Skip to main content

Advertisement

SpringerLink
Log in

Neuronal injury in simian immunodeficiency virus and other animal models of neuroAIDS

  • Review
  • Published:
Journal of NeuroVirology Aims and scope Submit manuscript

Abstract

The success of antiretroviral therapy has reduced the incidence of severe neurological complication resulting from human immunodeficiency virus (HIV) infection. However, increased patient survival has been associated with an increased prevalence of protracted forms of HIV encephalitis leading to moderate cognitive impairment. NeuroAIDS remains a great challenge to patients, their families, and our society. Thus development of preclinical models that will be suitable for testing promising new compounds with neurotrophic and neuroprotective capabilities is of critical importance. The simian immunodeficiency virus (SIV)-infected macaque is the premiere model to study HIV neuropathogenesis. This model was central to the seminal work of Dr. Opendra “Bill” Narayan. Similar to patients with HIV encephalitis, in the SIV model there is injury to the synaptodendritic structure of excitatory pyramidal neurons and inhibitory calbindin-immunoreactive interneurons. This article, which is part of a special issue of the Journal of NeuroVirology in honor of Dr. Bill Narayan, discusses the most important neurodegenerative features in preclinical models of neuroAIDS and their potential for treatment development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Achim CL, Wiley CA (1996). Inflammation in AIDS and the role of the macrophage in brain pathology. Curr Opin Neurol 9: 221–225.

    CAS  PubMed  Google Scholar 

  • Alirezaei M, Watry DD, Flynn CF, Kiosses WB, Masliah E, Williams BR, Kaul M, Lipton SA, Fox HS (2007). Human immunodeficiency virus-1/surface glycoprotein 120 induces apoptosis through RNA-activated protein kinase signaling in neurons. J Neurosci 27: 11047–11055.

    CAS  PubMed  Google Scholar 

  • Anderson ER, Boyle J, Zink WE, Persidsky Y, Gendelman HE, Xiong H (2003). Hippocampal synaptic dysfunction in a murine model of human immunodeficiency virus type 1 encephalitis. Neuroscience 118: 359–369.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Barker PB, Lee RR, McArthur JC (1995). AIDS dementia complex: evaluation with proton MR spectroscopic imaging. Radiology 195: 58–64.

    CAS  PubMed  Google Scholar 

  • Bell JE (2004). An update on the neuropathology of HIV in the HAART era. Histopathology 45: 549–559.

    CAS  PubMed  Google Scholar 

  • Bellizzi MJ, Lu SM, Masliah E, Gelbard HA (2005). Synaptic activity becomes excitotoxic in neurons exposed to elevated levels of platelet-activating factor. J Clin Invest 115: 3185–3192.

    CAS  PubMed  Google Scholar 

  • Bissel SJ, Wang G, Ghosh M, Reinhart TA, Capuano S 3rd, Stefano Cole K, Murphey-Corb M, Piatak M, Jr, Lifson JD, Wiley CA (2002). Macrophages relate presynaptic and postsynaptic damage in simian immunodeficiency virus encephalitis. Am J Pathol 160: 927–941.

    PubMed  Google Scholar 

  • Brandimarti R, Khan MZ, Fatatis A, Meucci O (2004). Regulation of cell cycle proteins by chemokine receptors: A novel pathway in human immunodeficiency virus neuropathogenesis? J Neuro Virol 10(Suppl 1): 108–112.

    Google Scholar 

  • Brew B, Rosenblum M, Cronin K, Price R (1995). AIDS dementia comples and HIV-1 brain infection: clinicalvirological correlations. Ann Neurol 38: 563–570.

    CAS  PubMed  Google Scholar 

  • Brown J, Cooper-Kuhn CM, Kempermann G, Van Praag H, Winkler J, Gage FH, Kuhn HG (2003). Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. Eur J Neurosci 17: 2042–2046.

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Bruel-Jungerman E, Laroche S, Rampon C (2005). New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment. Eur J Neurosci 21: 513–521.

    PubMed  Google Scholar 

  • Budka H, Costanzi G, Cristina S, Lechi A, Parravicini C, Trabattoni R, Vago L (1987). Brain pathology induced by infection with the human immunodeficiency virus (HIV). A histological, immunocytochemical, and electron microscopical study of 100 autopsy cases. Acta Neuropathol (Berl) 75: 185–198.

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Chana G, Everall IP, Crews L, Langford D, Adame A, Grant I, Cherner M, Lazzaretto D, Heaton R, Ellis R, Masliah E (2006). Cognitive deficits and degeneration of interneurons in HIV+ methamphetamine users. Neurology 67: 1486–1489.

    CAS  PubMed  Google Scholar 

  • Chang L, Ernst T, Leonido-Yee M, Witt M, Speck O, Walot I, Miller EN (1999). Highly active antiretroviral therapy reverses brain metabolite abnormalities in mild HIV dementia. Neurology 53: 782–789.

