The neuropathogenesis of AIDS

Childs, E. A. et al. Plasma viral load and CD4 lymphocytes predict HIV-associated dementia and sensory neuropathy. Neurology 52, 607–613 (1999).

McArthur, J. C. et al. Human immunodeficiency virus-associated dementia: an evolving disease. J. Neurovirol. 9, 205–221 (2003). Excellent review of the changing patterns of neurological manifestations of AIDS in the era of HAART, including comments about neuropathy.

Cherner, M. et al. Neurocognitive dysfunction predicts postmortem findings of HIV encephalitis. Neurology 59, 1563–1567 (2002). Describes the importance of MCMD in the spectrum of neuropathogenesis of AIDS.

Sacktor, N. et al. HIV-associated cognitive impairment before and after the advent of combination therapy. J. Neurovirol. 8, 136–142 (2002).

Neuenburg, J. K. et al. HIV-related neuropathology, 1985 to 1999: rising prevalence of HIV encephalopathy in the era of highly active antiretroviral therapy. J. Acquir. Immune Defic. Syndr. 31, 171–177 (2002).

Letendre, S. L, et al. Enhancing antiretroviral therapy for HIV cognitive disorders. Ann. Neurol. 56, 416–423 (2004).

Clements, J. E. & Zink, M. C. Molecular biology and pathogenesis of animal lentivirus infections. Clin. Microbiol. Rev. 9, 100–117 (1996). Excellent review of the spectrum of diseases caused by lentiviruses. Also provides a historical perspective not present in more recent reviews.

An, S. F., Groves, M., Gray, F. & Scaravilli, F. Early entry and widespread cellular involvement of HIV-1 DNA in brains of HIV-1 positive asymptomatic individuals. J. Neuropathol. Exp. Neurol. 58, 1156–1162 (1999).

Davis, L. E. et al. Early viral brain invasion in iatrogenic human immunodeficiency virus infection. Neurology 42, 1736–1739 (1992).

Hickey, W. F. Leukocyte traffic in the central nervous system: the participants and their roles. Semin. Immunol. 11, 125–137 (1999).

Haase, A. T. Pathogenesis of lentivirus infections. Nature 322, 130–136 (1986).

Peluso, R., Haase, A., Stowring, L., Edwards, M. & Ventura, P. A Trojan Horse mechanism for the spread of visna virus in monocytes. Virology 147, 231–236 (1985).

Wiley, C. A., Schrier, R. D., Nelson, J. A., Lampert, P. W. & Oldstone, M. B. Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc. Natl Acad. Sci. USA 83, 7089–7093 (1986). Reference 13, together with references 15–17, provides the currently accepted evidence for infection of CNS cells. These references emphasize the role of perivascular macrophages, and reference 16 also provides an alternative point of view regarding the involvement of microglia.

Takahashi, K. et al. Localization of HIV-1 in human brain using polymerase chain reaction/in situ hybridization and immunocytochemistry. Ann. Neurol. 39, 705–711 (1996).

Fischer-Smith, T. et al. Macrophage/microglial accumulation and proliferating cell nuclear antigen expression in the central nervous system in human immunodeficiency virus encephalopathy. Am. J. Pathol. 164, 2089–2099 (2004).

Cosenza, M. A., Zhao, M. L., Si, Q. & Lee, S. C. Human brain parenchymal microglia express CD14 and CD45 and are productively infected by HIV-1 in HIV-1 encephalitis. Brain Pathol. 12, 442–455 (2002).

Williams, K. C. et al. 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 (2001).

Pumarola-Sune, T., Navia, B. A., Cordon-Cardo, C., Cho, E. S. & Price, R. W. HIV antigen in the brains of patients with the AIDS dementia complex. Ann. Neurol. 21, 490–496 (1987).

Petito, C. K. & Cash, K. S. Blood–brain barrier abnormalities in the acquired immunodeficiency syndrome: immunohistochemical localization of serum proteins in postmortem brain. Ann. Neurol. 32, 658–666 (1992).

Williams, K. C. & Hickey, W. F. Central nervous system damage, monocytes and macrophages, and neurological disorders in AIDS. Annu. Rev. Neurosci. 25, 537–562 (2002).

Gartner, S. HIV infection and dementia. Science 287, 602–604 (2000). References 20 and 21 are good reviews that discuss the contribution of infection and cellular activation to neuropathogenesis caused by HIV.

Bomsel, M. Transcytosis of infectious human immunodeficiency virus across a tight human epithelial cell line barrier. Nature Med. 3, 42–47 (1997).

