epidemiology, phylogeny and biology of isolates from naturally SIV infected non-human primates (NHP) in Africa. Front Biosci 9:225–254
Argyris EG, Acheampong E, Nunnari G, Mukhtar M, Williams KJ, Pomerantz RJ (2003) Human immunodeficiency virus type 1 enters primary human brain microvascular endothelial cells by a mechanism involving cell surface proteoglycans independent of lipid rafts. J Virol 77:12140–12151
Avgeropoulos N, Kelley B, Middaugh L, Arrigo S, Persidsky Y, Gendelman HE, Tyor WR (1998) SCID mice with HIV encephalitis develop behavioral abnormalities. J Acquir Immune Defic Syndr Hum Retrovirol 18:13–20
Baldeweg T, Catalan J, Gazzard BG (1998) Risk of HIV dementia and opportunistic brain disease in AIDS and zidovudine therapy. J Neurol Neurosurg Psychiatry 65:34–41
Bandopadhyay R, Orte C, Lawrenson JG, Reid AR, De Silva S, Allt G (2001) Contractile proteins in pericytes at the blood–brain and blood–retinal barriers. J Neurocytol 30:35–44
Banks WA, Akerstrom V, Kastin AJ (1998) Adsorptive endocytosis mediates the passage of HIV-1 across the blood–brain barrier: evidence for a post-internalization coreceptor. J Cell Sci 111(Pt 4):533–540
Banks WA, Freed EO, Wolf KM, Robinson SM, Franko M, Kumar VB (2001) Transport of human immunodeficiency virus type 1 pseudoviruses across the blood–brain barrier: role of envelope proteins and adsorptive endocytosis. J Virol 75:4681–4691
Benagiano V, Virgintino D, Maiorano E, Rizzi A, Palombo S, Roncali L, Ambrosi G (1996) VIP-like immunoreactivity within neurons and perivascular neuronal processes of the human cerebral cortex. Eur J Histochem 40:53–56
Bennett BA, Rusyniak DE, Hollingsworth CK (1995) HIV-1 gp120-induced neurotoxicity to midbrain dopamine cultures. Brain Res 705:168–176
Bitran M, Tapia W, Eugenin E, Orio P, Boric MP (1999) Neuropeptide Y induced inhibition of noradrenaline release in rat hypothalamus: role of receptor subtype and nitric oxide. Brain Res 851:87–93
Bobardt MD, Salmon P, Wang L, Esko JD, Gabuzda D, Fiala M, Trono D, Van der Schueren B, David G, Gallay PA (2004) Contribution of proteoglycans to human immunodeficiency virus type 1 brain invasion. J Virol 78:6567–6584
Boven LA, Middel J, Verhoef J, De Groot CJ, Nottet HS (2000) Monocyte infiltration is highly associated with loss of the tight junction protein zonula occludens in HIV-1-associated dementia. Neuropathol Appl Neurobiol 26:356–360
Braet K, Paemeleire K, D'Herde K, Sanderson MJ, Leybaert L (2001) Astrocyte–endothelial cell calcium signals conveyed by two signalling pathways. Eur J Neurosci 13:79–91
Browning Paul J, Wang EJ, Pettoello-Mantovani M, Raker C, Yurasov S, Goldstein MM, Horner JW, Chan J, Goldstein H (2000) Mice transgenic for monocyte-tropic HIV type 1 produce infectious virus and display plasma viremia: a new in vivo system for studying the postintegration phase of HIV replication. AIDS Res Hum Retroviruses 16:481–492
Buch S, Sui Y, Dhillon N, Potula R, Zien C, Pinson D, Li S, Dhillon S, Nicolay B, Sidelnik A, Li C, Villinger T, Bisarriya K, Narayan O (2004) Investigations on four host response factors whose expression is enhanced in X4 SHIV encephalitis. J Neuroimmunol 157:71–80
Burack JH, Barrett DC, Stall RD, Chesney MA, Ekstrand ML, Coates TJ (1993) Depressive symptoms and CD4 lymphocyte decline among HIV-infected men. JAMA 270:2568–2573
Cartier L, Hartley O, Dubois-Dauphin M, Krause KH (2005) Chemokine receptors in the central nervous system: role in brain inflammation and neurodegenerative diseases. Brain Res Brain Res Rev 48:16–42
Clapham PR, Weber JN, Whitby D, McIntosh K, Dalgleish AG, Maddon PJ, Deen KC, Sweet RW, Weiss RA (1989) Soluble CD4 blocks the infectivity of diverse strains of HIV and SIV for T cells and monocytes but not for brain and muscle cells. Nature 337:368–370
Clapham PR, Blanc D, Weiss RA (1991) Specific cell surface requirements for the infection of CD4-positive cells by human immunodeficiency virus types 1 and 2 and by simian immunodeficiency virus. Virology 181:703–715
Clements JE, Anderson MG, Zink MC, Joag SV, Narayan O (1994) The SIV model of AIDS encephalopathy. Role of neurotropic viruses in diseases. Res Publ Assoc Res Nerv Ment Dis 72:147–157
Clements JE, Li M, Gama L, Bullock B, Carruth LM, Mankowski JL, Zink MC (2005) The central nervous system is a viral reservoir in simian immunodeficiency virus-infected macaques on combined antiretroviral therapy: a model for human immunodeficiency virus patients on highly active antiretroviral therapy. J Neurovirol 11:180–189
Clerici M, Sarin A, Henkart PA, Shearer GM (1997) Apoptotic cell death and cytokine dysregulation in human immunodeficiency virus infection: pivotal factors in disease progression. Cell Death Differ 4:699–706
Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P (1995) Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science 270:1811–1815
Collard CD, Park KA, Montalto MC, Alapati S, Buras JA, Stahl GL, Colgan SP (2002) Neutrophil-derived glutamate regulates vascular endothelial barrier function. J Biol Chem 277:14801–14811
Colovic M, Caccia S (2003) Liquid chromatographic determination of minocycline in brain-to-plasma distribution studies in the rat. J Chromatogr B Anal Technol Biomed Life Sci 791:337–343
Conant K, Garzino-Demo A, Nath A, McArthur JC, Halliday W, Power C, Gallo RC, Major EO (1998) Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia. Proc Natl Acad Sci USA 95:3117–3121
Czub S, Czub M, Koutsilieri E, Sopper S, Villinger F, Muller JG, Stahl-Hennig C, Riederer P, Ter Meulen V, Gosztonyi G (2004) Modulation of simian immunodeficiency virus neuropathology by dopaminergic drugs. Acta Neuropathol (Berl) 107:216–226
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
D'Aversa TG, Eugenin EA, Berman JW (2005) NeuroAIDS: contributions of the human immunodeficiency virus-1 proteins Tat and gp120 as well as CD40 to microglial activation. J Neurosci Res 81:436–446
