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HIV Neuropathogenesis: a Tight Rope Walk of Innate Immunity

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Abstract

During the course of HIV-1 disease, virus neuroinvasion occurs as an early event, within weeks following infection. Intriguingly, subsequent central nervous system (CNS) complications manifest only decades after the initial virus exposure. Although CNS is commonly regarded as an immune-privileged site, emerging evidence indicates that innate immunity elicited by the CNS glial cells is a critical determinant for the establishment of protective immunity. Sustained expression of these protective immune responses, however, can be a double-edged sword. As protective immune mediators, cytokines have the ability to function in networks and co-operate with other host/viral mediators to tip the balance from a protective to toxic state in the CNS. Herein, we present an overview of some of the essential elements of the cerebral innate immunity in HIV neuropathogenesis including the key immune cell types of the CNS with their respective soluble immune mediators: (1) cooperative interaction of IFN-γ with the host/virus factor (platelet-derived host factor (PDGF)/viral Tat) in the induction of neurotoxic chemokine CXCL10 by macrophages, (2) response of astrocytes to viral infection, and (3) protective role of PDGF and MCP-1 in neuronal survival against HIV Tat toxicity. These components of the cerebral innate immunity do not act separately from each other but form a functional immunity network. The ultimate outcome of HIV infection in the CNS will thus be dependent on the regulation of the net balance of cell-specific protective versus detrimental responses.

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References

  • Adamson DC, Dawson TM, Zink MC, Clements JE, Dawson VL (1996) Neurovirulent simian immunodeficiency virus infection induces neuronal, endothelial, and glial apoptosis. Mol Med 2:417–428

    Article  PubMed  CAS  Google Scholar 

  • Adler V, Yin Z, Tew KD, Ronai Z (1999) Role of redox potential and reactive oxygen species in stress signaling. Oncogene 18:6104–6111

    Article  PubMed  CAS  Google Scholar 

  • Antoniades HN, Bravo MA, Avila RE, Galanopoulos T, Neville-Golden J, Maxwell M, Selman M (1990) Platelet-derived growth factor in idiopathic pulmonary fibrosis. J Clin Invest 86:1055–1064

    Article  PubMed  CAS  Google Scholar 

  • Asensio VC, Maier J, Milner R, Boztug K, Kincaid C, Moulard M, Phillipson C, Lindsley K, Krucker T, Fox HS, Campbell IL (2001) Interferon-independent, human immunodeficiency virus type 1 gp120-mediated induction of CXCL10/IP-10 gene expression by astrocytes in vivo and in vitro. J Virol 75:7067–7077

    Article  PubMed  CAS  Google Scholar 

  • Babior BM (1999) NADPH oxidase: an update. Blood 93:1464–1476

    PubMed  CAS  Google Scholar 

  • Bell JE (1998) The neuropathology of adult HIV infection. Rev Neurol (Paris) 154:816–829

    CAS  Google Scholar 

  • Bokhari SM, Yao H, Bethel-Brown C, Fuwang P, Williams R, Dhillon NK, Hegde R, Kumar A, Buch SJ (2009) Morphine enhances Tat-induced activation in murine microglia. J Neurovirol 22:1–10

    Google Scholar 

  • Brenneman DE, Westbrook GL, Fitzgerald SP, Ennist DL, Elkins KL, Ruff MR, Pert CB (1988) Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide. Nature 335:639–642

    Article  PubMed  CAS  Google Scholar 

  • Budka H (1991) Neuropathology of human immunodeficiency virus infection. Brain Pathol 1:163–175

    Article  PubMed  CAS  Google Scholar 

  • Chanock SJ, el Benna J, Smith RM, Babior BM (1994) The respiratory burst oxidase. J Biol Chem 269:24519–24522