Banks, W. A. et al. 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 (2001).

Liu, N. Q. et al. 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 (2002).

Argyris, E. G. et al. 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 (2003).

Bobardt, M. D. et al. Contribution of proteoglycans to human immunodeficiency virus type 1 brain invasion. J. Virol. 78, 6567–6584 (2004).

Edinger, A. L. et al. CD4-independent, CCR5-dependent infection of brain capillary endothelial cells by a neurovirulent simian immunodeficiency virus strain. Proc. Natl Acad. Sci. USA 94, 14742–14747 (1997).

Gehrmann, J., Matsumoto, Y. & Kreutzberg, G. W. Microglia: intrinsic immuneffector cell of the brain. Brain Res. Brain Res. Rev. 20, 269–287 (1995).

Carson, M. J., Reilly, C. R., Sutcliffe, J. G. & Lo, D. Mature microglia resemble immature antigen-presenting cells. Glia 22, 72–85 (1998).

Shaked, I., Porat, Z., Gersner, R., Kipnis, J. & Schwartz, M. Early activation of microglia as antigen-presenting cells correlates with T cell-mediated protection and repair of the injured central nervous system. J. Neuroimmunol. 146, 84–93 (2004).

Kipnis, J., Avidan, H., Caspi, R. R. & Schwartz, M. Dual effect of CD4+CD25+ regulatory T cells in neurodegeneration: a dialogue with microglia. Proc. Natl Acad. Sci. USA 101 (Suppl. 2), 14663–14669 (2004).

Del Rio-Hortega, P. in Cytology and Cellular Pathology of the Nervous System (ed. Penfield, W.) 483–534 (Hoeber, New York, 1932).

Guillemin, G. J. & Brew, B. J. Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification. J. Leukoc. Biol. 75, 388–397 (2004).

Ulvestad, E. et al. Human microglial cells have phenotypic and functional characteristics in common with both macrophages and dendritic antigen-presenting cells. J. Leukoc. Biol. 56, 732–740 (1994).

Ulvestad, E., Williams, K., Mork, S., Antel, J. & Nyland, H. Phenotypic differences between human monocytes/macrophages and microglial cells studied in situ and in vitro. J. Neuropathol. Exp. Neurol. 53, 492–501 (1994).

Lassmann, H., Schmied, M., Vass, K. & Hickey, W. F. Bone marrow derived elements and resident microglia in brain inflammation. Glia 7, 19–24 (1993).

Hickey, W. F., Vass, K. & Lassmann, H. Bone marrow-derived elements in the central nervous system: an immunohistochemical and ultrastructural survey of rat chimeras. J. Neuropathol. Exp. Neurol. 51, 246–256 (1992).

Krall, W. J., Challita, P. M., Perlmutter, L. S., Skelton, D. C. & Kohn, D. B. Cells expressing human glucocerebrosidase from a retroviral vector repopulate macrophages and central nervous system microglia after murine bone marrow transplantation. Blood 83, 2737–2748 (1994).

Unger, E. R. et al. Male donor-derived cells in the brains of female sex-mismatched bone marrow transplant recipients: a Y-chromosome specific in situ hybridization study. J. Neuropathol. Exp. Neurol. 52, 460–470 (1993).

Fischer-Smith, T. et al. CNS invasion by CD14+/CD16+ peripheral blood-derived monocytes in HIV dementia: perivascular accumulation and reservoir of HIV infection. J. Neurovirol. 7, 528–541 (2001). Shows that the CD14+CD16+ monocyte subpopulation accumulates in the CNS and potentially has a role in HAD.

Shieh, J. T. et al. Chemokine receptor utilization by human immunodeficiency virus type 1 isolates that replicate in microglia. J. Virol. 72, 4243–4249 (1998).

Strizki, J. M. et al. Infection of primary human microglia and monocyte-derived macrophages with human immunodeficiency virus type 1 isolates: evidence of differential tropism. J. Virol. 70, 7654–7662 (1996).

Watkins, B. A. et al. Specific tropism of HIV-1 for microglial cells in primary human brain cultures. Science 249, 549–553 (1990).

Rottman, J. B. et al. Cellular localization of the chemokine receptor CCR5. Correlation to cellular targets of HIV-1 infection. Am. J. Pathol. 151, 1341–1351 (1997).

Albright, A. V. et al. 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 (1999).

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

Sharer, L. R. et al. Pathologic features of AIDS encephalopathy in children: evidence for LAV/HTLV-III infection of brain. Hum. Pathol. 17, 271–284 (1986).