Dallasta LM, Pisarov LA, Esplen JE, Werley JV, Moses AV, Nelson JA, Achim CL (1999) Blood–brain barrier tight junction disruption in human immunodeficiency virus-1 encephalitis. Am J Pathol 155:1915–1927
Dantzer R, Kelley KW (1989) Stress and immunity: an integrated view of relationships between the brain and the immune system. Life Sci 44:1995–2008
Dehouck MP, Vigne P, Torpier G, Breittmayer JP, Cecchelli R, Frelin C (1997) Endothelin-1 as a mediator of endothelial cell–pericyte interactions in bovine brain capillaries. J Cereb Blood Flow Metab 17:464–469
Del Maschio A, De Luigi A, Martin-Padura I, Brockhaus M, Bartfai T, Fruscella P, Adorini L, Martino G, Furlan R, De Simoni MG, Dejana E (1999) Leukocyte recruitment in the cerebrospinal fluid of mice with experimental meningitis is inhibited by an antibody to junctional adhesion molecule (JAM). J Exp Med 190:1351–1356
Desrosiers RC, Daniel MD, Li Y (1989) HIV-related lentiviruses of nonhuman primates. AIDS Res Hum Retroviruses 5:465–473
Diesing TS, Swindells S, Gelbard H, Gendelman HE (2002) HIV-1-associated dementia: a basic science and clinical perspective. AIDS Read 12:358–368
Dore-Duffy P, Owen C, Balabanov R, Murphy S, Beaumont T, Rafols JA (2000) Pericyte migration from the vascular wall in response to traumatic brain injury. Microvasc Res 60:55–69
Dou H, Ellison B, Bradley J, Kasiyanov A, Poluektova LY, Xiong H, Maggirwar S, Dewhurst S, Gelbard HA, Gendelman HE (2005) Neuroprotective mechanisms of lithium in murine human immunodeficiency virus-1 encephalitis. J Neurosci 25:8375–8385
Dzenko KA, Song L, Ge S, Kuziel WA, Pachter JS (2005) CCR2 expression by brain microvascular endothelial cells is critical for macrophage transendothelial migration in response to CCL2. Microvasc Res 70:53–64
Ebnet K, Suzuki A, Ohno S, Vestweber D (2004) Junctional adhesion molecules (JAMs): more molecules with dual functions? J Cell Sci 117:19–29
Edinger AL, Amedee A, Miller K, Doranz BJ, Endres M, Sharron M, Samson M, Lu ZH, Clements JE, Murphey-Corb M, Peiper SC, Parmentier M, Broder CC, Doms RW (1997) Differential utilization of CCR5 by macrophage and T cell tropic simian immunodeficiency virus strains. Proc Natl Acad Sci USA 94:4005–4010
Edinger AL, Hoffman TL, Sharron M, Lee B, Yi Y, Choe W, Kolson DL, Mitrovic B, Zhou Y, Faulds D, Collman RG, Hesselgesser J, Horuk R, Doms RW (1998) An orphan seven-transmembrane domain receptor expressed widely in the brain functions as a coreceptor for human immunodeficiency virus type 1 and simian immunodeficiency virus. J Virol 72:7934–7940
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
El-Hage N, Wu G, Wang J, Ambati J, Knapp PE, Reed JL, Bruce-Keller AJ, Hauser KF (2006) HIV-1 Tat and opiate-induced changes in astrocytes promote chemotaxis of microglia through the expression of MCP-1 and alternative chemokines. Glia 53:132–146
Elfont RM, Sundaresan PR, Sladek CD (1989) Adrenergic receptors on cerebral microvessels: pericyte contribution. Am J Physiol 256:R224–230
Ellis RJ, Childers ME, Cherner M, Lazzaretto D, Letendre S, Grant I (2003) Increased human immunodeficiency virus loads in active methamphetamine users are explained by reduced effectiveness of antiretroviral therapy. J Infect Dis 188:1820–1826
Encinas M, Iglesias M, Liu Y, Wang H, Muhaisen A, Cena V, Gallego C, Comella JX (2000) Sequential treatment of SH-SY5Y cells with retinoic acid and brain-derived neurotrophic factor gives rise to fully differentiated, neurotrophic factor-dependent, human neuron-like cells. J Neurochem 75:991–1003
Eugenin EA, Branes MC, Berman JW, Saez JC (2003a) TNF-alpha plus IFN-gamma induce connexin43 expression and formation of gap junctions between human monocytes/macrophages that enhance physiological responses. J Immunol 170:1320–1328
Eugenin EA, D'Aversa TG, Lopez L, Calderon TM, Berman JW (2003b) MCP-1 (CCL2) protects human neurons and astrocytes from NMDA or HIV-tat-induced apoptosis. J Neurochem 85:1299–1311
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
Eugenin EA, Osiecki K, Lopez L, Goldstein H, Calderon TM, Berman JW (2006a) CCL2/monocyte chemoattractant protein-1 mediates enhanced transmigration of human immunodeficiency virus (HIV)-infected leukocytes across the blood–brain barrier: a potential mechanism of HIV-CNS invasion and NeuroAIDS. J Neurosci 26:1098–1106
Eugenin EA, Gamss R, Buckner C, Buono D, Klein RS, Schoenbaum EE, Calderon TM, Berman JW (2006b) Shedding of PECAM-1 during HIV infection: a potential role for soluble PECAM-1 in the pathogenesis of NeuroAIDS. J Leukoc Biol 79:444–452
Evans DL, Leserman J, Pedersen CA, Golden RN, Lewis MH, Folds JA, Ozer H (1989) Immune correlates of stress and depression. Psychopharmacol Bull 25:319–324
Everall IP, Trillo-Pazos G, Bell C, Mallory M, Sanders V, Masliah E (2001) Amelioration of neurotoxic effects of HIV envelope protein gp120 by fibroblast growth factor: a strategy for neuroprotection. J Neuropathol Exp Neurol 60:293–301
Everall I, Salaria S, Roberts E, Corbeil J, Sasik R, Fox H, Grant I, Masliah E (2005) Methamphetamine stimulates interferon inducible genes in HIV infected brain. J Neuroimmunol 170:158–171
Fiala AM, Gan XH, Newton T, Chiappelli F, Shapshak P, Kermani V, Kung MA, Diagne A, Martinez O, Way D, Weinand M, Witte M, Graves M (1996) Divergent effects of cocaine on cytokine production by lymphocytes and monocyte/macrophages: HIV-1 enhancement by cocaine within the blood–brain barrier. Adv Exp Med Biol 402:145–156
Fiala M, Looney DJ, Stins M, Way DD, Zhang L, Gan X, Chiappelli F, Schweitzer ES, Shapshak P, Weinand M, Graves MC, Witte M, Kim KS (1997) TNF-alpha opens a paracellular route for HIV-1 invasion across the blood–brain barrier. Mol Med 3:553–564
Fiala M, Gan XH, Zhang L, House SD, Newton T, Graves MC, Shapshak P, Stins M, Kim KS, Witte M, Chang SL (1998) Cocaine enhances monocyte migration across the blood–brain barrier. Cocaine's connection to AIDS dementia and vasculitis? Adv Exp Med Biol 437:199–205