    CAS  PubMed  Google Scholar 

  • Cherner M, Masliah E, Ellis RJ, Marcotte TD, Moore DJ, Grant I, Heaton RK (2002). Neurocognitive dysfunction predicts postmortem findings of HIV encephalitis. Neurology 59: 1563–1567.

    CAS  PubMed  Google Scholar 

  • Chong WK, Sweeney B, Wilkinson ID, Paley M, Hall-Craggs MA, Kendall BE, Shepard JK, Beecham M, Miller RF, Weller IV, et al (1993). Proton spectroscopy of the brain in HIV infection: correlation with clinical, immunologic, and MR imaging findings. Radiology 188: 119–124.

    CAS  PubMed  Google Scholar 

  • Clements JE, Babas T, Mankowski JL, Suryanarayana K, Piatak M Jr, Tarwater PM, Lifson JD, Zink MC (2002). The central nervous system as a reservoir for simian im-munodeficiency virus (SIV): steady-state levels of SIV DNA in brain from acute through asymptomatic infection. J Infect Dis 186: 905–913.

    CAS  PubMed  Google Scholar 

  • Del Corno M, Liu QH, Schols D, de Clercq E, Gessani S, Freedman BD, Collman RG (2001). HIV-1 gp120 and chemokine activation of Pyk2 and mitogen-activated protein kinases in primary macrophages mediated by calcium-dependent, pertussis toxin-insensitive chemokine receptor signaling. Blood 98: 2909–2916.

    PubMed  Google Scholar 

  • Desrosiers RC (1990a). HIV-1 origins. A finger on the missing link. Nature 345: 288–289.

    CAS  PubMed  Google Scholar 

  • Desrosiers RC (1990b). The simian immunodeficiency viruses. Annu Rev Immunol 8: 557–578.

    CAS  PubMed  Google Scholar 

  • D’Hooge R, Franck F, Mucke L, De Deyn PP (1999). Agerelated behavioural deficits in transgenic mice expressing the HIV-1 coat protein gp120. Eur J Neurosci 11: 4398–4402.

    PubMed  Google Scholar 

  • Diesing TS, Swindells S, Gelbard H, Gendelman HE (2002). HIV-1-associated dementia: a basic science and clinical perspective. AIDS Read 12: 358–368.

    PubMed  Google Scholar 

  • Dou H, Birusingh K, Faraci J, Gorantla S, Poluektova LY, Maggirwar SB, Dewhurst S, Gelbard HA, Gendelman HE (2003). Neuroprotective activities of sodium valproate in a murine model of human immunodeficiency virus-1 encephalitis. J Neurosci 23: 9162–9170.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Everall I, Luthert P, Lantos P (1991). Neuronal loss in the frontal cortex in HIV infection. Lancet 337: 1119–1121.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Fischer A, Sananbenesi F, Pang PT, Lu B, Tsai LH (2005). Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron 48: 825–838.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Gage FH, Kempermann G, Palmer TD, Peterson DA, Ray J (1998). Multipotent progenitor cells in the adult dentate gyrus. J Neurobiol 36: 249–266.

    CAS  PubMed  Google Scholar 

  • Gao F, Bailes E, Robertson DL, Chen Y, Rodenburg CM, Michael SF, Cummins LB, Arthur LO, Peeters M, Shaw GM, Sharp PM, Hahn BH (1999). Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature 397: 436–441.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Gendelman H, Lipton S, Tardieu M, Bukrinsky M, Nottet H (1994). The neuropathogenesis of HIV-1 infection. J Leukoc Biol 56: 389–398.

    CAS  PubMed  Google Scholar 

  • Gendelman HE, Persidsky Y, Ghorpade A, Limoges J, Stins M, Fiala M, Morrisett R (1997). The neuropathogenesis of the AIDS dementia complex. AIDS 11(Suppl A): S35-S45.

    PubMed  Google Scholar 

  • Giulian D, Vaca K, Noonan C (1990). Secretion of neuro-toxins by mononuclear phagocytes infected with HIV-1. Science 250: 1593–1596.

    CAS  PubMed  Google Scholar 

  • Glass J, Fedor H, Wesselingh S, McArthur J (1995). Immunocytochemical quantification of human immunod-eficiency virus in the brain: correlations with dementia. Ann Neurol 38: 755–762.

    CAS  PubMed  Google Scholar 

  • Gonzalez RG, Cheng LL, Westmoreland SV, Sakaie KE, Becerra LR, Lee PL, Masliah E, Lackner AA (2000). Early brain injury in the SIV-macaque model of AIDS. AIDS 14: 2841–2849.