Sharer, L. R., Cho, E. S. & Epstein, L. G. Multinucleated giant cells and HTLV-III in AIDS encephalopathy. Hum. Pathol. 16, 760 (1985).

Dick, A. D., Pell, M., Brew, B. J., Foulcher, E. & Sedgwick, J. D. Direct ex vivo flow cytometric analysis of human microglial cell CD4 expression: examination of central nervous system biopsy specimens from HIV-seropositive patients and patients with other neurological disease. AIDS 11, 1699–1708 (1997).

Peudenier, S., Hery, C., Montagnier, L. & Tardieu, M. Human microglial cells: characterization in cerebral tissue and in primary culture, and study of their susceptibility to HIV-1 infection. Ann. Neurol. 29, 152–161 (1991).

Peudenier, S., Hery, C., Ng, K. H. & Tardieu, M. HIV receptors within the brain: a study of CD4 and MHC-II on human neurons, astrocytes and microglial cells. Res. Virol. 142, 145–149 (1991).

Jordan, C. A., Watkins, B. A., Kufta, C. & Dubois-Dalcq, M. Infection of brain microglial cells by human immunodeficiency virus type 1 is CD4 dependent. J. Virol. 65, 736–742 (1991).

Hickey, W. F., Hsu, B. L. & Kimura, H. T-lymphocyte entry into the central nervous system. J. Neurosci. Res. 28, 254–260 (1991).

Shapshak, P. et al. Independent evolution of HIV type 1 in different brain regions. AIDS Res. Hum. Retroviruses 15, 811–820 (1999).

Epstein, L. G. et al. HIV-1 V3 domain variation in brain and spleen of children with AIDS: tissue-specific evolution within host-determined quasispecies. Virology 180, 583–590 (1991).

Kodama, T., Mori, K., Kawahara, T., Ringler, D. J. & Desrosiers, R. C. Analysis of simian immunodeficiency virus sequence variation in tissues of rhesus macaques with simian AIDS. J. Virol. 67, 6522–6534 (1993).

Korber, B. T. et al. Genetic differences between blood- and brain-derived viral sequences from human immunodeficiency virus type 1-infected patients: evidence of conserved elements in the V3 region of the envelope protein of brain-derived sequences. J. Virol. 68, 7467–7481 (1994).

Reddy, R. T. et al. Sequence analysis of the V3 loop in brain and spleen of patients with HIV encephalitis. AIDS Res. Hum. Retroviruses 12, 477–482 (1996).

Wong, J. K. et al. In vivo compartmentalization of human immunodeficiency virus: evidence from the examination of pol sequences from autopsy tissues. J. Virol. 71, 2059–2071 (1997).

Ryzhova, E. V. et al. Simian immunodeficiency virus encephalitis: analysis of envelope sequences from individual brain multinucleated giant cells and tissue samples. Virology 297, 57–67 (2002).

Miyake, A. et al. The quantity and diversity of infectious viruses in various tissues of SHIV-infected monkeys at the early and AIDS stages. Arch. Virol. 149, 943–955 (2004).

Gorry, P. R. et al. Increased CCR5 affinity and reduced CCR5/CD4 dependence of a neurovirulent primary human immunodeficiency virus type 1 isolate. J. Virol. 76, 6277–6292 (2002). Indicates that increased neurovirulence might be associated with a higher efficiency in the interaction of the HIV envelope and the viral co-receptor CCR5.

Martín, J., LaBranche, C. C. & González-Scarano, F. Differential CD4/CCR5 utilization, gp120 conformation, and neutralization sensitivity between envelopes from a microglia-adapted human immunodeficiency virus type 1 and its parental isolate. J. Virol. 75, 3568–3580 (2001).

Watry, D., Lane, T. E., Streb, M. & Fox, H. S. Transfer of neuropathogenic simian immunodeficiency virus with naturally infected microglia. Am. J. Pathol. 146, 914–923 (1995).

Peters, P. J. et al. Biological analysis of human immunodeficiency virus type 1 R5 envelopes amplified from brain and lymph node tissues of AIDS patients with neuropathology reveals two distinct tropism phenotypes and identifies envelopes in the brain that confer an enhanced tropism and fusigenicity for macrophages. J. Virol. 78, 6915–6926 (2004). First study that shows a reduced CD4 dependence of viral envelopes from primary brain-derived HIV isolates compared with peripheral isolates, in HIV-infected individuals.

Martín-García, J., Kolson, D. L. & González-Scarano, F. Chemokine receptors in the brain: their role in HIV infection and pathogenesis. AIDS 16, 1709–1730 (2002).