Fiala M, Eshleman AJ, Cashman J, Lin J, Lossinsky AS, Suarez V, Yang W, Zhang J, Popik W, Singer E, Chiappelli F, Carro E, Weinand M, Witte M, Arthos J (2005) Cocaine increases human immunodeficiency virus type 1 neuroinvasion through remodeling brain microvascular endothelial cells. J Neurovirol 11:281–291
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
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
Fox HS, Phillips TR (2002) FIV and neuroAIDS. J Neurovirol 8:155–157
Fox HS, Gold LH, Henriksen SJ, Bloom FE (1997) Simian immunodeficiency virus: a model for neuroAIDS. Neurobiol Dis 4:265–274
Fuentes ME, Durham SK, Swerdel MR, Lewin AC, Barton DS, Megill JR, Bravo R, Lira SA (1995) Controlled recruitment of monocytes and macrophages to specific organs through transgenic expression of monocyte chemoattractant protein-1. J Immunol 155:5769–5776
Fujii Y, Otake K, Tashiro M, Adachi A (1996) Human immunodeficiency virus type 1 Nef protein on the cell surface is cytocidal for human CD4+ T cells. FEBS Lett 393:105–108
Gabuzda D, Wang J (1999) Chemokine receptors and virus entry in the central nervous system. J Neurovirol 5:643–658
Gabuzda D, He J, Ohagen A, Vallat AV (1998) Chemokine receptors in HIV-1 infection of the central nervous system. Semin Immunol 10:203–213
Galey D, Becker K, Haughey N, Kalehua A, Taub D, Woodward J, Mattson MP, Nath A (2003) Differential transcriptional regulation by human immunodeficiency virus type 1 and gp120 in human astrocytes. J Neurovirol 9:358–371
Gartner S (2000) HIV infection and dementia. Science 287:602–604
Gaskill PJ, Watry DD, Burdo TH, Fox HS (2005) Development and characterization of positively selected brain-adapted SIV. Virol J 2:44
Gaspers LD, Thomas AP (2005) Calcium signaling in liver. Cell Calcium 38:329–342
Gendelman HE, Grant I, Lipton SA, Everall I, Swindells S (2005) The Neurology of AIDS. Oxford University Press, London
Gloor SM, Wachtel M, Bolliger MF, Ishihara H, Landmann R, Frei K (2001) Molecular and cellular permeability control at the blood–brain barrier. Brain Res Brain Res Rev 36:258–264
Goldstein GW (1988) Endothelial cell–astrocyte interactions. A cellular model of the blood–brain barrier. Ann N Y Acad Sci 529:31–39
Gonul E, Duz B, Kahraman S, Kayali H, Kubar A, Timurkaynak E (2002) Early pericyte response to brain hypoxia in cats: an ultrastructural study. Microvasc Res 64:116–119
Gonzalez E, Rovin BH, Sen L, Cooke G, Dhanda R, Mummidi S, Kulkarni H, Bamshad MJ, Telles V, Anderson SA, Walter EA, Stephan KT, Deucher M, Mangano A, Bologna R, Ahuja SS, Dolan MJ, Ahuja SK (2002) HIV-1 infection and AIDS dementia are influenced by a mutant MCP-1 allele linked to increased monocyte infiltration of tissues and MCP-1 levels. Proc Natl Acad Sci USA 99:13795–13800
Goodkin K, Shapshak P, Metsch LR, McCoy CB, Crandall KA, Kumar M, Fujimura RK, McCoy V, Zhang BT, Reyblat S, Xin KQ, Kumar AM (1998) Cocaine abuse and HIV-1 infection: epidemiology and neuropathogenesis. J Neuroimmunol 83:88–101
Griffin WC 3rd, Middaugh LD, Cook JE, Tyor WR (2004) The severe combined immunodeficient (SCID) mouse model of human immunodeficiency virus encephalitis: deficits in cognitive function. J Neurovirol 10:109–115
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
Haorah J, Knipe B, Leibhart J, Ghorpade A, Persidsky Y (2005a) Alcohol-induced oxidative stress in brain endothelial cells causes blood–brain barrier dysfunction. J Leukoc Biol 78:1223–1232
Haorah J, Heilman D, Knipe B, Chrastil J, Leibhart J, Ghorpade A, Miller DW, Persidsky Y (2005b) Ethanol-induced activation of myosin light chain kinase leads to dysfunction of tight junctions and blood-brain barrier compromise. Alcohol Clin Exp Res 29:999–1009
Hatse S, Princen K, De Clercq E, Rosenkilde MM, Schwartz TW, Hernandez-Abad PE, Skerlj RT, Bridger GJ, Schols D (2005) AMD3465, a monomacrocyclic CXCR4 antagonist and potent HIV entry inhibitor. Biochem Pharmacol 70:752–761
Healy DP, Wilk S (1993) Localization of immunoreactive glutamyl aminopeptidase in rat brain. II. Distribution and correlation with angiotensin II. Brain Res 606:295–303
Hein A, Martin JP, Dorries R (2001) In vitro activation of feline immunodeficiency virus in ramified microglial cells from asymptomatically infected cats. J Virol 75:8090–8095
Hertz L, Peng L, Lai JC (1998) Functional studies in cultured astrocytes. Methods 16:293–310
Herz A (1995) Neurobiological principles of drug dependence. Exemplified by opioids and psychostimulants. Nervenarzt 66:3–14
Heyes MP, Ellis RJ, Ryan L, Childers ME, Grant I, Wolfson T, Archibald S, Jernigan TL (2001) Elevated cerebrospinal fluid quinolinic acid levels are associated with region-specific cerebral volume loss in HIV infection. Brain 124:1033–1042
Ho WZ, Douglas SD (2004) Substance P and neurokinin-1 receptor modulation of HIV. J Neuroimmunol 157:48–55
Ho WZ, Lai JP, Li Y, Douglas SD (2002) HIV enhances substance P expression in human immune cells. FASEB J 16:616–618
Homan JW, Steele AD, Martinand-Mari C, Rogers TJ, Henderson EE, Charubala R, Pfleiderer W, Reichenbach NL, Suhadolnik RJ (2002) Inhibition of morphine-potentiated HIV-1 replication in peripheral blood mononuclear cells with the nuclease-resistant 2-5A agonist analog, 2-5A(N6B). J Acquir Immune Defic Syndr 30:9–20
Hori S, Ohtsuki S, Hosoya K, Nakashima E, Terasaki T (2004) A pericyte-derived angiopoietin-1 multimeric complex induces occludin gene expression in brain capillary endothelial cells through Tie-2 activation in vitro. J Neurochem 89:503–513
Huber JD, Egleton RD, Davis TP (2001) Molecular physiology and pathophysiology of tight junctions in the blood–brain barrier. Trends Neurosci 24:719–725
Hurwitz AA, Berman JW, Lyman WD (1994) The role of the blood–brain barrier in HIV infection of the central nervous system. Adv Neuroimmunol 4:249–256