    CAS  PubMed  Google Scholar 

  • Gonzalez RG, Greco JB, He J, Lentz MR, O’Neil S, Pilkenton SJ, Ratai EM, Westmoreland S (2006). New insights into the neuroimmunity of SIV infection by magnetic resonance spectroscopy. J Neuroimmune Pharmacol 1: 152–159.

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  • Greco JB, Sakaie KE, Aminipour S, Lee PL, Chang LL, He J, Westmoreland S, Lackner AA, Gonzalez RG (2002). Magnetic resonance spectroscopy: an in vivo tool for monitoring cerebral injury in SIV-infected macaques. J Med Primatol 31: 228–236.

    CAS  PubMed  Google Scholar 

  • Greco JB, Westmoreland SV, Ratai EM, Lentz MR, Sakaie K, He J, Sehgal PK, Masliah E, Lackner AA, Gonzalez RG (2004). In vivo 1H MRS of brain injury and repair during acute SIV infection in the macaque model of neuro AIDS. Magn Reson Med 51: 1108–1114.

    CAS  PubMed  Google Scholar 

  • Hashimoto M, Sagara Y, Everall IP, Mallory M, Everson A, Langford D, Masliah E (2002). Fibroblast growth factor 1 regulates signaling via the GSK3beta pathway: implications for neuroprotection. J Biol Chem 277: 32985–32991.

    CAS  PubMed  Google Scholar 

  • Haughey NJ, Mattson MP (2002). Calcium dysregulation and neuronal apoptosis by the HIV-1 proteins Tat and gp120. J Acquir Immune Defic Syndr 31(Suppl 2): S55-S61.

    CAS  PubMed  Google Scholar 

  • Haughey NJ, Nath A, Mattson MP, Slevin JT, Geiger JD (2001). HIV-1 Tat through phosphorylation of NMDA receptors potentiates glutamate excitotoxicity. J Neurochem 78: 457–467.

    CAS  PubMed  Google Scholar 

  • Heaton R, Grant I, Butters N, White D, Kirson D, Atkinson J, McCutchan J, Taylor M, Kelly M, Ellis R, Wolfson T, Velin R, Marcotte T, Hesselink J, Jernigan T, Cahndler J, Wallace M, Abramson I, Group H (1995). The HNRC 500—neuropsychology of HIV infection at different disease stages. J Int Neuropsych Soc 1: 231–251.

    CAS  Google Scholar 

  • Jarvik JG, Lenkinski RE, Grossman RI, Gomori JM, Schnall MD, Frank I (1993). Proton MR spectroscopy of HIV-infected patients: characterization of abnormalities with imaging and clinical correlation. Radiology 186: 739–744.

    CAS  PubMed  Google Scholar 

  • Johansson JU, Lilja L, Chen XL, Higashida H, Meister B, Noda M, Zhong ZG, Yokoyama S, Berggren PO, Bark C (2005). Cyclin-dependent kinase 5 activators p35 and p39 facilitate formation of functional synapses. Brain Res Mol Brain Res 138: 215–227.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Kaul M, Garden GA, Lipton SA (2001). Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410: 988–994.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Kaul M, Lipton SA (2006). Mechanisms of neuronal injury and death in HIV-1 associated dementia. Curr HIV Res 4: 307–318.

    CAS  PubMed  Google Scholar 

  • Kodama T, Mori K, Kawahara T, Ringler DJ, Desrosiers RC (1993). Analysis of simian immunodeficiency virus sequence variation in tissues of rhesus macaques with simian AIDS. J Virol 67: 6522–6534.

    CAS  PubMed  Google Scholar 

  • Krathwohl MD, Kaiser JL (2004). HIV-1 promotes quiescence in human neural progenitor cells. J Infect Dis 190: 216–226.

    CAS  PubMed  Google Scholar 

  • Lackner A, Smith M, Munn R, Martfeld D, Gardner M, Marx P, Dandekar S (1991). Localization of simian immunod-eficiency virus in the central nervous system of rhesus monkeys. Am J Pathol 139: 609–621.

    CAS  PubMed  Google Scholar 

  • Lackner AA, Vogel P, Ramos RA, Kluge JD, Marthas M (1994). Early events in tissues during infection with pathogenic (SIVmac239) and nonpathogenic (SIV-mac1A11) molecular clones of simian immunodeficiency virus. Am J Pathol 145: 428–439.

    CAS  PubMed  Google Scholar 

  • Langford D, Adame A, Grigorian A, Grant I, McCutchan JA, Ellis RJ, Marcotte TD, Masliah E (2003). Patterns of selective neuronal damage in methamphetamine-user AIDS patients. J Acquir Immune Defic Syndr 34: 467–474.

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  • Langford D, Hurford R, Hashimoto M, Digicaylioglu M, Masliah E (2005). Signalling crosstalk in FGF2-mediated protection of endothelial cells from HIV-gp120. BMC Neurosci 6: 8.

