Neuroimmunology and the Pathogenesis of HIV-1 Encephalitis in the HAART Era: Implications for Neuroprotective Treatment

Seth W. Perry; Harris A. Gelbard

doi:10.1128/9781555815691.ch11

Chapter 11 : Neuroimmunology and the Pathogenesis of HIV-1 Encephalitis in the HAART Era: Implications for Neuroprotective Treatment

Authors: Seth W. Perry¹, Harris A. Gelbard²

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Affiliations: 1: Center for Aging and Developmental Biology, Kornberg Medical Research Institute, Departments of Neurology, Pediatrics, Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642; 2: Center for Aging and Developmental Biology, Kornberg Medical Research Institute, Departments of Neurology, Pediatrics, Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642

Content Type: Monograph

Publication Year: 2009

Category: Viruses and Viral Pathogenesis

Book DOI: 10.1128/9781555815691

Chapter DOI: 10.1128/9781555815691.ch11

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Abstract:

In 1991, a revision of the terminology was made by the American Academy of Neurology AIDS Task Force, which developed the term human immunodeficiency virus (HIV)-1-associated cognitive motor complex (HIV-CMC), to encompass both the milder HIV-1- associated minor cognitive motor disorder (HIV-MCMD) and the more severe HIV-1-associated dementia complex (HIV-DC) (American Academy of Neurology AIDS Task Force, 1991). Although the advent of highly active antiretroviral therapies (HAART) has made great strides in extending life for AIDS patients, this longer life span may present increasing opportunity for HIV dementia (or HAD) to develop. HIV-1 encephalitis, the histo- and neuropathological correlate of central nervous system (CNS) HIV infection and HAD, occurs in most but not all cases of HAD. Infiltration of infected and/or activated immune cells from the periphery is increased with HIV infection and likely to be essential for development of HAD. Passage of infected cells or virus across the blood-brain barrier (BBB) results in the presence of activated immune cells in the brain, primarily macrophages and microglia but also astrocytes, which are thought to be directly causal to developing HAD. Continuous exposure to these noxious molecules is not necessary for progressive neuronal dysfunction and death. As a consequence of these generalized pathogenic mechanisms, numerous molecules and signaling pathways are secreted and activated that are thought to be involved in precipitating the pathophysiology of HAD, many of which share functions in both normal cellular signaling and other neurodegenerative diseases.

Citation: Perry S, Gelbard H. 2009. Neuroimmunology and the Pathogenesis of HIV-1 Encephalitis in the HAART Era: Implications for Neuroprotective Treatment, p 137-149. In Goodkin K, Shapshak P, Verma A (ed), The Spectrum of Neuro-AIDS Disorders. ASM Press, Washington, DC. doi: 10.1128/9781555815691.ch11

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Neuroimmunology and the Pathogenesis of HIV-1 Encephalitis in the HAART Era: Implications for Neuroprotective Treatment

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/content/10.1128/9781555815691.ch11.ch11fig01

FIGURE 1

Schematic diagram of some purported HIV neurotoxin-induced neuronal dysfunctions in HIV dementia. Candidate HIV neurotoxins such as Tat, TNF-α, PAF, gp120, and others are thought to activate excitotoxic pathways involving glutamate receptor activation, calcium influx, increased excitotoxic synaptic activity, alterations in mitochondrial membrane potential (Δψm), productions of ROS, and ultimately synapse loss and neuronal cell death if left unchecked. Alterations in the activity of GSK-3β or other signal transduction pathways (not diagrammed here) may lead to changes in synaptic activity and/or direct neuronal apoptosis. The goal of adjunctive therapeutics for HAD is to interrupt the cycle of cellular dysfunction before deficits become chronic and before significant synapse loss and/or neuronal cell death occurs.

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FIGURE 1

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FIGURE 2

Tat upregulates synaptic proteins in rat cortical neurons. Treatment of rat cortical neurons for 24 h with 2.5 µg of Tat/ml up-regulated several key proteins involved in synaptic structure and function, including phosphorylated synapsin, total synapsin, and calcium calmodulin kinase II. Semiquantitative changes in protein expression were determined by densitometric analysis of mean band intensities from Western blots and were expressed as change with Tat treatment relative to control. A representative example of control and Tat synapsin bands (cut from blot film image after digital background subtraction) is shown. Percent values were generated from the average band intensity of duplicate samples (from separate treatment wells) per condition, run on the same gel. Treatment conditions were performed in duplicate or triplicate for at least two separate blots per target protein, and all changes were significant (P < 0.05, analysis of variance and Student’s t test).