Ickovics JR, Hamburger ME, Vlahov D, Schoenbaum EE, Schuman P, Boland RJ, Moore J (2001) Mortality, CD4 cell count decline, and depressive symptoms among HIV-seropositive women: longitudinal analysis from the HIV Epidemiology Research Study. JAMA 285:1466–1474
Ilani T, Strous RD, Fuchs S (2004) Dopaminergic regulation of immune cells via D3 dopamine receptor: a pathway mediated by activated T cells. FASEB J 18:1600–1602
Joseph AM, Kumar M, Mitra D (2005) Nef: “necessary and enforcing factor” in HIV infection. Curr HIV Res 3:87–94
Julg B, Goebel FD (2005) What's New in HIV/AIDS? Chemokine receptor antagonists: a new era of HIV therapy? Infection 33:408–410
Kanmogne GD, Kennedy RC, Grammas P (2002) HIV-1 gp120 proteins and gp160 peptides are toxic to brain endothelial cells and neurons: possible pathway for HIV entry into the brain and HIV-associated dementia. J Neuropathol Exp Neurol 61:992–1000
Kanmogne GD, Primeaux C, Grammas P (2005) HIV-1 gp120 proteins alter tight junction protein expression and brain endothelial cell permeability: implications for the pathogenesis of HIV-associated dementia. J Neuropathol Exp Neurol 64:498–505
Kelder W, McArthur JC, Nance-Sproson T, McClernon D, Griffin DE (1998) beta-Chemokines MCP-1 and RANTES are selectively increased in cerebrospinal fluid of patients with human immunodeficiency virus-associated dementia. Ann Neurol 44:831–835
Kern TS, Engerman RL (1996) Capillary lesions develop in retina rather than cerebral cortex in diabetes and experimental galactosemia. Arch Ophthalmol 114:306–310
King J, Eugenin EA, Buckner C, Berman JW (2006) HIV-tat and neurotoxicity. Microbes Infect, in press
Krizbai IA, Deli MA, Pestenacz A, Siklos L, Szabo CA, Andras I, Joo F (1998) Expression of glutamate receptors on cultured cerebral endothelial cells. J Neurosci Res 54:814–819
Kumar R, Torres C, Yamamura Y, Rodriguez I, Martinez M, Staprans S, Donahoe RM, Kraiselburd E, Stephens EB, Kumar A (2004) Modulation by morphine of viral set point in rhesus macaques infected with simian immunodeficiency virus and simian–human immunodeficiency virus. J Virol 78:11425–11428
Lackner AA, Vogel P, Ramos RA, Kluge JD, Marthas M (1994) Early events in tissues during infection with pathogenic (SIVmac239) and nonpathogenic (SIVmac1A11) molecular clones of simian immunodeficiency virus. Am J Pathol 145:428–439
Lane TE, Buchmeier MJ, Watry DD, Fox HS (1996) Expression of inflammatory cytokines and inducible nitric oxide synthase in brains of SIV-infected rhesus monkeys: applications to HIV-induced central nervous system disease. Mol Med 2:27–37
Langford D, Grigorian A, Hurford R, Adame A, Ellis RJ, Hansen L, Masliah E (2004) Altered P-glycoprotein expression in AIDS patients with HIV encephalitis. J Neuropathol Exp Neurol 63:1038–1047
Lavi E, Kolson DL, Ulrich AM, Fu L, Gonzalez-Scarano F (1998) Chemokine receptors in the human brain and their relationship to HIV infection. J Neurovirol 4:301–311
Leserman J (2003) HIV disease progression: depression, stress, and possible mechanisms. Biol Psychiatry 54:295–306
Leserman J, Petitto JM, Perkins DO, Folds JD, Golden RN, Evans DL (1997) Severe stress, depressive symptoms, and changes in lymphocyte subsets in human immunodeficiency virus-infected men. A 2-year follow-up study. Arch Gen Psychiatry 54:279–285
Leserman J, Jackson ED, Petitto JM, Golden RN, Silva SG, Perkins DO, Cai J, Folds JD, Evans DL (1999) Progression to AIDS: the effects of stress, depressive symptoms, and social support. Psychosom Med 61:397–406
Leserman J, Petitto JM, Golden RN, Gaynes BN, Gu H, Perkins DO, Silva SG, Folds JD, Evans DL (2000) Impact of stressful life events, depression, social support, coping, and cortisol on progression to AIDS. Am J Psychiatry 157:1221–1228
Leserman J, Petitto JM, Gu H, Gaynes BN, Barroso J, Golden RN, Perkins DO, Folds JD, Evans DL (2002) Progression to AIDS, a clinical AIDS condition and mortality: psychosocial and physiological predictors. Psychol Med 32:1059–1073
Letendre S, Marquie-Beck J, Singh KK, de Almeida S, Zimmerman J, Spector SA, Grant I, Ellis R (2004) The monocyte chemotactic protein-1-2578G allele is associated with elevated MCP-1 concentrations in cerebrospinal fluid. J Neuroimmunol 157:193–196
Li Y, Douglas SD, Song L, Sun S, Ho WZ (2001) Substance P enhances HIV-1 replication in latently infected human immune cells. J Neuroimmunol 121:67–75
Lindahl P, Johansson BR, Leveen P, Betsholtz C (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277:242–245
Lipton SA (1994) HIV-related neuronal injury. Potential therapeutic intervention with calcium channel antagonists and NMDA antagonists. Mol Neurobiol 8:181–196
Lipton SA (1998) Neuronal injury associated with HIV-1: approaches to treatment. Annu Rev Pharmacol Toxicol 38:159–177
Liu ZQ, Muhkerjee S, Sahni M, McCormick-Davis C, Leung K, Li Z, Gattone VH, 2nd, Tian C, Doms RW, Hoffman TL, Raghavan R, Narayan O, Stephens EB (1999) Derivation and biological characterization of a molecular clone of SHIV(KU-2) that causes AIDS, neurological disease, and renal disease in rhesus macaques. Virology 260:295–307
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
Liu NQ, Lossinsky AS, Popik W, Li X, Gujuluva C, Kriederman B, Roberts J, Pushkarsky T, Bukrinsky M, Witte M, Weinand M, Fiala M (2002a) Human immunodeficiency virus type 1 enters brain microvascular endothelia by macropinocytosis dependent on lipid rafts and the mitogen-activated protein kinase signaling pathway. J Virol 76:6689–6700
Liu X, Jana M, Dasgupta S, Koka S, He J, Wood C, Pahan K (2002b) Human immunodeficiency virus type 1 (HIV-1) tat induces nitric-oxide synthase in human astroglia. J Biol Chem 277:39312–39319
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
Liu Y, Shaw SK, Ma S, Yang L, Luscinskas FW, Parkos CA (2004) Regulation of leukocyte transmigration: cell surface interactions and signaling events. J Immunol 172:7–13
Loscher W, Potschka H (2005) Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci 6:591–602