Horuk, R. et al. Expression of chemokine receptors by subsets of neurons in the central nervous system. J. Immunol. 158, 2882–2890 (1997).

Coughlan, C. M. et al. Expression of multiple functional chemokine receptors and monocyte chemoattractant protein-1 in human neurons. Neuroscience 97, 591–600 (2000).

Meucci, O. et al. Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity. Proc. Natl Acad. Sci. USA 95, 14500–14505 (1998). Indicates a role for certain chemokine–chemokine receptor interactions in neuroprotection, in addition to their proposed role in neurotoxicity.

Xia, M. Q., Bacskai, B. J., Knowles, R. B., Qin, S. X. & Hyman, B. T. Expression of the chemokine receptor CXCR3 on neurons and the elevated expression of its ligand IP-10 in reactive astrocytes: in vitro ERK1/2 activation and role in Alzheimer's disease. J. Neuroimmunol. 108, 227–235 (2000).

Tanabe, S. et al. Functional expression of the CXC-chemokine receptor-4/fusin on mouse microglial cells and astrocytes. J. Immunol. 159, 905–911 (1997).

Bajetto, A. et al. Glial and neuronal cells express functional chemokine receptor CXCR4 and its natural ligand stromal cell-derived factor 1. J. Neurochem. 73, 2348–2357 (1999).

Lavi, E., Kolson, D. L., Ulrich, A. M., Fu, L. & González-Scarano, F. Chemokine receptors in the human brain and their relationship to HIV infection. J. Neurovirol. 4, 301–311 (1998). Reviews the expression of chemokine receptors in the brain and their relevance to neuropathogenesis caused by HIV.

Dorf, M. E., Berman, M. A., Tanabe, S., Heesen, M. & Luo, Y. Astrocytes express functional chemokine receptors. J. Neuroimmunol. 111, 109–121 (2000).

Westmoreland, S. V., Rottman, J. B., Williams, K. C., Lackner, A. A. & Sasseville, V. G. Chemokine receptor expression on resident and inflammatory cells in the brain of macaques with simian immunodeficiency virus encephalitis. Am. J. Pathol. 152, 659–665 (1998).

Vallat, A. V. et al. Localization of HIV-1 co-receptors CCR5 and CXCR4 in the brain of children with AIDS. Am. J. Pathol. 152, 167–178 (1998).

Xia, M. Q., Qin, S. X., Wu, L. J., Mackay, C. R. & Hyman, B. T. Immunohistochemical study of the β-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer's disease brains. Am. J. Pathol. 153, 31–37 (1998).

Klein, R. S. et al. Chemokine receptor expression and signaling in macaque and human fetal neurons and astrocytes: implications for the neuropathogenesis of AIDS. J. Immunol. 163, 1636–1646 (1999).

Tanabe, S. et al. Murine astrocytes express a functional chemokine receptor. J. Neurosci. 17, 6522–6528 (1997).

Harrison, J. K. et al. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc. Natl Acad. Sci. USA 95, 10896–10901 (1998).

Maciejewski-Lenoir, D., Chen, S., Feng, L., Maki, R. & Bacon, K. B. Characterization of fractalkine in rat brain cells: migratory and activation signals for CX3CR-1-expressing microglia. J. Immunol. 163, 1628–1635 (1999).

Schwaeble, W. J. et al. Neuronal expression of fractalkine in the presence and absence of inflammation. FEBS Lett. 439, 203–207 (1998).

Meucci, O., Fatatis, A., Simen, A. A. & Miller, R. J. Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival. Proc. Natl Acad. Sci. USA 97, 8075–8080 (2000).

Ancuta, P. et al. Fractalkine preferentially mediates arrest and migration of CD16+ monocytes. J. Exp. Med. 197, 1701–1707 (2003). Highlights the potential role of CX 3 CL1 in the interaction between different brain cell types and the response to insults in the CNS.

Zheng, J. et al. Intracellular CXCR4 signaling, neuronal apoptosis and neuropathogenic mechanisms of HIV-1-associated dementia. J. Neuroimmunol. 98, 185–200 (1999).

Schmidtmayerova, H. et al. Human immunodeficiency virus type 1 infection alters chemokine β peptide expression in human monocytes: implications for recruitment of leukocytes into brain and lymph nodes. Proc. Natl Acad. Sci. USA 93, 700–704 (1996).

Sasseville, V. G. et al. Chemokine expression in simian immunodeficiency virus-induced AIDS encephalitis. Am. J. Pathol. 149, 1459–1467 (1996).