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FIGURE 2

References

/content/book/10.1128/9781555815691.ch11

1. Acharya, J.,, R. Delgado,, K. Jalink,, P. Labarca, and, C. Zuker. 1998. Synaptic defects and compensatory regulation of inositol metabolism in inositol polyphosphate 1-phosphatase mutants. Neuron 20: 1219– 1229.

2. American Academy of Neurology AIDS Task Force. 1991. Nomenclature and research case definitions for neurologic manifestations of human immunodeficiency virus-type 1 (HIV-1) infection. Report of a Working Group of the American Academy of Neurology AIDS Task Force. Neurology 41: 778– 785.

3. Anthony, I.,, J. Bell,, F. Carnie, and, S. Ramage. 2005. Influence of HAART on HIV-related CNS disease and neuroinflammation. J. Neuropathol. Exp. Neurol. 64: 529– 536.

4. Battaglia, P.,, F. Gigliani,, A. Macchini, and, S. Zito. 2001. A Drosophila model of HIV-Tat-related pathogenicity. J. Cell Sci. 114: 2787– 2794.

5. Bazan, J. F.,, K. B. Bacon,, G. Hardiman,, W. Wang,, K. Soo,, D. Rossi,, D. R. Greaves,, A. Zlotkin, and, T. J. Schall. 1997. A new class of membrane-bound chemokine with a CX3C motif. Nature 385: 640– 644.

6. Bazan, N.,, G. Clark, and, C. Zorumski. 1993. The activation of phospholipase A2 and release of arachidonic acid and other lipid mediators at the synapse: the role of platelet-activating factor. J. Lipid Mediat. 6: 421– 427.

7. Beattie, E.,, M. Beattie,, J. Bresnahan,, B. Ha,, R. Malenka,, W. Morishita,, D. Stellwagen, and, M. Von Zastrow. 2002. Control of synaptic strength by glial TNF-alpha. Science 295: 2282– 2285.

8. Berger, J.,, and G. Arendt. 2000. HIV dementia: the role of the basal ganglia and dopaminergic systems. J. Psychopharmacol. 14: 214– 221.

9. Biber, K.,, H. Boddeke,, I. Dijkstra, and, M. Zuurman. 2002. Chemokines in the brain: neuroimmunology and beyond. Curr. Opin. Pharmacol. 2: 63– 68.

10. Bolton, S.,, D. Anthony, and, V. Perry. 1998. Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood-brain barrier breakdown in vivo. Neuroscience 86: 1245– 1257.

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

12. Cartier, L.,, M. Dubois-Dauphin,, O. Hartley, and, K. Krause. 2005. Chemokine receptors in the central nervous system: role in brain inflammation and neurodegenerative diseases. Brain Res. Brain Res. Rev. 48: 16– 42.

13. Casaccia-Bonnefil, P.,, M. Chao, and, C. Gu. 1999. Neurotrophins in cell survival/death decisions. Adv. Exp. Med. Biol. 468: 275– 282.

14. Chen, C. H.,, S. L. Hwang,, S. L. Howng,, C. K. Chou, and, Y. R. Hong. 2000. Three rat brain alternative splicing dynamin-like protein variants: interaction with the glycogen synthase kinase 3beta and action as a substrate. Biochem. Biophys. Res. Commun. 268: 893– 898.

15. Chen, G.,, L. Huang,, Y. Jiang, and, H. Manji. 1999. The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3. J. Neurochem. 72: 1327– 1330.

16. Cheng, J.,, J. Geiger,, S. Hochman,, B. Knudsen,, M. Ma,, D. Magnuson, and, A. Nath. 1998. Neuronal excitatory properties of human immunodeficiency virus type 1 Tat protein. Neuroscience 82: 97– 106.

17. Chong, Z. Z.,, F. Li, and, K. Maiese. 2005. Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease. Prog. Neurobiol. 75: 207– 246.