    PubMed  CAS  Google Scholar 

  • Chen Z, Huang Y, Zhao X, Skulsky E, Lin D, Ip J, Gettie A, Ho DD (2000) Enhanced infectivity of an R5-tropic simian/human immunodeficiency virus carrying human immunodeficiency virus type 1 subtype C envelope after serial passages in pig-tailed macaques (Macaca nemestrina). J Virol 74:6501–6510

    Article  PubMed  CAS  Google Scholar 

  • Conant K, Garzino-Demo A, Nath A, McArthur JC, Halliday W, Power C, Gallo RC, Major EO (1998) Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia. Proc Natl Acad Sci U S A 95:3117–3121

    Article  PubMed  CAS  Google Scholar 

  • Dhillon NK, Peng F, Ransohoff RM, Buch S (2007) PDGF synergistically enhances IFN-gamma-induced expression of CXCL10 in blood-derived macrophages: implications for HIV dementia. J Immunol 179:2722–2730

    PubMed  CAS  Google Scholar 

  • Dhillon N, Zhu X, Peng F, Yao H, Williams R, Qiu J, Callen S, Ladner AO, Buch S (2008) Molecular mechanism(s) involved in the synergistic induction of CXCL10 by human immunodeficiency virus type 1 Tat and interferon-gamma in macrophages. J Neurovirol 14:196–204

    Article  PubMed  CAS  Google Scholar 

  • Dong Y, Benveniste EN (2001) Immune function of astrocytes. Glia 36:180–190

    Article  PubMed  CAS  Google Scholar 

  • Dreyer EB, Kaiser PK, Offermann JT, Lipton SA (1990) HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists. Science 248:364–367

    Article  PubMed  CAS  Google Scholar 

  • El-Benna J, Dang PM, Gougerot-Pocidalo MA, Elbim C (2005) Phagocyte NADPH oxidase: a multicomponent enzyme essential for host defenses. Arch Immunol Ther Exp (Warsz) 53:199–206

    CAS  Google Scholar 

  • Eugenin EA, D'Aversa TG, Lopez L, Calderon TM, Berman JW (2003) MCP-1 (CCL2) protects human neurons and astrocytes from NMDA or HIV-tat-induced apoptosis. J Neurochem 85:1299–1311

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Hof PR, Lee PY, Yeung G, Wang RF, Podos SM, Morrison JH (1998) Glutamate receptor subunit GluR2 and NMDAR1 immunoreactivity in the retina of macaque monkeys with experimental glaucoma does not identify vulnerable neurons. Exp Neurol 153:234–241

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Kolb SA, Sporer B, Lahrtz F, Koedel U, Pfister HW, Fontana A (1999) Identification of a T cell chemotactic factor in the cerebrospinal fluid of HIV-1-infected individuals as interferon-gamma inducible protein 10. J Neuroimmunol 93:172–181

    Article  PubMed  CAS  Google Scholar 

  • Kolson DL, Pomerantz RJ (1996) AIDS dementia and HIV-1-induced neurotoxicity: possible pathogenic associations and mechanisms. J Biomed Sci 3:389–414

    Article  PubMed  CAS  Google Scholar 

  • Kruman I, Guo Q, Mattson MP (1998) Calcium and reactive oxygen species mediate staurosporine-induced mitochondrial dysfunction and apoptosis in PC12 cells. J Neurosci Res 51:293–308

    Article  PubMed  CAS  Google Scholar 

  • Kutsch O, Oh J, Nath A, Benveniste EN (2000) Induction of the chemokines interleukin-8 and IP-10 by human immunodeficiency virus type 1 tat in astrocytes. J Virol 74:9214–9221

    Article  PubMed  CAS  Google Scholar 

  • Lane TE, Buchmeier MJ, Watry DD, Fox HS (1996) Expression of inflammatory cytokines and inducible nitric oxide synthase in brains of SIV-infected rhesus monkeys: applications to HIV-induced central nervous system disease. Mol Med 2:27–37

    PubMed  CAS  Google Scholar 

  • Lipton SA, Gendelman HE (1995) Seminars in medicine of the Beth Israel Hospital, Boston. Dementia associated with the acquired immunodeficiency syndrome. N Engl J Med 332:934–940