    PubMed  Google Scholar 

  • Langford D, Masliah E (2001). Crosstalk between components of the blood brain barrier and cells of the CNS in microglial activation in AIDS. Brain Pathol 11: 306–312.

    CAS  PubMed  Google Scholar 

  • Langford TD, Letendre SL, Marcotte TD, Ellis RJ, McCutchan JA, Grant I, Mallory ME, Hansen LA, Archibald S, Jernigan T, Masliah E (2002). Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy. AIDS 16: 1019–1029.

    PubMed  Google Scholar 

  • Lannuzel A, Barnier JV, Hery C, Huynh VT, Guibert B, Gray F, Vincent JD, Tardieu M (1997). Human immunodeficiency virus type 1 and its coat protein gp120 induce apoptosis and activate JNK and ERK mitogen-activated protein kinases in human neurons. Ann Neurol 42: 847–856.

    CAS  PubMed  Google Scholar 

  • Laubenberger J, Haussinger D, Bayer S, Thielemann S, Schneider B, Mundinger A, Hennig J, Langer M (1996). HIV-related metabolic abnormalities in the brain: depiction with proton MR spectroscopy with short echo times. Radiology 199: 805–810.

    CAS  PubMed  Google Scholar 

  • Lawrence DM, Durham LC, Schwartz L, Seth P, Maric D, Major EO (2004). Human immunodeficiency virus type 1 infection of human brain-derived progenitor cells. J Virol 78: 7319–7328.

    CAS  PubMed  Google Scholar 

  • Lawrence DM, Major EO (2002). HIV-1 and the brain: connections between HIV-1-associated dementia, neuropathology and neuroimmunology. Microbes Infect 4: 301–308.

    CAS  PubMed  Google Scholar 

  • Lee PL, Yiannoutsos CT, Ernst T, Chang L, Marra CM, Jarvik JG, Richards TL, Kwok EW, Kolson DL, Simpson D, Tang CY, Schifitto G, Ketonen LM, Meyerhoff DJ, Lenkinski RE, Gonzalez RG, Navia BA (2003). A multi-center 1H MRS study of the AIDS dementia complex: validation and preliminary analysis. J Magn Reson Imaging 17: 625–633.

    PubMed  Google Scholar 

  • Lentz MR, Kim JP, Westmoreland SV, Greco JB, Fuller RA, Ratai EM, He J, Sehgal PK, Halpern EF, Lackner AA, Masliah E, Gonzalez RG (2005). Quantitative neuropathologic correlates of changes in ratio of N- acetylaspartate to creatine in macaque brain. Radiology 235: 461–468.

    PubMed  Google Scholar 

  • Letendre SL, Woods SP, Ellis RJ, Atkinson JH, Masliah E, van den Brande G, Durelle J, Grant I, Everall I (2006). Lithium improves HIV-associated neurocognitive impairment. Aids 20: 1885–1888.

    CAS  PubMed  Google Scholar 

  • Li W, Galey D, Mattson MP, Nath A (2005). Molecular and cellular mechanisms of neuronal cell death in HIV dementia. Neurotox Res 8: 119–134.

    CAS  PubMed  Google Scholar 

  • Lie DC, Colamarino SA, Song HJ, Desire L, Mira H, Consiglio A, Lein ES, Jessberger S, Lansford H, Dearie AR, Gage FH (2005). Wnt signalling regulates adult hippocampal neurogenesis. Nature 437: 1370–1375.

    CAS  PubMed  Google Scholar 

  • Lipton S (1992a). HIV-related neurotoxicity. Brain Pathol 1: 193–199.

    Google Scholar 

  • Lipton S (1992b). Requirement for macrophages in neuronal injury induced by HIV envelope protein gp120. Neuro Report 3: 913–915.

    CAS  Google Scholar 

  • Lipton SA, Brenneman DE, Silverstein FS, Masliah E, Mucke L (1995). gp120 and neurotoxicity in vivo. Trends Pharmacol Sci 16: 122.

    CAS  PubMed  Google Scholar 

  • Lopez-Villegas D, Lenkinski RE, Frank I (1997). Biochemical changes in the frontal lobe of HIV-infected individuals detected by magnetic resonance spectroscopy. Proc Natl Acad Sci U S A 94: 9854–9859.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Marcondes MC, Burudi EM, Huitron-Resendiz S, Sanchez-Alavez M, Watry D, Zandonatti M, Henriksen SJ, Fox HS (2001). 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.

    CAS  PubMed  Google Scholar 

  • Marcus CD, Taylor-Robinson SD, Sargentoni J, Ainsworth JG, Frize G, Easterbrook PJ, Shaunak S, Bryant DJ (1998). 1H MR spectroscopy of the brain in HIV-1-seropositive subjects: evidence for diffuse metabolic abnormalities. Metab Brain Dis 13: 123–136.