Zink, M. C. et al. Increased macrophage chemoattractant protein-1 in cerebrospinal fluid precedes and predicts simian immunodeficiency virus encephalitis. J. Infect. Dis. 184, 1015–1021 (2001).

Conant, K. et al. 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 (1998).

Kelder, W., McArthur, J. C., Nance-Sproson, T., McClernon, D. & Griffin, D. E. β-chemokines MCP-1 and RANTES are selectively increased in cerebrospinal fluid of patients with human immunodeficiency virus-associated dementia. Ann. Neurol. 44, 831–835 (1998).

Kaul, M. & Lipton, S. A. Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis. Proc. Natl Acad. Sci. USA 96, 8212–8216 (1999). Indicates a role for the HIV envelope glycoprotein in directly inducing apoptosis of neurons.

Hesselgesser, J. et al. Neuronal apoptosis induced by HIV-1 gp120 and the chemokine SDF-1α is mediated by the chemokine receptor CXCR4. Curr. Biol. 8, 595–598 (1998).

Lazarini, F. et al. 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 (2000).

Sanders, V. J., Everall, I. P., Johnson, R. W. & Masliah, E. Fibroblast growth factor modulates HIV coreceptor CXCR4 expression by neural cells. J. Neurosci. Res. 59, 671–679 (2000).

Zheng, J. et al. Lymphotropic virions affect chemokine receptor-mediated neural signaling and apoptosis: implications for human immunodeficiency virus type 1-associated dementia. J. Virol. 73, 8256–8267 (1999).

Pandey, V. & Bolsover, S. R. Immediate and neurotoxic effects of HIV protein gp120 act through CXCR4 receptor. Biochem. Biophys. Res. Commun. 274, 212–215 (2000).

Ohagen, A. et al. Apoptosis induced by infection of primary brain cultures with diverse human immunodeficiency virus type 1 isolates: evidence for a role of the envelope. J. Virol. 73, 897–906 (1999).

Barks, J. D., Liu, X. H., Sun, R. & Silverstein, F. S. gp120, a human immunodeficiency virus-1 coat protein, augments excitotoxic hippocampal injury in perinatal rats. Neuroscience 76, 397–409 (1997).

Xin, K. Q. et al. Evidence of HIV type 1 glycoprotein 120 binding to recombinant N-methyl-D-aspartate receptor subunits expressed in a baculovirus system. AIDS Res. Hum. Retroviruses 15, 1461–1467 (1999).

Corasaniti, M. T. et al. Apoptosis induced by gp120 in the neocortex of rat involves enhanced expression of cyclooxygenase type 2 and is prevented by NMDA receptor antagonists and by the 21-aminosteroid U-74389G. Biochem. Biophys. Res. Commun. 274, 664–669 (2000).

Meucci, O. & Miller, R. J. gp120-induced neurotoxicity in hippocampal pyramidal neuron cultures: protective action of TGF-β1. J. Neurosci. 16, 4080–4088 (1996).

Bezzi, P. et al. CXCR4-activated astrocyte glutamate release via TNFα: amplification by microglia triggers neurotoxicity. Nature Neurosci. 4, 702–710 (2001).

Garden, G. A. et al. Caspase cascades in human immunodeficiency virus-associated neurodegeneration. J. Neurosci. 22, 4015–4024 (2002).

Klasse, P. J. & Moore, J. P. Is there enough gp120 in the body fluids of HIV-1-infected individuals to have biologically significant effects? Virology 323, 1–8 (2004). Recent paper that sheds light and perspective on the conflicting issue of the relevance of many in vitro studies to the biological effects of viral proteins.

Chang, H. C., Samaniego, F., Nair, B. C., Buonaguro, L. & Ensoli, B. HIV-1 Tat protein exits from cells via a leaderless secretory pathway and binds to extracellular matrix-associated heparan sulfate proteoglycans through its basic region. AIDS 11, 1421–1431 (1997).

Andras, I. E. et al. HIV-1 Tat protein alters tight junction protein expression and distribution in cultured brain endothelial cells. J. Neurosci. Res. 74, 255–265 (2003).

McManus, C. M. et al. Chemokine and chemokine-receptor expression in human glial elements: induction by the HIV protein, Tat, and chemokine autoregulation. Am. J. Pathol. 156, 1441–1453 (2000).

Park, I. W., Wang, J. F. & Groopman, J. E. HIV-1 Tat promotes monocyte chemoattractant protein-1 secretion followed by transmigration of monocytes. Blood 97, 352–358 (2001).