    Article  PubMed  CAS  Google Scholar 

  • Luster AD, Ravetch JV (1987) Biochemical characterization of a gamma interferon-inducible cytokine (IP-10). J Exp Med 166:1084–1097

    Article  PubMed  CAS  Google Scholar 

  • Majumder S, Zhou LZ, Chaturvedi P, Babcock G, Aras S, Ransohoff RM (1998a) Regulation of human IP-10 gene expression in astrocytoma cells by inflammatory cytokines. J Neurosci Res 54:169–180

    Article  CAS  Google Scholar 

  • Majumder S, Zhou LZ, Chaturvedi P, Babcock G, Aras S, Ransohoff RM (1998b) p48/STAT-1alpha-containing complexes play a predominant role in induction of IFN-gamma-inducible protein, 10 kDa (IP-10) by IFN-gamma alone or in synergy with TNF-alpha. J Immunol 161:4736–4744

    CAS  Google Scholar 

  • McArthur JC, Hoover DR, Bacellar H, Miller EN, Cohen BA, Becker JT, Graham NM, McArthur JH, Selnes OA, Jacobson LP et al (1993) Dementia in AIDS patients: incidence and risk factors. Multicenter AIDS Cohort Study. Neurology 43:2245–2252

    PubMed  CAS  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

    Article  PubMed  CAS  Google Scholar 

  • Meucci O, Fatatis A, Simen AA, Miller RJ (2000) Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival. Proc Natl Acad Sci U S A 97:8075–8080

    Article  PubMed  CAS  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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Navia BA, Cho ES, Petito CK, Price RW (1986) The AIDS dementia complex: II. Neuropathology. Ann Neurol 19:525–535

    Article  PubMed  CAS  Google Scholar 

  • Ohmori Y, Hamilton TA (1993) Cooperative interaction between interferon (IFN) stimulus response element and kappa B sequence motifs controls IFN gamma- and lipopolysaccharide-stimulated transcription from the murine IP-10 promoter. J Biol Chem 268:6677–6688

    PubMed  CAS  Google Scholar 

  • Ohmori Y, Hamilton TA (1995) The interferon-stimulated response element and a kappa B site mediate synergistic induction of murine IP-10 gene transcription by IFN-gamma and TNF-alpha. J Immunol 154:5235–5244

    PubMed  CAS  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 immunodeficiency virus and the development of encephalitis. J Virol 76:5797–5802

    Article  PubMed  CAS  Google Scholar 

  • Park J, Choi K, Jeong E, Kwon D, Benveniste EN, Choi C (2004) Reactive oxygen species mediate chloroquine-induced expression of chemokines by human astroglial cells. Glia 47:9–20

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Peng F, Dhillon NK, Yao H, Zhu X, Williams R, Buch S (2008a) Mechanisms of platelet-derived growth factor-mediated neuroprotection—implications in HIV dementia. Eur J NeuroSci 28:1255–1264

    Article  Google Scholar 

  • Peng F, Dhillon N, Callen S, Yao H, Bokhari S, Zhu X, Baydoun HH, Buch S (2008b) Platelet-derived growth factor protects neurons against gp120-mediated toxicity. J Neurovirol 14:62–72

    Article  CAS  Google Scholar 

  • Potula R, Dhillion N, Sui Y, Zien CA, Funa K, Pinson D, Mayo MS, Singh DK, Narayan O, Buch S (2004) Association of platelet-derived growth factor-B chain with simian human immunodeficiency virus encephalitis. Am J Pathol 165:815–824

    PubMed  CAS  Google Scholar 

  • Raad H, Paclet MH, Boussetta T, Kroviarski Y, Morel F, Quinn MT, Gougerot-Pocidalo MA, Dang PM, El-Benna J (2008) Regulation of the phagocyte NADPH oxidase activity: phosphorylation of gp91phox/NOX2 by protein kinase C enhances its diaphorase activity and binding to Rac2, p67phox, and p47phox. Faseb J