18. Chuang, D. 2005. The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials. Ann. N. Y. Acad. Sci. 1053: 195– 204.

19. Conant, K.,, R. Gallo,, A. Garzino-Demo,, W. Halliday,, E. Major,, J. McArthur,, A. Nath, and, C. Power. 1998. Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation dementia. Proc. Natl. Acad. Sci. USA 95: 3117– 3121.

20. Cotter, R.,, D. Erichsen,, A. Lopez,, H. Peng,, L. Ryan,, C. Williams, and, J. Zheng. 2002. Fractalkine (CX3CL1) and brain inflammation: implications for HIV-1-associated dementia. J. Neurovirol. 8: 585– 598.

21. Dana Consortium on the Therapy of HIV Dementia and Related Cognitive Disorders. 1997. Safety and tolerability of the antioxidant OPC-14117 in HIV-associated cognitive impairment. Neurology 49: 142– 146.

22. Diesing, T.,, H. Gelbard,, H. Gendelman, and, S. Swindells. 2002. HIV-1-associated dementia: a basic science and clinical perspective. AIDS Read. 12: 358– 368.

23. Dou, H.,, K. Birusingh,, S. Dewhurst,, J. Faraci,, H. Gelbard,, H. Gendelman,, S. Gorantla,, S. B. Maggirwar, and, L. Poluektova. 2003. Neuroprotective activities of sodium valproate in a murine model of human immunodeficiency virus-1 encephalitis. J. Neurosci. 23: 9162– 9170.

24. Dou, H.,, J. Bradley,, S. Dewhurst,, B. Ellison,, H. Gendelman,, A. Kasiyanov,, S. Maggirwar,, L. Poluektova, and, H. Xiong. 2005. Neuroprotective mechanisms of lithium in murine human immunodeficiency virus-1 encephalitis. J. Neurosci. 25: 8375– 8385.

25. Dou, H.,, H. Gelbard,, H. Gendelman,, J. Kingsley, and, R. Mosley. 2004. Neuroprotective strategies for HIV-1 associated dementia. Neurotox. Res. 6: 503– 521.

26. Ellis, R.,, I. Abramson,, J. Atkinson,, R. Deutsch,, I. Grant,, R. Heaton,, T. Marcotte,, J. McCutchan,, J. Nelson,, L. Thal,, M. Wallace, et al. 1997. Neurocognitive impairment is an independent risk factor for death in HIV infection. Arch. Neurol. 54: 416– 424.

27. Epstein, L.,, E. Cho,, M. Myenhofer,, B. Navia,, R. Price, and, L. Sharer. 1984. HTLV-III/LAV-like retrovirus particles in the brains of patients with AIDS encephalopathy. AIDS Res. 1: 447– 454.

28. Epstein, L., and H. Gelbard. 1999. HIV-1-induced neuronal injury in the developing brain. J. Leukoc. Biol. 65: 453– 457.

29. Everall, I.,, J. Atkinson,, R. Ellis,, I. Grant,, R. Heaton,, M. Mallory,, T. Marcotte,, E. Masliah,, J. McCutchan, et al. 1999. Cortical synaptic density is reduced in mild to moderate human immunodeficiency virus neurocognitive disorder. Brain Pathol. 9: 209– 217.

30. Fine, S.,, R. Angel,, S. Dewhurst,, L. Epstein,, H. Gelbard,, S. Perry, and, J. Rothstein. 1996. Tumor necrosis factor alpha inhibits glutamate uptake by primary human astrocytes. Implications for pathogenesis of HIV-1 dementia. J. Biol. Chem. 271: 15303– 15306.

31. Gelbard, H.,, B. Blumberg,, L. Epstein,, H. James,, A. Kazee,, S. Perry,, Y. Saito, and, L. Sharer. 1995. Apoptotic neurons in brains from paediatric patients with HIV-1 encephalitis and progressive encephalopathy. Neuropathol. Appl. Neurobiol. 21: 208– 217.

32. Gelbard, H.,, Y. Choi,, K. Dzenko,, P. Genis,, H. Nottet,, S. Swindells,, M. Jett,, R. White,, L. Wang,, D. Zhang,, S. Lipton,, W. Tourtellotte,, L. Epstein, and, H. Gendelman. 1994. Platelet-activating factor: a candidate human immunodeficiency virus type 1-induced neurotoxin. J. Virol. 68: 4628– 4635.