    CAS  PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Maschke M, Kastrup O, Esser S, Ross B, Hengge U, Hufnagel A (2000). Incidence and prevalence of neurological disorders associated with HIV since the introduction of highly active antiretroviral therapy (HAART). J Neurol Neurosurg Psychiatry 69: 376–380.

    CAS  PubMed  Google Scholar 

  • Masliah E, Achim C, Ge N, DeTeresa R, Terry R, Wiley C (1992a). Spectrum of human immunodeficiency virusassociated neocortical damage. Ann Neurol 32: 321–329.

    CAS  PubMed  Google Scholar 

  • Masliah E, Ge N, Achim C, DeTeresa R, Wiley C (1996). Patterns of neurodegeneration in HIV encephalitis. Neuro AIDS 1: 161–173.

    CAS  Google Scholar 

  • Masliah E, Ge N, Achim C, Hansen L, Wiley C (1992b). Selective neuronal vulnerability in HIV encephalitis. J Neuropathol Exp Neurol 51: 585–593.

    CAS  PubMed  Google Scholar 

  • Masliah E, Ge N, Achim C, Wiley C (1995). Differential vulnerability of calbindin-immunoreactive neurons in HIV encephalitis. J Neuropathol Exp Neurol 54: 350–357.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Masliah E, Roberts ES, Langford D, Everall I, Crews L, Adame A, Rockenstein E, Fox HS (2004). Patterns of gene dysregulation in the frontal cortex of patients with HIV encephalitis. J Neuroimmunol 157: 163–175.

    CAS  PubMed  Google Scholar 

  • Mattson MP (2002). Oxidative stress, perturbed calcium homeostasis, and immune dysfunction in Alzheimer’s disease. J Neuro Virol 8: 539–550.

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • McArthur JC, Haughey N, Gartner S, Conant K, Pardo C, Nath A, Sacktor N (2003). Human immunodeficiency virus-associated dementia: an evolving disease. J Neuro Virol 9: 205–221.

    CAS  Google Scholar 

  • McArthur JC, McClernon DR, Cronin MF, Nance-Sproson TE, Saah AJ, St Clair M, Lanier ER (1997). Relationship between human immunodeficiency virus-associated dementia and viral load in cerebrospinal fluid and brain. Ann Neurol 42: 689–698.

    CAS  PubMed  Google Scholar 

  • Menon DK, Ainsworth JG, Cox IJ, Coker RC, Sargentoni J, Coutts GA, Baudouin CJ, Kocsis AE, Harris JR (1992). Proton MR spectroscopy of the brain in AIDS dementia complex. J Comput Assist Tomogr 16: 538–542.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Meyerhoff DJ, Bloomer C, Cardenas V, Norman D, Weiner MW, Fein G (1999). Elevated subcortical choline metabolites in cognitively and clinically asymptomatic HIV+ patients. Neurology 52: 995–1003.

    CAS  PubMed  Google Scholar 

  • Meyerhoff DJ, MacKay S, Bachman L, Poole N, Dillon WP, Weiner MW, Fein G (1993). Reduced brain Nacetylaspartate suggests neuronal loss in cognitively impaired human immunodeficiency virus-seropositive individuals: in vivo 1H magnetic resonance spectroscopic imaging. Neurology 43: 509–515.

    CAS  PubMed  Google Scholar 

  • Minagar A, Shapshak P, Fujimura R, Ownby R, Heyes M, Eisdorfer C (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.

    CAS  PubMed  Google Scholar 

  • Mirra S, del Rio C (1989). The fine structure of acquired immunodeficiency syndrome encephalopathy. Arch Pathol Lab Med 113: 858–865.

    CAS  PubMed  Google Scholar 

  • Moore DJ, Masliah E, Rippeth JD, Gonzalez R, Carey CL, Cherner M, Ellis RJ, Achim CL, Marcotte TD, Heaton RK, Grant I (2006). Cortical and subcortical neurodegeneration is associated with HIV neurocognitive impairment. AIDS 20: 879–887.

    PubMed  Google Scholar 

  • Narayan O, Joag S, Stephens E (1995). Selected models of HIV-induced neurological disease. Curr Topics Microbiol Immunol 202: 151–166.

    CAS  Google Scholar 

  • Nath A (1999). Pathobiology of human immunodeficiency virus dementia. Semin Neurol 19: 113–127.

    CAS  PubMed  Google Scholar 

  • Nath A (2002). Human immunodeficiency virus (HIV) proteins in neuropathogenesis of HIV dementia. J Infect Dis 186(Suppl 2): S193-S198.