Song, L., Nath, A., Geiger, J. D., Moore, A. & Hochman, S. 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 (2003).

Sherman, M. P., De Noronha, C. M., Williams, S. A. & Greene, W. C. Insights into the biology of HIV-1 viral protein R. DNA Cell Biol. 21, 679–688 (2002).

Patel, C. A., Mukhtar, M., Harley, S., Kulkosky, J. & Pomerantz, R. J. Lentiviral expression of HIV-1 Vpr induces apoptosis in human neurons. J. Neurovirol. 8, 86–99 (2002).

Patel, C. A., Mukhtar, M. & Pomerantz, R. J. Human immunodeficiency virus type 1 Vpr induces apoptosis in human neuronal cells. J. Virol. 74, 9717–9726 (2000).

Levy, D. N., Refaeli, Y. & Weiner, D. B. Extracellular Vpr protein increases cellular permissiveness to human immunodeficiency virus replication and reactivates virus from latency. J. Virol. 69, 1243–1252 (1995).

Marcondes, M. C. et al. Highly activated CD8+ T cells in the brain correlate with early central nervous system dysfunction in simian immunodeficiency virus infection. J. Immunol. 167, 5429–5438 (2001).

Kim, W. K. et al. Identification of T lymphocytes in simian immunodeficiency virus encephalitis: distribution of CD8+ T cells in association with central nervous system vessels and virus. J. Neurovirol. 10, 315–325 (2004).

Glass, J. D., Fedor, H., Wesselingh, S. L. & McArthur, J. C. Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlations with dementia. Ann. Neurol. 38, 755–762 (1995).

Achim, C. L., Heyes, M. P. & Wiley, C. A. Quantitation of human immunodeficiency virus, immune activation factors, and quinolinic acid in AIDS brains. J. Clin. Invest. 91, 2769–2775 (1993).

Wesselingh, S. L. et al. Intracerebral cytokine messenger RNA expression in acquired immunodeficiency syndrome dementia. Ann. Neurol. 33, 576–582 (1993).

Adamson, D. C., McArthur, J. C., Dawson, T. M. & Dawson, V. L. Rate and severity of HIV-associated dementia (HAD): correlations with gp41 and iNOS. Mol. Med. 5, 98–109 (1999).

Bukrinsky, M. I. et al. Regulation of nitric oxide synthase activity in human immunodeficiency virus type 1 (HIV-1)-infected monocytes: implications for HIV-associated neurological disease. J. Exp. Med. 181, 735–745 (1995).

Blond, D. et al. Nitric oxide synthesis during acute SIVMAC251 infection of macaques. Res. Virol. 149, 75–86 (1998).

Blond, D., Raoul, H., Le Grand, R. & Dormont, D. Nitric oxide synthesis enhances human immunodeficiency virus replication in primary human macrophages. J. Virol. 74, 8904–8912 (2000).

Thompson, K. A., McArthur, J. C. & Wesselingh, S. L. Correlation between neurological progression and astrocyte apoptosis in HIV-associated dementia. Ann. Neurol. 49, 745–752 (2001).

Conant, K. et al. Cerebrospinal fluid levels of MMP-2, 7, and 9 are elevated in association with human immunodeficiency virus dementia. Ann. Neurol. 46, 391–398 (1999).

Johnston, J. B. et al. Lentivirus infection in the brain induces matrix metalloproteinase expression: role of envelope diversity. J. Virol. 74, 7211–7220 (2000).

Persidsky, Y. et al. Reduction in glial immunity and neuropathology by a PAF antagonist and an MMP and TNFa inhibitor in SCID mice with HIV-1 encephalitis. J. Neuroimmunol. 114, 57–68 (2001).

Stins, M. F. et al. Induction of intercellular adhesion molecule-1 on human brain endothelial cells by HIV-1 gp120: role of CD4 and chemokine coreceptors. Lab. Invest. 83, 1787–1798 (2003).

Sasseville, V. G. et al. Elevated vascular cell adhesion molecule-1 in AIDS encephalitis induced by simian immunodeficiency virus. Am. J. Pathol. 141, 1021–1030 (1992).

Shrikant, P., Benos, D. J., Tang, L. P. & Benveniste, E. N. HIV glycoprotein 120 enhances intercellular adhesion molecule-1 gene expression in glial cells. Involvement of Janus kinase/signal transducer and activator of transcription and protein kinase C signaling pathways. J. Immunol. 156, 1307–1314 (1996).