33. Gilman, C. P.,, and M. P. Mattson. 2002. Do apoptotic mechanisms regulate synaptic plasticity and growth-cone motility? Neuromol. Med. 2: 197– 214.

34. Giulian, D.,, J. Li,, X. Li,, S. N. Lin,, C. Noonan,, R. Schwarcz,, D. Tom,, E. Wendt, and, J. Yu. 1996. Study of receptor-mediated neurotoxins released by HIV-1-infected mononuclear phagocytes found in human brain. J. Neurosci. 16: 3139– 3153.

35. Glass, J.,, H. Fedor,, J. McArthur, and, S. Wesselingh. 1995. Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlations with dementia. Ann. Neurol. 38: 755– 762.

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

37. Gray, F.,, F. Chretien,, A. Vallat-Decouvelaere, and, F. Scaravilli. 2003. The changing pattern of HIV neuropathology in the HAART era. J. Neuropathol. Exp. Neurol. 62: 429– 440.

38. Hall, A.,, A. Brennan,, K. Cleverley,, R. Goold,, F. Lucas,, P. Salinas, and, P. Gordon-Weeks. 2002. Valproate regulates GSK-3-mediated axonal remodeling and synapsin I clustering in developing neurons. Mol. Cell. Neurosci. 20: 257– 270.

39. Hao, Y.,, G. Chen,, T. Creson,, F. Du,, T. Gould,, P. Li,, H. Manji,, P. Yuan, and, L. Zhang. 2004. Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J. Neurosci. 24: 6590– 6599.

40. Harrison, J.,, S. Adhikari,, K. Bacon,, P. Botti,, S. Chen,, L. Feng,, Y. Jiang,, D. Maciejewski,, R. K. McNamara,, M. Salafranca,, W. Streit,, D. Thompson, and, Y. Xia. 1998. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc. Natl. Acad. Sci. USA 95: 10896.

41. Haughey, N.,, J. Geiger,, C. Holden, and, A. Nath. 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.

42. Haughey, N.,, J. Geiger,, M. Mattson,, A. Nath, and, J. Slevin. 2001. HIV-1 Tat through phosphorylation of NMDA receptors potentiates glutamate excitotoxicity. J. Neurochem. 78: 457– 467.

43. Heyes, P.,, B. Brew,, J. Keilp,, A. Martin,, M. Mouradian,, R. Price,, A. Sadler,, A. Salazar,, J. Sidtis, and, J. Yergey. 1991. Quinolinic acid in cerebrospinal fluid and serum in HIV-1 infection: relationship to clinical and neurological status. Ann. Neurol. 29: 202– 209.

44. Huber, J.,, T. Davis, and, R. Egleton. 2001. Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier. Trends Neurosci. 24: 719– 725.

45. Jin, Y.,, N. Dragicevic,, W. Maragos,, M. McEwen,, S. Nottingham,, J. Springer, and, P. Sullivan. 2004. The mitochondrial uncoupling agent 2,4-dinitrophenol improves mitochondrial function, attenuates oxidative damage, and increases white matter sparing in the contused spinal cord. J. Neurotrauma 21: 1396– 1404.

46. Kaul, M.,, G. Garden, and, S. Lipton. 2001. Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410: 988– 994.

47. Kaul, M.,, and S. Lipton. 2004. Signaling pathways to neuronal damage and apoptosis in human immunodeficiency virus type 1-associated dementia: chemokine receptors, excitotoxicity, and beyond. J. Neurovirol. 10: 97– 101.

48. Klein, P.,, and D. Melton. 1996. A molecular mechanism for the effect of lithium on development. Proc. Natl. Acad. Sci. USA 93: 8455– 8459.

49. Korde, A.,, L. Craddock,, W. Maragos, and, S. Pettigrew. 2005. The mitochondrial uncoupler 2,4-dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia. J. Neurochem. 94: 1676– 1684.

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

51. Krathwohl, M. D.,, R. Hromas,, D. R. Brown,, H. E. Broxmeyer, and, K. H. Fife. 1997. Functional characterization of the C—C chemokine-like molecules encoded by molluscum contagiosum virus types 1 and 2. Proc. Natl. Acad. Sci. USA 94: 9875– 9880.