Lyketsos CG, Hoover DR, Guccione M, Senterfitt W, Dew MA, Wesch J, VanRaden MJ, Treisman GJ, Morgenstern H (1993) Depressive symptoms as predictors of medical outcomes in HIV infection. Multicenter AIDS Cohort Study. JAMA 270:2563–2567
Maclean AG, Belenchia GE, Bieniemy DN, Moroney-Rasmussen TA, Lackner AA (2005) Simian immunodeficiency virus disrupts extended lengths of the blood–brain barrier. J Med Primatol 34:237–242
Madden LJ, Zandonatti MA, Flynn CT, Taffe MA, Marcondes MC, Schmitz JE, Reimann KA, Henriksen SJ, Fox HS (2004) CD8+ cell depletion amplifies the acute retroviral syndrome. J Neurovirol 10(Suppl 1):58–66
Mahajan SD, Schwartz SA, Shanahan TC, Chawda RP, Nair MP (2002) Morphine regulates gene expression of alpha- and beta-chemokines and their receptors on astroglial cells via the opioid mu receptor. J Immunol 169:3589–3599
Malessa R, Heimbach M, Brockmeyer NH, Hengge U, Rascher W, Michel MC (1996) Increased neuropeptide Y-like immunoreactivity in cerebrospinal fluid and plasma of human immunodeficiency virus-infected patients: relationship to HIV encephalopathy. J Neurol Sci 136:154–158
Mankowski JL, Spelman JP, Ressetar HG, Strandberg JD, Laterra J, Carter DL, Clements JE, Zink MC (1994) Neurovirulent simian immunodeficiency virus replicates productively in endothelial cells of the central nervous system in vivo and in vitro. J Virol 68:8202–8208
Mankowski JL, Queen SE, Clements JE, Zink MC (2004) Cerebrospinal fluid markers that predict SIV CNS disease. J Neuroimmunol 157:66–70
Mann K, Agartz I, Harper C, Shoaf S, Rawlings RR, Momenan R, Hommer DW, Pfefferbaum A, Sullivan EV, Anton RF, Drobes DJ, George MS, Bares R, Machulla HJ, Mundle G, Reimold M, Heinz A (2001) Neuroimaging in alcoholism: ethanol and brain damage. Alcohol Clin Exp Res 25:104S–109S
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
Marechal V, Prevost MC, Petit C, Perret E, Heard JM, Schwartz O (2001) Human immunodeficiency virus type 1 entry into macrophages mediated by macropinocytosis. J Virol 75:11166–11177
Martin-Garcia J, Kolson DL, Gonzalez-Scarano F (2002) Chemokine receptors in the brain: their role in HIV infection and pathogenesis. Aids 16:1709–1730
Martin-Padura I, Lostaglio S, Schneemann M, Williams L, Romano M, Fruscella P, Panzeri C, Stoppacciaro A, Ruco L, Villa A, Simmons D, Dejana E (1998) Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol 142:117–127
Martiney JA, Berman JW, Brosnan CF (1992) Chronic inflammatory effects of interleukin-1 on the blood–retina barrier. J Neuroimmunol 41:167–176
Marx PA, Chen Z (1998) The function of simian chemokine receptors in the replication of SIV. Semin Immunol 10:215–223
Matthes HW, Maldonado R, Simonin F, Valverde O, Slowe S, Kitchen I, Befort K, Dierich A, Le Meur M, Dolle P, Tzavara E, Hanoune J, Roques BP, Kieffer BL (1996) Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature 383:819–823
McArthur JC, Hoover DR, Bacellar H, Miller EN, Cohen BA, Becker JT, Graham NM, McArthur JH, Selnes OA, Jacobson LP et al (1993) Dementia in AIDS patients: incidence and risk factors. Multicenter AIDS Cohort Study. Neurology 43:2245–2252
McArthur JC, Haughey N, Gartner S, Conant K, Pardo C, Nath A, Sacktor N (2003) Human immunodeficiency virus-associated dementia: an evolving disease. J Neurovirol 9:205–221
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
Meyerhoff DJ (2001) Effects of alcohol and HIV infection on the central nervous system. Alcohol Res Health 25:288–298
Moses AV, Bloom FE, Pauza CD, Nelson JA (1993) Human immunodeficiency virus infection of human brain capillary endothelial cells occurs via a CD4/galactosylceramide-independent mechanism. Proc Natl Acad Sci USA 90:10474–10478
Muller WA (2003) Leukocyte–endothelial-cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol 24:327–334
Murray EA, Rausch DM, Lendvay J, Sharer LR, Eiden LE (1992) Cognitive and motor impairments associated with SIV infection in rhesus monkeys. Science 255:1246–1249
Muthumani K, Choo AY, Premkumar A, Hwang DS, Thieu KP, Desai BM, Weiner DB (2005) Human immunodeficiency virus type 1 (HIV-1) Vpr-regulated cell death: insights into mechanism. Cell Death Differ 12(Suppl 1):962–970
Narcisse L, Scemes E, Zhao Y, Lee SC, Brosnan CF (2005) The cytokine IL-1beta transiently enhances P2X7 receptor expression and function in human astrocytes. Glia 49:245–258
Nath A, Maragos WF, Avison MJ, Schmitt FA, Berger JR (2001) Acceleration of HIV dementia with methamphetamine and cocaine. J Neurovirol 7:66–71
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
Nathanson MH, Burgstahler AD, Mennone A, Fallon MB, Gonzalez CB, Saez JC (1995) Ca2+ waves are organized among hepatocytes in the intact organ. Am J Physiol 269:G167–G171
Nosheny RL, Mocchetti I, Bachis A (2005) Brain-derived neurotrophic factor as a prototype neuroprotective factor against HIV-1-associated neuronal degeneration. Neurotox Res 8:187–198
Nottet HS, Persidsky Y, Sasseville VG, Nukuna AN, Bock P, Zhai QH, Sharer LR, McComb RD, Swindells S, Soderland C, Gendelman HE (1996) Mechanisms for the transendothelial migration of HIV-1-infected monocytes into brain. J Immunol 156:1284–1295
Nukuna A, Gendelman HE, Limoges J, Rasmussen J, Poluektova L, Ghorpade A, Persidsky Y (2004) Levels of human immunodeficiency virus type 1 (HIV-1) replication in macrophages determines the severity of murine HIV-1 encephalitis. J Neurovirol 10(Suppl 1):82–90
Nuovo GJ, Alfieri ML (1996) AIDS dementia is associated with massive, activated HIV-1 infection and concomitant expression of several cytokines. Mol Med 2:358–366
Olivetta E, Percario Z, Fiorucci G, Mattia G, Schiavoni I, Dennis C, Jager J, Harris M, Romeo G, Affabris E, Federico M (2003) HIV-1 Nef induces the release of inflammatory factors from human monocyte/macrophages: involvement of Nef endocytotic signals and NF-kappa B activation. J Immunol 170:1716–1727