    CAS  PubMed  Google Scholar 

  • Nath A, Maragos WF, Avison MJ, Schmitt FA, Berger JR (2001). Acceleration of HIV dementia with methamphetamine and cocaine. J Neuro Virol 7: 66–71.

    CAS  Google Scholar 

  • Okamoto S, Kang Y-J, Brechtel CW, Siviglia E, Russo R, Clemente A, Harrop A, McKercher S, Kaul M, Lipton SA (2007). HIV/gp120 decreases adult neural progenitor cell proliferation via checkpoint kinase-mediated cellcycle withdrawal and G1 arrest. Cell Stem Cell 1: 230–236.

    CAS  PubMed  Google Scholar 

  • Olson AK, Eadie BD, Ernst C, Christie BR (2006). Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways. Hippocampus 16: 250–260.

    CAS  PubMed  Google Scholar 

  • 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 immunod-eficiency virus and the development of encephalitis. J Virol 76: 5797–5802.

    CAS  PubMed  Google Scholar 

  • Persidsky Y, Gendelman HE (2002). Murine models for human immunodeficiency virus type 1-associated dementia: the development of new treatment testing paradigms. J Neuro Virol 8(Suppl 2): 49–52.

    CAS  Google Scholar 

  • Pulliam L, Clarke JA, McGuire D, McGrath MS (1994). Investigation of HIV-infected macrophage neurotoxin production from patients with AIDS dementia. Adv Neuroimmunol 4: 195–198.

    CAS  PubMed  Google Scholar 

  • Pulliam L, Herndier B, Tang N, McGrath M (1991). Human immunodeficiency virus-infected macrophages produce soluble factors that cause histological and neurochemical alterations in cultured human brains. J Clin Invest 87: 503–512.

    CAS  PubMed  Google Scholar 

  • Pulliam L, Zhou M, Stubblebine M, Bitler CM (1998). Differential modulation of cell death proteins in human brain cells by tumor necrosis factor alpha and platelet activating factor. J Neurosci Res 54: 530–538.

    CAS  PubMed  Google Scholar 

  • Reid W, Sadowska M, Denaro F, Rao S, Foulke J Jr, Hayes N, Jones O, Doodnauth D, Davis H, Sill A, O’Driscoll P, Huso D, Fouts T, Lewis G, Hill M, Kamin-Lewis R, Wei C, Ray P, Gallo RC, Reitz M, Bryant J (2001). An HIV-1 transgenic rat that develops HIV-related pathology and immunologic dysfunction. Proc Natl Acad Sci U S A 98: 9271–9276.

    CAS  PubMed  Google Scholar 

  • Rockenstein E, Torrance M, Adame A, Mante M, Bar-on P, Rose JB, Crews L, Masliah E (2007). Neuroprotective effects of regulators of the glycogen synthase kinase-3beta signaling pathway in a transgenic model of Alzheimer’s disease are associated with reduced amyloid precursor protein phosphorylation. J Neurosci 27: 1981–1991.

    CAS  PubMed  Google Scholar 

  • Rusnati M, Urbinati C, Musulin B, Ribatti D, Albini A, Noonan D, Marchisone C, Waltenberger J, Presta M (2001). Activation of endothelial cell mitogen activated protein kinase ERK(1/2) by extracellular HIV-1 Tat protein. Endothelium 8: 65–74.

    CAS  PubMed  Google Scholar 

  • Ryan LA, Cotter RL, Zink WE, 2nd, Gendelman HE, Zheng J (2002). Macrophages, chemokines and neuronal injury in HIV-1-associated dementia. Cell Mol Biol (Noisy-le-grand) 48: 137–150.

    CAS  Google Scholar 

  • Sacktor N, McDermott MP, Marder K, Schifitto G, Selnes OA, McArthur JC, Stern Y, Albert S, Palumbo D, Kieburtz K, De Marcaida JA, Cohen B, Epstein L (2002). HIV-associated cognitive impairment before and after the advent of combination therapy. J Neuro Virol 8: 136–142.

    Google Scholar 

  • Sanders VJ, Pittman CA, White MG, Wang G, Wiley CA, Achim CL (1998). Chemokines and receptors in HIV encephalitis. AIDS 12: 1021–1026.

    CAS  PubMed  Google Scholar 

  • 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 (1999a). Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283: 857–860.

    CAS  PubMed  Google Scholar 

  • Schmitz JE, Simon MA, Kuroda MJ, Lifton MA, Ollert MW, Vogel CW, Racz P, Tenner-Racz K, Scallon BJ, Dalesandro M, Ghrayeb J, Rieber EP, Sasseville VG, Reimann KA (1999b). A nonhuman primate model for the selective elimination of CD8+ lymphocytes using a mouse-human chimeric monoclonal antibody. Am J Pathol 154: 1923–1932.