52. Kumar, A.,, B. Aggarwal,, S. Dhawan, and, S. Manna. 1998. HIV-Tat protein activates c-Jun N-terminal kinase and activator protein-1. J. Immunol. 161: 776– 781.

53. Langford, T.,, S. Letendre,, G. Larrea, and, E. Masliah. 2003. Changing patterns in the neuropathogenesis of HIV during the HAART era. Brain Pathol. 13: 195– 210.

54. Lehrman, G.,, R. Bosch,, J. Coffin,, R. Coombs,, I. Hogue,, C. Jennings,, A. Landay,, D. Margolis,, J. Mellors,, S. Palmer,, D. Richman,, C. Spina, and, A. Wiegand. 2005. Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet 366: 549– 555.

55. Lipton, S. 1998. Neuronal injury associated with HIV-1: approaches to treatment. Annu. Rev. Pharmacol. Toxicol. 38: 159– 177.

56. Lopez, O.,, J. Becker,, M. Dew,, J. Sanchez, and, J. Wess. 1999. Neurological characteristics of HIV-infected men and women seeking primary medical care. Eur. J. Neurol. 6: 205– 209.

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

58. Maragos, W.,, W. Cass,, M. Guseva,, A. Nath,, J. Pauly,, J. Turchan, and, K. Young. 2002. Human immunodeficiency virus-1 Tat protein and methamphetamine interact synergistically to impair striatal dopaminergic function. J. Neurochem. 83: 955– 963.

59. Maragos, W.,, J. Dean,, K. Rockich, and, K. Young. 2003. Pre-or post-treatment with the mitochondrial uncoupler 2,4-dinitrophenol attenuates striatal quinolinate lesions. Brain Res. 966: 312-316.

60. Maragos, W.,, and A. Korde. 2004. Mitochondrial uncoupling as a potential therapeutic target in acute central nervous system injury. J. Neurochem. 91: 257– 262.

61. Marchetti, B.,, and M. Abbracchio. 2005. To be or not to be (inflamed)-is that the question in anti-inflammatory drug therapy of neurodegenerative disorders? Trends Pharmacol. Sci. 26: 517– 525.

62. Martinez, A.,, M. Alonso,, A. Castro, and, I. Dorronsoro. 2002. Glycogen synthase kinase 3 (GSK-3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation. Med. Res. Rev. 22: 373– 384.

63. Masliah, E.,, C. Achim,, J. Atkinson,, R. Ellis,, I. Grant,, R. Heaton,, M. Mallory,, T. Marcotte,, J. McCutchan,, J. Nelson,, C. Wiley, et al. 1997. Dendritic injury is a pathological substrate for human immunodeficiency virus-related cognitive disorders. Ann. Neurol. 42: 963– 972.

64. Matarrese, P.,, A. Cassone,, L. Gambardella,, S. Vella,, R. Cauda, and, W. Malorni. 2003. Mitochondrial membrane hyperpolarization hijacks activated T lymphocytes toward the apoptotic-prone phenotype: homeostatic mechanisms of HIV protease inhibitors. J. Immunol. 170: 6006.

65. Mattson, M.,, and D. Liu. 2002. Energetics and oxidative stress in synaptic plasticity and neurodegenerative disorders. Neuromol. Med. 2: 215– 231.

66. McArthur, J. 2004. HIV dementia: an evolving disease. J. Neuroimmunol. 157: 3– 10.

67. Meucci, O.,, T. Bushell,, A. Fatatis,, P. Gray,, R. Miller, and, A. Simen. 1998. Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity. Proc. Natl. Acad. Sci. USA 95: 14500.

68. Minagar, A.,, C. Eisdorfer,, R. Fujimura,, M. Heyes,, R. Ownby, and, P. Shapshak. 2002. The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis. J. Neurol. Sci. 202: 13– 23.

69. Mollace, V.,, P. Clayette,, C. Muscoli,, H. S. Nottet,, D. Salvemini,, M. Perno, and, C. Turco. 2001. Oxidative stress and neuroAIDS: triggers, modulators and novel antioxidants. Trends Neurosci. 24: 411– 416.