Orandle MS, MacLean AG, Sasseville VG, Alvarez X, Lackner AA (2002) Enhanced expression of proinflammatory cytokines in the central nervous system is associated with neuroinvasion by simian immunodeficiency virus and the development of encephalitis. J Virol 76:5797–5802
Osiecki K, Xie L, Zheng JH, Squires R, Pettoello-Mantovani M, Goldstein H (2005) Identification of granulocyte–macrophage colony-stimulating factor and lipopolysaccharide-induced signal transduction pathways that synergize to stimulate HIV type 1 production by monocytes from HIV type 1 transgenic mice. AIDS Res Hum Retroviruses 21:125–139
Ostermann G, Weber KS, Zernecke A, Schroder A, Weber C (2002) JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol 3:151–158
Owens T, Tran E, Hassan-Zahraee M, Krakowski M (1998) Immune cell entry to the CNS—a focus for immunoregulation of EAE. Res Immunol 149:781–789; discussion 844–786, 855–760
Paemeleire K (2002a) The cellular basis of neurovascular metabolic coupling. Acta Neurol Belg 102:153–157
Paemeleire K. (2002b) Calcium signaling in and between brain astrocytes and endothelial cells. Acta Neurol Belg 102:137–140
Pardridge WM, Choi TB (1986) Neutral amino acid transport at the human blood–brain barrier. Fed Proc 45:2073–2078
Pardridge WM, Triguero D, Yang J, Cancilla PA (1990) Comparison of in vitro and in vivo models of drug transcytosis through the blood–brain barrier. J Pharmacol Exp Ther 253:884–891
Patel CA, Mukhtar M, Pomerantz RJ (2000) Human immunodeficiency virus type 1 Vpr induces apoptosis in human neuronal cells. J Virol 74:9717–9726
Perry SW, Norman JP, Gelbard HA (2005) Adjunctive therapies for HIV-1 associated neurologic disease. Neurotox Res 8:161–166
Persidsky Y, Limoges J, McComb R, Bock P, Baldwin T, Tyor W, Patil A, Nottet HS, Epstein L, Gelbard H, Flanagan E, Reinhard J, Pirruccello SJ, Gendelman HE (1996) Human immunodeficiency virus encephalitis in SCID mice. Am J Pathol 149:1027–1053
Persidsky Y, Stins M, Way D, Witte MH, Weinand M, Kim KS, Bock P, Gendelman HE, Fiala M (1997) A model for monocyte migration through the blood–brain barrier during HIV-1 encephalitis. J Immunol 158:3499–3510
Persidsky Y, Ghorpade A, Rasmussen J, Limoges J, Liu XJ, Stins M, Fiala M, Way D, Kim KS, Witte MH, Weinand M, Carhart L, Gendelman HE (1999) Microglial and astrocyte chemokines regulate monocyte migration through the blood–brain barrier in human immunodeficiency virus-1 encephalitis. Am J Pathol 155:1599–1611
Persidsky Y, Potula R, Haorah J (2005) Rodent model systems for studies of HIV-1 associated dementia. Neurotox Res 8:91–106
Peruzzi F, Bergonzini V, Aprea S, Reiss K, Sawaya BE, Rappaport J, Amini S, Khalili K (2005) Cross talk between growth factors and viral and cellular factors alters neuronal signaling pathways: implication for HIV-associated dementia. Brain Res Brain Res Rev 50:114–125
Poli A, Pistello M, Carli MA, Abramo F, Mancuso G, Nicoletti E, Bendinelli M (1999) Tumor necrosis factor-alpha and virus expression in the central nervous system of cats infected with feline immunodeficiency virus. J Neurovirol 5:465–473
Potash MJ, Chao W, Bentsman G, Paris N, Saini M, Nitkiewicz J, Belem P, Sharer L, Brooks AI, Volsky DJ (2005) A mouse model for study of systemic HIV-1 infection, antiviral immune responses, and neuroinvasiveness. Proc Natl Acad Sci USA 102:3760–3765
Potula R, Dhillion N, Sui Y, Zien CA, Funa K, Pinson D, Mayo MS, Singh DK, Narayan O, Buch S (2004) Association of platelet-derived growth factor-B chain with simian human immunodeficiency virus encephalitis. Am J Pathol 165:815–824
Princen K, Schols D (2005) HIV chemokine receptor inhibitors as novel anti-HIV drugs. Cytokine Growth Factor Rev 16:659–677
Princen K, Hatse S, Vermeire K, Aquaro S, De Clercq E, Gerlach LO, Rosenkilde M, Schwartz TW, Skerlj R, Bridger G, Schols D (2004) Inhibition of human immunodeficiency virus replication by a dual CCR5/CXCR4 antagonist. J Virol 78:12996–13006
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
Raghavan R, Stephens EB, Joag SV, Adany I, Pinson DM, Li Z, Jia F, Sahni M, Wang C, Leung K, Foresman L, Narayan O (1997) Neuropathogenesis of chimeric simian/human immunodeficiency virus infection in pig-tailed and rhesus macaques. Brain Pathol 7:851–861
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
Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ (2003) Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 348:1333–1341
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
Risau W (1991) Induction of blood–brain barrier endothelial cell differentiation. Ann N Y Acad Sci 633:405–419
Risau W, Wolburg H (1990) Development of the blood–brain barrier. Trends Neurosci 13:174–178
Roberts ES, Zandonatti MA, Watry DD, Madden LJ, Henriksen SJ, Taffe MA, Fox HS (2003) Induction of pathogenic sets of genes in macrophages and neurons in NeuroAIDS. Am J Pathol 162:2041–2057
Roberts ES, Burudi EM, Flynn C, Madden LJ, Roinick KL, Watry DD, Zandonatti MA, Taffe MA, Fox HS (2004) Acute SIV infection of the brain leads to upregulation of IL6 and interferon-regulated genes: expression patterns throughout disease progression and impact on neuroAIDS. J Neuroimmunol 157:81–92
Robertson KR, Robertson WT, Ford S, Watson D, Fiscus S, Harp AG, Hall CD (2004) Highly active antiretroviral therapy improves neurocognitive functioning. J Acquir Immune Defic Syndr 36:562–566
Rogers TJ, Peterson PK (2003) Opioid G protein-coupled receptors: signals at the crossroads of inflammation. Trends Immunol 24:116–121
Rubin LL, Staddon JM (1999) The cell biology of the blood–brain barrier. Annu Rev Neurosci 22:11–28
Sanders VJ, Pittman CA, White MG, Wang G, Wiley CA, Achim CL (1998) Chemokines and receptors in HIV encephalitis. Aids 12:1021–1026
Sasseville VG, Smith MM, Mackay CR, Pauley DR, Mansfield KG, Ringler DJ, Lackner AA (1996) Chemokine expression in simian immunodeficiency virus-induced AIDS encephalitis. Am J Pathol 149:1459–1467
