Abstract
To begin to unravel the complexity of HIV-associated changes in the brain, broader, multifaceted analyses of cerebrospinal fluid (CSF) are needed that examine a wide range of proteins reflecting different functions. To provide the first broad profiles of protein changes in the CSF of HIV-infected patients, we used antibody arrays to measure 120 cytokines, chemokines, growth factors, and other proteins. CSF from HIV-infected patients with a range of cognitive deficits was compared to CSF from uninfected, cognitively normal patients to begin to identify protein changes associated with HIV infection and neurological disease progression. Uninfected patients showed relatively consistent patterns of protein expression. Highly expressed proteins in CSF included monocyte chemotactic protein-1, tissue inhibitors of metalloproteases, granulocyte colony-stimulating factor, adiponectin, soluble tumor necrosis factor receptor-1, urokinase-type plasminogen activator receptor, and insulin-like growth factor binding protein-2. Inflammatory and anti-inflammatory cytokines were expressed at low levels. HIV-infected patients showed increases in inflammatory proteins (interferon-gamma, tumor necrosis factor-alpha), anti-inflammatory proteins (IL-13), and chemokines but these correlated poorly with neurological status. The strongest correlation with increasing severity of neurological disease was a decline in growth factors, particularly, brain-derived neurotrophic factor and NT-3. These studies illustrate that HIV infection is associated with parallel changes in both inflammatory and neuroprotective proteins in the CSF. The inverse relationship between growth factors and neurological disease severity suggests that a loss of growth factor neuroprotection may contribute to the development of neural damage and may provide useful markers of disease progression.
Similar content being viewed by others
References
Achim CL, Heyes MP, Wiley CA (1993) Quantitation of human immunodeficiency virus, immune activation factors, and quinolinic acid in AIDS brains. J Clin Invest 91:2769–2775
Albrecht D, Garcia L, Cartier L, Kettlun AM, Vergara C, Collados L, Valenzuela MA (2006) Trophic factors in cerebrospinal fluid and spinal cord of patients with tropical spastic paraparesis, HIV, and Creutzfeldt–Jakob disease. AIDS Res Hum Retroviruses 22:248–254
Axelsson J, Heimburger O, Lindholm B, Stenvinkel P (2005) Adipose tissue and its relation to inflammation: the role of adipokines. J Ren Nutr 15:131–136
Bachis A, Mocchetti I (2005) Brain-derived neurotrophic factor is neuroprotective against human immunodeficiency virus-1 envelope proteins. Ann NY Acad Sci 1053:247–257
Bandaru VV, McArthur JC, Sacktor N, Cutler RG, Knapp EL, Mattson MP, Haughey NJ (2007) Associative and predictive biomarkers of dementia in HIV-1-infected patients. Neurology 68:1481–1487
Barone FC, Arvin B, White RF, Miller A, Webb CL, Willette RN, Lysko PG, Feuerstein GZ (1997) Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury. Stroke 28:1233–1244
Bazan NG, Marcheselli VL, Cole-Edwards K (2005) Brain response to injury and neurodegeneration: endogenous neuroprotective signaling. Ann NY Acad Sci 1053:137–147
Berg AH, Combs TP, Scherer PE (2002) ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab 13:84–89
Bouwman FH, Skolasky RL, Hes D, Selnes OA, Glass JD, Nance-Sproson TE, Royal W, Dal Pan GJ, McArthur JC (1998) Variable progression of HIV-associated dementia. Neurology 50:1814–1820
Bragg DC, Robertson K, Hall CD, Meeker RB (2000) Techniques to measure neurologic disease progression in HIV-1 patients. Science Online: NeuroAIDS 3:1–9
Brew BJ, Pemberton L, Blennow K, Wallin A, Hagberg L (2005) CSF amyloid beta42 and tau levels correlate with AIDS dementia complex. Neurology 65:1490–1492