70. Moses, A.,, S. Stenglein,, J. Strussenberg,, K. Wehrly, and, J. Nelson. 1996. Sequences regulating tropism of human immunodeficiency virus type 1 for brain capillary endothelial cells map to a unique region on the viral genome. J. Virol. 70: 3401– 3406.

71. Murase, S.,, E. Mosser, and, E. Schuman. 2002. Depolarization drives beta-Catenin into neuronal spines promoting changes in synaptic structure and function. Neuron 35: 91– 105.

72. Nath, A. 2002. Human immunodeficiency virus (HIV) proteins in neuropathogenesis of HIV dementia. J. Infect. Dis. 2: S193– S198.

73. Nath, A.,, C. Anderson,, J. Bell,, R. Booze,, K. Hauser,, M. Jones,, C. Mactutus,, W. Maragos, and, M. Mattson. 2000. Neurotoxicity and dysfunction of dopaminergic systems associated with AIDS dementia. J. Psychopharmacol. 14: 222– 227.

74. New, D.,, S. Dewhurst,, L. G. Epstein,, H. Gelbard, and, S. Maggirwar. 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.

75. Nicholls, D. G. 2002. Mitochondrial function and dysfunction in the cell: its relevance to aging and aging-related disease. Int. J. Biochem. Cell Biol. 34: 1372.

76. Nishimura, W.,, Y. Hata,, J. Iida,, N. Tanaka, and, I. Yao. 2002. Interaction of synaptic scaffolding molecule and Beta-catenin. J. Neurosci. 22: 757– 765.

77. Nori, A.,, and J. Kopecek. 2005. Intracellular targeting of polymer-bound drugs for cancer chemotherapy. Adv. Drug Deliv. Rev. 57: 609– 636.

78. Norman, J. P.,, S. W. Perry,, K. A. Kasischke,, D. J Volsky, and, H. A. Gelbard. 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.

79. Nuovo, G.,, A. Braun,, F. Gallery, and, P. MacConnell. 1994. In situ detection of polymerase chain reaction-amplified HIV-1 nucleic acids and tumor necrosis factor-alpha RNA in the central nervous system. Am. J. Pathol. 144: 659– 666.

80. Pace, G.,, and C. Leaf. 1995. The role of oxidative stress in HIV disease. Free Radic. Biol. Med. 19: 523– 528.

81. Packard, M.,, V. Budnik, and, D. Mathew. 2003. Wnts and TGF beta in synaptogenesis: old friends signalling at new places. Nat. Rev. Neurosci. 4: 113– 120.

82. Perry, S.,, M. Bellizzi,, S. Dewhurst, and, H. Gelbard. 2002. Tumor necrosis factor-alpha in normal and diseased brain: conflicting effects via intraneuronal receptor crosstalk? J. Neurovirol. 8: 611– 624.

83. Perry, S.,, G. Dbaibo,, S. Dewhurst,, K. Dzenko,, L. Epstein,, J. Hamilton,, Y. Hannun,, L. Tjoelker, and, J. Whittaker. 1998. Platelet-activating factor receptor activation. An initiator step in HIV-1 neuropathogenesis. J. Biol. Chem. 273: 17660– 17664.

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

85. Perry, S.,, and H. Gelbard. 2005. Adjunctive therapies for HIV-1 associated neurologic disease. Neurotox. Res. 8: 161– 166.

86. Perry, S.,, H. Gelbard,, A. Litzburg, and, J. Norman. 2004. Antioxidants are required during the early critical period, but not later, for neuronal survival. J. Neurosci. Res. 78: 482.

87. Petrache, I.,, A. Birukova,, J. Garcia,, H. Gelbard,, S. Ramirez, and, A. Verin. 2003. The role of the microtubules in tumor necrosis factor-alpha-induced endothelial cell permeability. Am. J. Respir. Cell Mol. Biol. 28: 574– 581.

88. Rock, R.,, M. Cheeran,, G. Gekker,, S. Hu,, J. Lokensgard,, P. Peterson, and, W. Sheng. 2004. Role of microglia in central nervous system infections. Clin. Microbiol. Rev. 17: 942– 964.

89. Romero, I.,, M. Prevost,, E. Perret,, P. Adamson,, J. Greenwood,, P. Couraud, and, S. Ozden. 2000. Interactions between brain endothelial cells and human T-cell leukemia virus type 1-infected lymphocytes: mechanisms of viral entry into the central nervous system. J. Virol. 74: 6021– 6030.