Grimaldi, L. M. et al. Elevated α-tumor necrosis factor levels in spinal fluid from HIV-1-infected patients with central nervous system involvement. Ann. Neurol. 29, 21–25 (1991).

Wahl, S. M. et al. Macrophage- and astrocyte-derived transforming growth factor-β as a mediator of central nervous system dysfunction in acquired immune deficiency syndrome. J. Exp. Med. 173, 981–991 (1991).

Tyor, W. R. et al. Cytokine expression in the brain during the acquired immunodeficiency syndrome. Ann. Neurol. 31, 349–360 (1992).

Nottet, H. S. et al. A regulatory role for astrocytes in HIV-1 encephalitis. An overexpression of eicosanoids, platelet-activating factor, and tumor necrosis factor-α by activated HIV-1-infected monocytes is attenuated by primary human astrocytes. J. Immunol. 154, 3567–3581 (1995).

Wilt, S. G. et al. In vitro evidence for a dual role of tumor necrosis factor-α in human immunodeficiency virus type 1 encephalopathy. Ann. Neurol. 37, 381–394 (1995).

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

Bhat, N. R., Zhang, P., Lee, J. C. & Hogan, E. L. Extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor-α gene expression in endotoxin-stimulated primary glial cultures. J. Neurosci. 18, 1633–1641 (1998).

Wang, C. X. & Shuaib, A. Involvement of inflammatory cytokines in central nervous system injury. Prog. Neurobiol. 67, 161–172 (2002).

Foos, T. M. & Wu, J. Y. The role of taurine in the central nervous system and the modulation of intracellular calcium homeostasis. Neurochem. Res. 27, 21–26 (2002).

Zhang, K. et al. HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration. Nature Neurosci. 6, 1064–1071 (2003).

Cheng, B., Christakos, S. & Mattson, M. P. Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis. Neuron 12, 139–153 (1994).

Barger, S. W. et al. Tumor necrosis factors-α and-β protect neurons against amyloid β-peptide toxicity: evidence for involvement of a κB-binding factor and attenuation of peroxide and Ca2+ accumulation. Proc. Natl Acad. Sci. USA 92, 9328–9332 (1995). Describes a neuroprotective role for TNF through activation of anti-oxidant pathways and maintenance of calcium homeostasis.

Tamatani, M. et al. Tumor necrosis factor induces Bcl-2 and Bcl-x expression through NFκB activation in primary hippocampal neurons. J. Biol. Chem. 274, 8531–8538 (1999).

Fontaine, V. et al. Neurodegenerative and neuroprotective effects of tumor necrosis factor (TNF) in retinal ischemia: opposite roles of TNF receptor 1 and TNF receptor 2. J. Neurosci. 22, RC216 (2002).

Marchetti, L., Klein, M., Schlett, K., Pfizenmaier, K. & Eisel, U. L. Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-Methyl-D-aspartate receptor activation: essential role of a TNF receptor 2-mediated phosphatidylinositol 3-kinase-dependent NF-κB pathway. J. Biol. Chem. 279, 32869–32881 (2004).

Diem, R., Meyer, R., Weishaupt, J. H. & Bahr, M. Reduction of potassium currents and phosphatidylinositol 3-kinase-dependent AKT phosphorylation by tumor necrosis factor-α rescues axotomized retinal ganglion cells from retrograde cell death in vivo. J. Neurosci. 21, 2058–2066 (2001).

Mattson, M. P. & Camandola, S. NF-κB in neuronal plasticity and neurodegenerative disorders. J. Clin. Invest. 107, 247–254 (2001).

Guo, H. et al. Regulation of β-chemokine mRNA expression in adult rat astrocytes by lipopolysaccharide, proinflammatory and immunoregulatory cytokines. Scand. J. Immunol. 48, 502–508 (1998).

Yoshida, H. et al. Synergistic stimulation, by tumor necrosis factor-α and interferon-γ, of fractalkine expression in human astrocytes. Neurosci. Lett. 303, 132–136 (2001).

Medvedev, A. E., Espevik, T., Ranges, G. & Sundan, A. Distinct roles of the two tumor necrosis factor (TNF) receptors in modulating TNF and lymphotoxin-α effects. J. Biol. Chem. 271, 9778–9784 (1996).

Scorziello, A., Florio, T., Bajetto, A., Thellung, S. & Schettini, G. TGF-β1 prevents gp120-induced impairment of Ca2+ homeostasis and rescues cortical neurons from apoptotic death. J. Neurosci. Res. 49, 600–607 (1997).

da Cunha, A., Jefferson, J. A., Jackson, R. W. & Vitkovic, L. Glial cell-specific mechanisms of TGF-β 1 induction by IL-1 in cerebral cortex. J. Neuroimmunol. 42, 71–85 (1993).