    CAS  PubMed  Google Scholar 

  • Schwartz GK, Shah MA (2005). Targeting the cell cycle: a new approach to cancer therapy. J Clin Oncol 23: 9408–9421.

    CAS  PubMed  Google Scholar 

  • Simon MA, Chalifoux LV, Ringler DJ (1992). Pathologic features of SIV-induced disease and the association of macrophage infection with disease evolution. AIDS Res Hum Retroviruses 8: 327–337.

    CAS  PubMed  Google Scholar 

  • Sopper S, Sauer U, Hemm S, Demuth M, Muller J, Stahl-Hennig C, Hunsmann G, ter Meulen V, Dorries R (1998). Protective role of the virus-specific immune response for development of severe neurologic signs in simian immunodeficiency virus-infected macaques. J Virol 72: 9940–9947.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Stankoff B, Tourbah A, Suarez S, Turell E, Stievenart JL, Payan C, Coutellier A, Herson S, Baril L, Bricaire F, Calvez V, Cabanis EA, Lacomblez L, Lubetzki C (2001). Clinical and spectroscopic improvement in HIV-associated cognitive impairment. Neurology 56: 112–115.

    CAS  PubMed  Google Scholar 

  • Stephens EB, Liu ZQ, Zhu GW, Adany I, Joag SV, Foresman L, Berman NE, Narayan O (1995). Lymphocyte-tropic simian immunodeficiency virus causes persistent infection in the brains of rhesus monkeys. Virology 213: 600–614.

    CAS  PubMed  Google Scholar 

  • Sundar S, Cierpial M, Kamaraju L, Long S, Hsieh S, Lorenz C, Aaron M, Ritchie J, Weiss J (1991). Human immunodeficiency virus glycoprotein (gp120) infused into rat brain induces interleukin 1 to elevate pituitary-adrenal activity and decreased peripheral cellular immune responses. Proc Natl Acad Sci U S A 88: 11246–11250.

    CAS  PubMed  Google Scholar 

  • Tarasow E, Wiercinska-Drapalo A, Kubas B, Dzienis W, Orzechowska-Bobkiewicz A, Prokopowicz D, Walecki J (2003). Cerebral MR spectroscopy in neurologically asymptomatic HIV-infected patients. Acta Radiol 44: 206–212.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Tracey I, Carr CA, Guimaraes AR, Worth JL, Navia BA, Gonzalez RG (1996). Brain choline-containing compounds are elevated in HIV-positive patients before the onset of AIDS dementia complex: a proton magnetic resonance spectroscopic study. Neurology 46: 783–788.

    CAS  PubMed  Google Scholar 

  • Tracey I, Hamberg LM, Guimaraes AR, Hunter G, Chang I, Navia BA, Gonzalez RG (1998). Increased cerebral blood volume in HIV-positive patients detected by functional MRI. Neurology 50: 1821–1826.

    CAS  PubMed  Google Scholar 

  • Tran PB, Miller RJ (2005). HIV-1, chemokines and neurogenesis. Neurotox Res 8: 149–158.

    CAS  PubMed  Google Scholar 

  • Turchan J, Pocernich CB, Gairola C, Chauhan A, Schifitto G, Butterfield DA, Buch S, Narayan O, Sinai A, Geiger J, Berger JR, Elford H, Nath A (2003). Oxidative stress in HIV demented patients and protection ex vivo with novel antioxidants. Neurology 60: 307–314.

    CAS  PubMed  Google Scholar 

  • van Marle G, Antony JM, Silva C, Sullivan A, Power C (2005). Aberrant cortical neurogenesis in a pediatric neuro AIDS model: neurotrophic effects of growth hormone. AIDS 19: 1781–1791.

    PubMed  Google Scholar 

  • Vigorito M, LaShomb AL, Chang SL (2007). Spatial learning and memory in HIV-1 transgenic rats. J Neuroimmune Pharmacol 2: 319–328.

    PubMed  Google Scholar 

  • Wang Z, Trillo-Pazos G, Kim SY, Canki M, Morgello S, Sharer LR, Gelbard HA, Su ZZ, Kang DC, Brooks AI, Fisher PB, Volsky DJ (2004). Effects of human immunodeficiency virus type 1 on astrocyte gene expression and function: potential role in neuropathogenesis. J Neuro Virol 10(Suppl 1): 25–32.

    Google Scholar 

  • Weis S, Haug H, Budka H (1993). Neuronal damage in the cerebral cortex of AIDS brains: a morphometric study. Acta Neuropathol 85: 185–189.

    CAS  PubMed  Google Scholar 

  • Westmoreland SV, Halpern E, Lackner AA (1998). Simian immunodeficiency virus encephalitis in rhesus macaques is asociated with rapid disease progression. J Neuro Virol 4: 260–268.