  • Ross R, Raines EW (1988) Platelet-derived growth factor—its role in health and disease. Adv Exp Med Biol 234:9–21

    PubMed  CAS  Google Scholar 

  • Ross R, Faggiotto A, Bowen-Pope D, Raines E (1984) The role of endothelial injury and platelet and macrophage interactions in atherosclerosis. Circulation 70:III77–III82

    PubMed  CAS  Google Scholar 

  • Ross R, Bowen-Pope DF, Raines EW (1985) Platelet-derived growth factor: its potential roles in wound healing, atherosclerosis, neoplasia, and growth and development. Ciba Found Symp 116:98–112

    PubMed  CAS  Google Scholar 

  • Ross R, Raines EW, Bowen-Pope DF (1986) The biology of platelet-derived growth factor. Cell 46:155–169

    Article  PubMed  CAS  Google Scholar 

  • Rostene W, Kitabgi P, Parsadaniantz SM (2007) Chemokines: a new class of neuromodulator? Nat Rev Neurosci 8:895–903

    Article  PubMed  CAS  Google Scholar 

  • Sacktor N, Lyles RH, Skolasky R, Kleeberger C, Selnes OA, Miller EN, Becker JT, Cohen B, McArthur JC (2001) HIV-associated neurologic disease incidence changes: multicenter AIDS cohort study, 1990–1998. Neurology 56:257–260

    PubMed  CAS  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

    Article  PubMed  CAS  Google Scholar 

  • Sasseville VG, Smith MM, Mackay CR, Pauley DR, Mansfield KG, Ringler DJ, Lackner AA (1996) Chemokine expression in simian immunodeficiency virus-induced AIDS encephalitis. Am J Pathol 149:1459–1467

    PubMed  CAS  Google Scholar 

  • Shapshak P, Duncan R, Minagar A, Rodriguez de la Vega P, Stewart RV, Goodkin K (2004) Elevated expression of IFN-gamma in the HIV-1 infected brain. Front Biosci 9:1073–1081

    Article  PubMed  CAS  Google Scholar 

  • Song HY, Ryu J, Ju SM, Park LJ, Lee JA, Choi SY, Park J (2007) Extracellular HIV-1 Tat enhances monocyte adhesion by up-regulation of ICAM-1 and VCAM-1 gene expression via ROS-dependent NF-kappaB activation in astrocytes. Exp Mol Med 39:27–37

    PubMed  CAS  Google Scholar 

  • Spencer DC, Price RW (1992) Human immunodeficiency virus and the central nervous system. Annu Rev Microbiol 46:655–693

    Article  PubMed  CAS  Google Scholar 

  • Sui Y, Potula R, Pinson D, Adany I, Li Z, Day J, Buch E, Segebrecht J, Villinger F, Liu Z, Huang M, Narayan O, Buch S (2003) Microarray analysis of cytokine and chemokine genes in the brains of macaques with SHIV-encephalitis. J Med Primatol 32:229–239

    Article  PubMed  CAS  Google Scholar 

  • Sui Y, Stehno-Bittel L, Li S, Loganathan R, Dhillon NK, Pinson D, Nath A, Kolson D, Narayan O, Buch S (2006) CXCL10-induced cell death in neurons: role of calcium dysregulation. Eur J NeuroSci 23:957–964

    Article  PubMed  Google Scholar 

  • Sundaresan M, Yu ZX, Ferrans VJ, Irani K, Finkel T (1995) Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 270:296–299

    Article  PubMed  CAS  Google Scholar 

  • Tarzami ST, Calderon TM, Deguzman A, Lopez L, Kitsis RN, Berman JW (2005) MCP-1/CCL2 protects cardiac myocytes from hypoxia-induced apoptosis by a G(alphai)-independent pathway. Biochem Biophys Res Commun 335:1008–1016