90. Ryan, L. A.,, R. L. Cotter,, W. E. Zink II,, H. E. Gendelman, and, J. Zheng. 2002. Macrophages chemokines and neuronal injury in HIV-1-associated dementia. Cell. Mol. Biol. 48: 137– 150.

91. Ryves, W.,, E. Dalton,, A. Harwood, and, R. Williams. 2005. GSK-3 activity in neocortical cells is inhibited by lithium but not carbamazepine or valproic acid. Bipolar Disord. 7: 260– 265.

92. Sacktor, N.,, J. Becker,, B. Cohen,, C. Kleeberger,, R. Lyles,, E. Miller,, O. Selnes, and, R. Skolasky. 2001. HIV-associated neurologic disease incidence changes: Multicenter AIDS Cohort Study, 1990-1998. Neurology 56: 257– 260.

93. Saito, Y.,, B. Blumberg,, A. Cvetkovich,, L. Epstein,, K. Golding,, M. Louder,, J. Michaels,, M. T. Mintz, and, L. Sharer. 1994. Overexpression of nef as a marker for restricted HIV-1 infection of astrocytes in postmortem pediatric central nervous tissues. Neurology 44: 474– 481.

94. Saksena, N.,, and T. Smit. 2005. HAART & the molecular biology of AIDS dementia complex. Indian J. Med. Res. 121: 256– 269.

95. Salinas, P.,, and A. Hall. 1999. Lithium and synaptic plasticity. Bipolar Disord. 1: 87– 90.

96. Sanders, V.,, C. Achim,, C. Pittman,, G. Wang,, M. White, and, C. Wiley. 1998. Chemokines and receptors in HIV encephalitis. AIDS 12: 1021.

97. Sauer, H.,, J. Hescheler, and, M. Wartenberg. 2001. Reactive oxygen species as intracellular messengers during cell growth and differentiation. Cell. Physiol. Biochem. 11: 173– 186.

98. Sawaya, B.,, S. Amini,, J. Brady,, L. Denisova,, K. Khalili, and, P. Thatikunta. 1998. Regulation of TNFalpha and TGFbeta-1 gene transcription by HIV-1 Tat in CNS cells. J. Neuroimmunol. 87: 33– 42.

99. Shi, B.,, J. Busciglio,, D. Gabuzda,, A. Lorenzo, and, J. Raina. 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.

100. Smith, S. M. 2005. Valproic acid and HIV-1 latency: beyond the sound bite. Retrovirology 2: 56.

101. Song, L.,, J. Geiger,, S. Hochman,, A. Moore, and, A. Nath. 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.

102. Sperber, K.,, and L. Shao. 2003. Neurologic consequences of HIV infection in the era of HAART. AIDS Patient Care STDs 17: 509– 518.

103. Spiegel, S.,, O. Cuvillier,, L. Edsall,, T. Kohama,, R. Menzeleev,, Z. Olah,, A. Olivera,, G. Pirianov,, D. Thomas,, Z. Tu,, J. Van Brocklyn, and, F. Wang. 1998. Sphingosine-1-phosphate in cell growth and cell death. Ann. N. Y. Acad. Sci. 845: 11– 18.

104. Stoll, G. 2002. Inflammatory cytokines in the nervous system: multifunctional mediators in autoimmunity and cerebral ischemia. Rev. Neurol. 158: 887– 891.

105. Stoll, G.,, S. Jander, and, M. Schroeter. 2000. Cytokines in CNS disorders: neurotoxicity versus neuroprotection. J. Neural Transm. 59: 81– 89.

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

107. Toggas, S.,, C. Abraham,, E. Masliah,, L. Mucke,, G. Rall, and, E. Rockenstein. 1994. Central nervous system damage produced by expression of the HIV-1 coat protein gp120 in transgenic mice. Nature 367: 188– 193.

108. Tong, N.,, A. Brooks,, H. Bal,, D. Dairaghi,, S. Dewhurst,, H. Gelbard,, H. Gendelman,, L. Epstein,, S. Fine,, H. Guo,, H. James,, S. Kinnear,, T. Schall,, L. Sharer, and, Q. Zhang. 2000. Neuronal fractalkine expression in HIV-1 encephalitis: roles for macrophage recruitment and neuroprotection in the central nervous system. J. Immunol. 164: 1333– 1339.