Dragic, T. et al. A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5. Proc. Natl Acad. Sci. USA 97, 5639–5644 (2000).

Reeves, J. D. et al. Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics. Proc. Natl Acad. Sci. USA 99, 16249–16254 (2002).

Hazuda, D. J. et al. Integrase inhibitors and cellular immunity suppress retroviral replication in rhesus macaques. Science 305, 528–532 (2004).

Toggas, S. M., Masliah, E. & Mucke, L. Prevention of HIV-1 gp120-induced neuronal damage in the central nervous system of transgenic mice by the NMDA receptor antagonist memantine. Brain Res. 706, 303–307 (1996).

Lipton, S. A. & Chen, H. S. Paradigm shift in neuroprotective drug development: clinically tolerated NMDA receptor inhibition by memantine. Cell Death Differ. 11, 18–20 (2004).

Chen, H. S. et al. Neuroprotective concentrations of the N-methyl-D-aspartate open-channel blocker memantine are effective without cytoplasmic vacuolation following post-ischemic administration and do not block maze learning or long-term potentiation. Neuroscience 86, 1121–1132 (1998).

Tariot, P. N. et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 291, 317–324 (2004).

Miguel-Hidalgo, J. J., Alvarez, X. A., Cacabelos, R. & Quack, G. Neuroprotection by memantine against neurodegeneration induced by β-amyloid(1–40). Brain Res. 958, 210–221 (2002).

Ganju, R. K. et al. The α-chemokine, stromal cell-derived factor-1α, binds to the transmembrane G protein-coupled CXCR-4 receptor and activates multiple signal transduction pathways. J. Biol. Chem. 273, 23169–23175 (1998).

Misse, D. et al. HIV-1 glycoprotein 120 induces the MMP-9 cytopathogenic factor production that is abolished by inhibition of the p38 mitogen-activated protein kinase signaling pathway. Blood 98, 541–547 (2001).

Martin, D. S. et al. Apoptotic changes in the aged brain are triggered by interleukin-1β-induced activation of p38 and reversed by treatment with eicosapentaenoic acid. J. Biol. Chem. 277, 34239–34246 (2002).

Choi, W. S. et al. Phosphorylation of p38 MAPK induced by oxidative stress is linked to activation of both caspase-8- and -9-mediated apoptotic pathways in dopaminergic neurons. J. Biol. Chem. 279, 20451–20460 (2004).

Song, Y. S. et al. Protective role of Bcl-2 on β-amyloid-induced cell death of differentiated PC12 cells: reduction of NF-κB and p38 MAP kinase activation. Neurosci. Res. 49, 69–80 (2004).

Chen, W. et al. Development of a human neuronal cell model for human immunodeficiency virus (HIV)-infected macrophage-induced neurotoxicity: apoptosis induced by HIV type 1 primary isolates and evidence for involvement of the Bcl-2/Bcl-xL-sensitive intrinsic apoptosis pathway. J. Virol. 76, 9407–9419 (2002).

Dong, Y. & Benveniste, E. N. Immune function of astrocytes. Glia 36, 180–190 (2001).

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

Sabri, F. et al. Nonproductive human immunodeficiency virus type 1 infection of human fetal astrocytes: independence from CD4 and major chemokine receptors. Virology 264, 370–384 (1999).

Ranki, A. et al. Abundant expression of HIV Nef and Rev proteins in brain astrocytes in vivo is associated with dementia. AIDS 9, 1001–1008 (1995).

Codazzi, F. et al. HIV-1 gp120 glycoprotein induces [Ca2+]i responses not only in type-2 but also type-1 astrocytes and oligodendrocytes of the rat cerebellum. Eur. J. Neurosci. 7, 1333–1341 (1995).

Adle-Biassette, H. et al. Neuronal apoptosis in HIV infection in adults. Neuropathol. Appl. Neurobiol. 21, 218–227 (1995).

Gelbard, H. A. et al. Apoptotic neurons in brains from paediatric patients with HIV-1 encephalitis and progressive encephalopathy. Neuropathol. Appl. Neurobiol. 21, 208–217 (1995).

Petito, C. K. & Roberts, B. Evidence of apoptotic cell death in HIV encephalitis. Am. J. Pathol. 146, 1121–1130 (1995). Presents evidence that neuronal apoptosis occurs in the brain in association with HIV infection.