    Article  PubMed  CAS  Google Scholar 

  • Thompson KA, McArthur JC, Wesselingh SL (2001) Correlation between neurological progression and astrocyte apoptosis in HIV-associated dementia. Ann Neurol 49:745–752

    Article  PubMed  CAS  Google Scholar 

  • Tong N, Perry SW, Zhang Q, James HJ, Guo H, Brooks A, Bal H, Kinnear SA, Fine S, Epstein LG, Dairaghi D, Schall TJ, Gendelman HE, Dewhurst S, Sharer LR, Gelbard HA (2000) Neuronal fractalkine expression in HIV-1 encephalitis: roles for macrophage recruitment and neuroprotection in the central nervous system. J Immunol 164:1333–1339

    PubMed  CAS  Google Scholar 

  • Turchan-Cholewo J, Dimayuga VM, Gupta S, Gorospe RM, Keller JN, Bruce-Keller AJ (2009) NADPH oxidase drives cytokine and neurotoxin release from microglia and macrophages in response to HIV-Tat. Antioxid Redox Signal 11:193–204

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  • Vergote D, Butler GS, Ooms M, Cox JH, Silva C, Hollenberg MD, Jhamandas JH, Overall CM, Power C (2006) Proteolytic processing of SDF-1alpha reveals a change in receptor specificity mediating HIV-associated neurodegeneration. Proc Natl Acad Sci U S A 103:19182–19187

    Article  PubMed  CAS  Google Scholar 

  • Wang X, Martindale JL, Liu Y, Holbrook NJ (1998) The cellular response to oxidative stress: influences of mitogen-activated protein kinase signalling pathways on cell survival. Biochem J 333(Pt 2):291–300

    PubMed  CAS  Google Scholar 

  • Wesselingh SL, Takahashi K, Glass JD, McArthur JC, Griffin JW, Griffin DE (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

    Article  PubMed  CAS  Google Scholar 

  • Westmoreland SV, Rottman JB, Williams KC, Lackner AA, Sasseville VG (1998) Chemokine receptor expression on resident and inflammatory cells in the brain of macaques with simian immunodeficiency virus encephalitis. Am J Pathol 152:659–665

    PubMed  CAS  Google Scholar 

  • Williams R, Dhillon NK, Hegde ST, Yao H, Peng F, Callen S, Chebloune Y, Davis RL, Buch SJ (2009) Proinflammatory cytokines and HIV-1 synergistically enhance CXCL10 expression in human astrocytes. Glia 57:734–743

    Article  PubMed  Google Scholar 

  • Williams R, Yao H, Peng F, Yang Y, Bethel-Brown C, Buch S (2010) Cooperative induction of CXCL10 involves NADPH oxidase: implications for HIV dementia. Glia 58:611–621

    PubMed  Google Scholar 

  • Yao H, Peng F, Fan Y, Zhu X, Hu G, Buch SJ (2009a) TRPC channel-mediated neuroprotection by PDGF involves Pyk2/ERK/CREB pathway. Cell Death Differ 16:1681–1693

    Google Scholar 

  • Yao H, Peng F, Dhillon N, Callen S, Bokhari S, Stehno-Bittel L, Ahmad SO, Wang JQ, Buch S (2009b) Involvement of TRPC channels in CCL2-mediated neuroprotection against tat toxicity. J Neurosci 29:1657–1669

    Article  CAS  Google Scholar 

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Acknowledgement

This work was supported by grants MH-068212, DA020392, DA023397, DA024442, and DA 027729 from the National Institutes of Health (SB).

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  1. Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center (DRC 8011), University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA

    Honghong Yao, Crystal Bethel-Brown, Cicy Zidong Li & Shilpa J. Buch

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Yao, H., Bethel-Brown, C., Li, C.Z. et al. HIV Neuropathogenesis: a Tight Rope Walk of Innate Immunity. J Neuroimmune Pharmacol 5, 489–495 (2010). https://doi.org/10.1007/s11481-010-9211-1

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