Schenkel AR, Mamdouh Z, Chen X, Liebman RM, Muller WA (2002) CD99 plays a major role in the migration of monocytes through endothelial junctions. Nat Immunol 3:143–150
Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA, Racz P, Tenner-Racz K, Dalesandro M, Scallon BJ, Ghrayeb J, Forman MA, Montefiori DC, Rieber EP, Letvin NL, Reimann KA (1999) Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283:857–860
Seilhean D, Dzia-Lepfoundzou A, Sazdovitch V, Cannella B, Raine CS, Katlama C, Bricaire F, Duyckaerts C, Hauw JJ (1997) Astrocytic adhesion molecules are increased in HIV-1-associated cognitive/motor complex. Neuropathol Appl Neurobiol 23:83–92
Sevigny JJ, Albert SM, McDermott MP, McArthur JC, Sacktor N, Conant K, Schifitto G, Selnes OA, Stern Y, McClernon DR, Palumbo D, Kieburtz K, Riggs G, Cohen B, Epstein LG, Marder K (2004) Evaluation of HIV RNA and markers of immune activation as predictors of HIV-associated dementia. Neurology 63:2084–2090
Sharp CD, Hines I, Houghton J, Warren A, Jackson THt, Jawahar A, Nanda A, Elrod JW, Long A, Chi A, Minagar A, Alexander JS (2003) Glutamate causes a loss in human cerebral endothelial barrier integrity through activation of NMDA receptor. Am J Physiol Heart Circ Physiol 285:H2592–H2598
Sharp CD, Houghton J, Elrod JW, Warren A, Jackson THt, Jawahar A, Nanda A, Minagar A, Alexander JS (2005a) N-Methyl-d-aspartate receptor activation in human cerebral endothelium promotes intracellular oxidant stress. Am J Physiol Heart Circ Physiol 288:H1893–H1899
Sharp PM, Shaw GM, Hahn BH (2005b) Simian immunodeficiency virus infection of chimpanzees. J Virol 79:3891–3902
Shibata R, Adachi A (1992) SIV/HIV recombinants and their use in studying biological properties. AIDS Res Hum Retroviruses 8:403–409
Shibata R, Kawamura M, Sakai H, Hayami M, Ishimoto A, Adachi A (1991) Generation of a chimeric human and simian immunodeficiency virus infectious to monkey peripheral blood mononuclear cells. J Virol 65:3514–3520
Si Q, Kim MO, Zhao ML, Landau NR, Goldstein H, Lee S (2002) Vpr- and Nef-dependent induction of RANTES/CCL5 in microglial cells. Virology 301:342–353
Si Q, Cosenza M, Kim MO, Zhao ML, Brownlee M, Goldstein H, Lee S (2004) A novel action of minocycline: inhibition of human immunodeficiency virus type 1 infection in microglia. J Neurovirol 10:284–292
Sidtis JJ, Gatsonis C, Price RW, Singer EJ, Collier AC, Richman DD, Hirsch MS, Schaerf FW, Fischl MA, Kieburtz K et al (1993) Zidovudine treatment of the AIDS dementia complex: results of a placebo-controlled trial. AIDS Clinical Trials Group. Ann Neurol 33:343–349
Simard M, Arcuino G, Takano T, Liu QS, Nedergaard M (2003) Signaling at the gliovascular interface. J Neurosci 23:9254–9262
Smit TK, Brew BJ, Tourtellotte W, Morgello S, Gelman BB, Saksena NK (2004) Independent evolution of human immunodeficiency virus (HIV) drug resistance mutations in diverse areas of the brain in HIV-infected patients, with and without dementia, on antiretroviral treatment. J Virol 78:10133–10148
Sobue K, Yamamoto N, Yoneda K, Hodgson ME, Yamashiro K, Tsuruoka N, Tsuda T, Katsuya H, Miura Y, Asai K, Kato T (1999) Induction of blood–brain barrier properties in immortalized bovine brain endothelial cells by astrocytic factors. Neurosci Res 35:155–164
Speth C, Dierich MP, Sopper S (2005) HIV-infection of the central nervous system: the tightrope walk of innate immunity. Mol Immunol 42:213–228
Steele AD, Henderson EE, Rogers TJ (2003) Mu-opioid modulation of HIV-1 coreceptor expression and HIV-1 replication. Virology 309:99–107
Stent G, Crowe SM (1997) Effects of HIV-1 on the surface expression of LFA-1 on cultured monocytes. J Acquir Immune Defic Syndr Hum Retrovirol 15:95–103
Stephens EB, Singh DK, Kohler ME, Jackson M, Pacyniak E, Berman NE (2003) The primary phase of infection by pathogenic simian–human immunodeficiency virus results in disruption of the blood–brain barrier. AIDS Res Hum Retroviruses 19:837–846
Strazielle N, Khuth ST, Ghersi-Egea JF (2004) Detoxification systems, passive and specific transport for drugs at the blood–CSF barrier in normal and pathological situations. Adv Drug Deliv Rev 56:1717–1740
Strelow LI, Janigro D, Nelson JA (2001) The blood–brain barrier and AIDS. Adv Virus Res 56:355–388
Sui Y, Potula R, Pinson D, Adany I, Li Z, Day J, Buch E, Segebrecht J, Villinger F, Liu Z, Huang M, Narayan O, Buch S (2003) Microarray analysis of cytokine and chemokine genes in the brains of macaques with SHIV-encephalitis. J Med Primatol 32:229–239
Sun J, Osiecki K, Zheng J, Falkin L, Santambrogio L, Littman DR, Goldstein H (2006) CD4-specific transgenic expression of human cyclin T1 markedly increases HIV-1 production by CD4+ lymphocytes and myeloid committed cells in mice trasgenic for a provirus encoding a monocyte-tropic HIV-1 isolate. J Virol 80:1850–1862
Suzuki S, Chuang AJ, Chuang LF, Doi RH, Chuang RY (2002) Morphine promotes simian acquired immunodeficiency syndrome virus replication in monkey peripheral mononuclear cells: induction of CC chemokine receptor 5 expression for virus entry. J Infect Dis 185:1826–1829
Swingler S, Mann A, Jacque J, Brichacek B, Sasseville VG, Williams K, Lackner AA, Janoff EN, Wang R, Fisher D, Stevenson M (1999) HIV-1 Nef mediates lymphocyte chemotaxis and activation by infected macrophages. Nat Med 5:997–1103
Thomas WE (1999) Brain macrophages: on the role of pericytes and perivascular cells. Brain Res Brain Res Rev 31:42–57
Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J (2001) Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci 21:2580–2588
Trillo-Pazos G, McFarlane-Abdulla E, Campbell IC, Pilkington GJ, Everall IP (2000) Recombinant nef HIV-IIIB protein is toxic to human neurons in culture. Brain Res 864:315–326
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
Tyor WR, Middaugh LD (1999) Do alcohol and cocaine abuse alter the course of HIV-associated dementia complex? J Leukoc Biol 65:475–481