    CAS  Google Scholar 

  • Westmoreland SV, Kolson D, Gonzalez-Scarano F (1996). Toxicity of TNF alpha and platelet activating factor for human NT2N neurons: a tissue culture model for human immunodeficiency virus dementia. J Neuro Virol 2: 118–126.

    CAS  Google Scholar 

  • Wiley C, Achim C (1994). HIV encephalitis is the pathologic correlate of dementia in AIDS. Ann Neurol 36: 673–676.

    CAS  PubMed  Google Scholar 

  • Wiley C, Masliah E, Morey M, Lemere C, DeTeresa R, Grafe M, Hansen L, Terry R (1991a). Neocortical damage during HIV infection. Ann Neurol 29: 651–657.

    CAS  PubMed  Google Scholar 

  • Wiley CA (2003). Detection of HIV-1 DNA in microglia/macrophages, astrocytes and neurons isolated from brain tissue with HIV-1 encephalitis by laser capture microdissection. Brain Pathol 13: 415; author reply 415–416.

    PubMed  Google Scholar 

  • Wiley CA, Masliah E, Achim CL (1994). Measurement of CNS HIV burden and its association with neurologic damage. Adv Neuroimmunol 4: 319–325.

    CAS  PubMed  Google Scholar 

  • Wiley CA, Schrier RD, Morey M, Achim C, Venable JC, Nelson JA (1991b). Pathogenesis of HIV encephalitis. Acta Pathol Jpn 41: 192–196.

    CAS  PubMed  Google Scholar 

  • Wilkinson ID, Lunn S, Miszkiel KA, Miller RF, Paley MN, Williams I, Chinn RJ, Hall-Craggs MA, Newman SP, Kendall BE, Harrison MJ (1997). Proton MRS and quantitative MRI assessment of the short term neurological response to antiretroviral therapy in AIDS. J Neurol Neurosurg Psychiatry 63: 477–482.

    CAS  PubMed  Google Scholar 

  • Williams K, Westmoreland S, Greco J, Ratai E, Lentz M, Kim WK, Fuller RA, Kim JP, Autissier P, Sehgal PK, Schinazi RF, Bischofberger N, Piatak M, Lifson JD, Masliah E, Gonzalez RG (2005). Magnetic resonance spectroscopy reveals that activated monocytes contribute to neuronal injury in SIV neuroAIDS. J Clin Invest 115: 2534–2545.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Xiong H, Zeng YC, Lewis T, Zheng J, Persidsky Y, Gendelman HE (2000). HIV-1 infected mononuclear phagocyte secretory products affect neuronal physiology leading to cellular demise: relevance for HIV-1-associated dementia. J Neuro Virol 6(Suppl 1): S14-S23.

    CAS  Google Scholar 

  • 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 Neuro Virol 10(Suppl 1): 91–96.

    CAS  Google Scholar 

  • 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 Neuro Virol 8(Suppl 2): 42–48.

    CAS  Google Scholar 

  • Zink MC, Spelman JP, Robinson RB, Clements JE (1998). SIV infection of macaques—modeling the progression to AIDS dementia. J Neuro Virol 4: 249–259.

    CAS  Google Scholar 

  • Zink WE, Anderson E, Boyle J, Hock L, Rodriguez-Sierra J, Xiong H, Gendelman HE, Persidsky Y (2002). Impaired spatial cognition and synaptic potentiation in a murine model of human immunodeficiency virus type 1 encephalitis. J Neurosci 22: 2096–2105.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, University of California San Diego, La Jolla, California, USA

    Leslie Crews & Eliezer Masliah

  2. Department of Neurosciences, University of California, 9500 Gilman Drive, 92093-0624, San Diego, La Jolla, CA, USA

    Eliezer Masliah

  3. Division of Neuroradiology and the A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts, USA

    Margaret R. Lentz & R. Gilberto González

  4. Department of Molecular and Integrative Neuroscience, The Scripps Research Institute, La Jolla, California, USA

    Howard S. Fox

Authors
  1. Leslie Crews
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Margaret R. Lentz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Gilberto González
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Howard S. Fox
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eliezer Masliah
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eliezer Masliah.

Additional information

Dedicated to the memory of Opendra “Bill” Narayan.

This work was supported by NIH grants NS050041 (R.G.G.), NS051129 (M.R.L.), NS34626 (R.G.G.), RR13213 (R.G.G.), NS34626 (R.G.G.), MH45294 (E.M.), MH59745 (E.M.), MH58164 (E.M.), and DA12065 (E.M.).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Crews, L., Lentz, M.R., González, R.G. et al. Neuronal injury in simian immunodeficiency virus and other animal models of neuroAIDS. Journal of NeuroVirology 14, 327–339 (2008). https://doi.org/10.1080/13550280802132840

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1080/13550280802132840

Keywords

Search

Navigation