109. Tong, N.,, S. Dewhurst,, H. Gelbard,, H. Guo,, S. Maggirwar,, S. Ramirez, and, J. Sanchez. 2001. Activation of glycogen synthase kinase 3 beta (GSK-3beta) by platelet activating factor mediates migration and cell death in cerebellar granule neurons. Eur. J. Neurosci. 13: 1913– 1922.

110. Tornatore, C.,, J. Berger,, R. Chandra, and, E. Major. 1994. HIV-1 infection of subcortical astrocytes in the pediatric central nervous system. Neurology 44: 481– 487.

111. Turchan, J.,, N. Sacktor,, V. Wojna,, K. Conant, and, A. Nath. 2003. Neuroprotective therapy for HIV dementia. Curr. HIV Res. 1: 373– 383.

112. Vallat, A.,, J. Bell,, U. De Girolami,, D. Gabuzda,, F. Gray,, J. He,, W. Marasco,, A. Mhashilkar,, B. Shi,, C. Keohane, and, T. Smith. 1998. Localization of HIV-1 co-receptors CCR5 and CXCR4 in the brain of children with AIDS. Am. J. Pathol. 152: 167.

113. Venters, H.,, R. Dantzer, and, K. Kelley. 2000. Tumor necrosis factor-alpha induces neuronal death by silencing survival signals generated by the type I insulin-like growth factor receptor. Ann. N. Y. Acad. Sci. 917: 210– 220.

114. Wang, G.,, L. Chang,, T. Ernst,, J. Fowler,, J. Logan,, F. Telang, and, N. Volkow. 2004. Decreased brain dopaminergic transporters in HIV-associated dementia patients. Brain 127: 2452– 2458.

115. Wesselingh, S.,, J. Farber,, J. Glass,, D. Griffin,, J. Griffin, and, C. Power. 1993. Intracerebral cytokine messenger RNA expression in acquired immunodeficiency syndrome dementia. Ann. Neurol. 33: 576– 582.

116. Wesselingh, S.,, J. Glass,, D. Griffin,, J. Griffin,, J. McArthur, and, K. Takahashi. 1997. Cellular localization of tumor necrosis factor mRNA in neurological tissue from HIV-infected patients by combined reverse transcriptase/polymerase chain reaction in situ hybridization and immunohistochemistry. J. Neuroimmunol. 74: 1– 8.

117. World Health Organization. 2004. AIDS Epidemic Update 2004. Joint United Nations Program on HIV/AIDS and World Health Organization (UNAIDS/WHO), World Health Organization, Geneva, Switzerland.

118. Wortman, M.,, J. Brady,, L. Chepenik,, G. Gallia,, R. Gordon,, E. Johnson,, J. Kim,, K. Khalili, and, C. Krachmarov. 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.

119. Xiong, H.,, H. Gendelman,, T. Lewis,, Y. Persidsky,, Y. Zeng, and, J. Zheng. 2000. HIV-1 infected mononuclear phagocyte secretory products affect neuronal physiology leading to cellular demise: relevance for HIV-1-associated dementia. J. Neurovirol. 1: S14– S23.

120. Ylisastigui, L.,, N. Archin,, R. Bosch,, G. Lehrman, and, D. Margolis. 2004. Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression. AIDS 18: 1101– 1108.

121. Zauli, G.,, S. Capitani,, D. Dowd,, D. Gibellini,, M. Mazzoni,, P. Mirandola,, D. Milani,, L. Rodella,, P. Secchiero, and, M. Vitale. 2000. HIV-1 Tat-mediated inhibition of the tyrosine hydroxylase gene expression in dopaminergic neuronal cells. J. Biol. Chem. 275: 4159– 4165.

122. Zauli, G.,, and D. Gibellini. 1996. The human immunodeficiency virus type-1 (HIV-1) Tat protein and Bcl-2 gene expression. Leuk. Lymphoma 23: 551– 560.

123. Zou, Y.,, A. Kottman,, M. Kuroda,, D. Littman, and, I. Taniuchi. 1998. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393: 595.