Tyor WR, Power C, Gendelman HE, Markham RB (1993) A model of human immunodeficiency virus encephalitis in scid mice. Proc Natl Acad Sci USA 90:8658–8662
Unutmaz D, Xiang W, Sunshine MJ, Campbell J, Butcher E, Littman DR (2000) The primate lentiviral receptor Bonzo/STRL33 is coordinately regulated with CCR5 and its expression pattern is conserved between human and mouse. J Immunol 165:3284–3292
van Buul JD, Hordijk PL (2004) Signaling in leukocyte transendothelial migration. Arterioscler Thromb Vasc Biol 24:824–833
van Zwieten EJ, Ravid R, Swaab DF, Van de Woude T (1988) Immunocytochemically stained vasopressin binding sites on blood vessels in the rat brain. Brain Res 474:369–373
Verbeek MM, de Waal RM, Schipper JJ, Van Nostrand WE (1997) Rapid degeneration of cultured human brain pericytes by amyloid beta protein. J Neurochem 68:1135–1141
Virgintino D, Robertson D, Errede M, Benagiano V, Bertossi M, Ambrosi G, Roncali L (2001) Expression of the gap junction protein connexin43 in human telencephalon microvessels. Microvasc Res 62:435–439
Wang X, Douglas SD, Metzger DS, Guo CJ, Li Y, O'Brien CP, Song L, Davis-Vogal A, Ho WZ (2002) Alcohol potentiates HIV-1 infection of human blood mononuclear phagocytes. Alcohol Clin Exp Res 26:1880–1886
Wang EJ, Sun J, Pettoello-Mantovani M, Anderson CM, Osiecki K, Zhao ML, Lopez L, Lee SC, Berman JW, Goldstein H (2003a) Microglia from mice transgenic for a provirus encoding a monocyte-tropic HIV type 1 isolate produce infectious virus and display in vitro and in vivo upregulation of lipopolysaccharide-induced chemokine gene expression. AIDS Res Hum Retroviruses 19:755–765
Wang Z, Pekarskaya O, Bencheikh M, Chao W, Gelbard HA, Ghorpade A, Rothstein JD, Volsky DJ (2003b) Reduced expression of glutamate transporter EAAT2 and impaired glutamate transport in human primary astrocytes exposed to HIV-1 or gp120. Virology 312:60–73
Wang GJ, 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
Weed MR, Steward DJ (2005) Neuropsychopathology in the SIV/macaque model of AIDS. Front Biosci 10:710–727
Weisse CS (1992) Depression and immunocompetence: a review of the literature. Psychol Bull 111:475–489
Weiss JM, Nath A, Major EO, Berman JW (1999) HIV-1 Tat induces monocyte chemoattractant protein-1-mediated monocyte transmigration across a model of the human blood–brain barrier and up-regulates CCR5 expression on human monocytes. J Immunol 163:2953–2959
Wetzel MA, Steele AD, Eisenstein TK, Adler MW, Henderson EE, Rogers TJ (2000) Mu-opioid induction of monocyte chemoattractant protein-1, RANTES, and IFN-gamma-inducible protein-10 expression in human peripheral blood mononuclear cells. J Immunol 165:6519–6524
Williams KC, Corey S, Westmoreland SV, Pauley D, Knight H, deBakker C, Alvarez X, Lackner AA (2001) Perivascular macrophages are the primary cell type productively infected by simian immunodeficiency virus in the brains of macaques: implications for the neuropathogenesis of AIDS. J Exp Med 193:905–915
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
Yi Y, Lee C, Liu QH, Freedman BD, Collman RG (2004) Chemokine receptor utilization and macrophage signaling by human immunodeficiency virus type 1 gp120: implications for neuropathogenesis. J Neurovirol 10(Suppl 1):91–96
Zhang L, Looney D, Taub D, Chang SL, Way D, Witte MH, Graves MC, Fiala M (1998) Cocaine opens the blood–brain barrier to HIV-1 invasion. J Neurovirol 4:619–626
Zhu HJ, Liu GQ (2004) Glutamate up-regulates P-glycoprotein expression in rat brain microvessel endothelial cells by an NMDA receptor-mediated mechanism. Life Sci 75:1313–1322
Zink MC, Clements JE (2000) A rapid, reproducible model of AIDS and encephalitis in SIV infected macaques demonstrates the role of viral load in CNS disease. NeuroAIDS 3: Online AAAS Science publication http://AID Science.org/NeuroAIDS/
Zink MC, Clements JE (2002) A novel simian immunodeficiency virus model that provides insight into mechanisms of human immunodeficiency virus central nervous system disease. J Neurovirol 8(Suppl 2):42–48
Zink MC, Spelman JP, Robinson RB, Clements JE (1998) SIV infection of macaques—modeling the progression to AIDS dementia. J Neurovirol 4:249–259
Zink MC, Suryanarayana K, Mankowski JL, Shen A, Piatak M Jr, Spelman JP, Carter DL, Adams RJ, Lifson JD, Clements JE (1999) High viral load in the cerebrospinal fluid and brain correlates with severity of simian immunodeficiency virus encephalitis. J Virol 73:10480–10488
Zink MC, Coleman GD, Mankowski JL, Adams RJ, Tarwater PM, Fox K, Clements JE (2001) Increased macrophage chemoattractant protein-1 in cerebrospinal fluid precedes and predicts simian immunodeficiency virus encephalitis. J Infect Dis 184:1015–1021
Zink MC, Uhrlaub J, DeWitt J, Voelker T, Bullock B, Mankowski J, Tarwater P, Clements J, Barber S (2005) Neuroprotective and anti-human immunodeficiency virus activity of minocycline. JAMA 293:2003–2011
Zukowska-Grojec Z, Karwatowska-Prokopczuk E, Rose W, Rone J, Movafagh S, Ji H, Yeh Y, Chen WT, Kleinman HK, Grouzmann E, Grant DS (1998) Neuropeptide Y: a novel angiogenic factor from the sympathetic nerves and endothelium. Circ Res 83:187–195
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This work was supported by the National Institute of Mental Health grant, MH52974 and MH0702297, National Institutes of Health grant NS11920, NIH Centers for AIDS Research grant AI-051519 (to all authors), and Molecular Neuropathology Training grant NIH NS07098 (to CMB).
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Buckner, C.M., Luers, A.J., Calderon, T.M. et al. Neuroimmunity and the Blood–Brain Barrier: Molecular Regulation of Leukocyte Transmigration and Viral Entry into the Nervous System with a Focus on NeuroAIDS. Jrnl NeuroImmune Pharm 1, 160–181 (2006). https://doi.org/10.1007/s11481-006-9017-3
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DOI: https://doi.org/10.1007/s11481-006-9017-3