Bronzetti E, Artico M, Kovacs I, Felici LM, Magliulo G, Vignone D, D’Ambrosio A, Forte F, Di Liddo R, Feher J (2007) Expression of neurotransmitters and neurotrophins in neurogenic inflammation of the rat retina. Eur J Histochem 51:251–260
Cinque P, Vago L, Mengozzi M, Torri V, Ceresa D, Vicenzi E, Transidico P, Vagani A, Sozzani S, Mantovani A, Lazzarin A, Poli G (1998) Elevated cerebrospinal fluid levels of monocyte chemotactic protein-1 correlate with HIV-1 encephalitis and local viral replication. AIDS 12:1327–1332
Cinque P, Nebuloni M, Santovito ML, Price RW, Gisslen M, Hagberg L, Bestetti A, Vago G, Lazzarin A, Blasi F, Sidenius N (2004) The urokinase receptor is overexpressed in the AIDS dementia complex and other neurological manifestations. Ann Neurol 55:687–694
Conant K, Garzino-Demo A, Nath A, McArthur JC, Halliday W, Power C, Gallo RC, Major EO (1998) Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia. Proc Natl Acad Sci USA 95:3117–3121
Conant K, McArthur JC, Griffin DE, Sjulson L, Wahl LM, Irani DN (1999) Cerebrospinal fluid levels of MMP-2, 7, and 9 are elevated in association with human immunodeficiency virus dementia. Ann Neurol 46:391–398
Elkabes S, DiCicco-Bloom EM, Black IB (1996) Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J Neurosci 16:2508–2521
Elovaara I, Muller KM (1993) Cytoimmunological abnormalities in cerebrospinal fluid in early stages of HIV-1 infection often precede changes in blood. J Neuroimmunol 44:199–204
Emsley HC, Smith CJ, Gavin CM, Georgiou RF, Vail A, Barberan EM, Illingworth K, Scarth S, Wickramasinghe V, Hoadley ME, Rothwell NJ, Tyrrell PJ, Hopkins SJ (2007) Clinical outcome following acute ischaemic stroke relates to both activation and autoregulatory inhibition of cytokine production. BMC Neurol 7:5
Enting RH, Foudraine NA, Lange JM, Jurriaans S, van der PT, Weverling GJ, Portegies P (2000) Cerebrospinal fluid beta2-microglobulin, monocyte chemotactic protein- 1, and soluble tumour necrosis factor alpha receptors before and after treatment with lamivudine plus zidovudine or stavudine. J Neuroimmunol 102:216–221
Epstein L, Gendelman H (1993) Human immunodeficiency virus type 1 infection of the nervous system: pathogenic mechanisms. Ann Neurol 33:429–436
Giralt M, Domingo P, Guallar JP, Rodriguez de la Concepcion ML, Alegre M, Domingo JC, Villarroya F (2006) HIV-1 infection alters gene expression in adipose tissue, which contributes to HIV-1/HAART-associated lipodystrophy. Antivir Ther 11:729–740
Gisslen M, Hagberg L, Brew BJ, Cinque P, Price RW, Rosengren L (2007) Elevated cerebrospinal fluid neurofilament light protein concentrations predict the development of AIDS dementia complex. J Infect Dis 195:1774–1778
Giulian D, Noonan CA (1998) Neurotoxins from HIV-infected mononuclear phagocytes. In: Gendelman HE, Lipton SAEL, Swindells S (eds) The neurology of AIDS. International Thompson, New York, pp 117–129
Giulian D, Yu J, Li X, Tom D, Li J, Wendt E, Lin S-N, Schwarcz R, Noonan C (1996) Study of receptor-mediated neurotoxins released by HIV-1-infected mononuclear phagocytes found in human brain. J Neurosci 16:3139–3153
Gora-Kupilas K, Josko J (2005) The neuroprotective function of vascular endothelial growth factor (VEGF). Folia Neuropathol 43:31–39
Groneberg DA, Fischer TC, Peckenschneider N, Noga O, Dinh QT, Welte T, Welker P (2007) Cell type-specific regulation of brain-derived neurotrophic factor in states of allergic inflammation. Clin Exp Allergy 37:1386–1391
Hagberg L, Fuchs D, Rosengren L, Gisslen M (2000) Intrathecal immune activation is associated with cerebrospinal fluid markers of neuronal destruction in AIDS patients. J Neuroimmunol 102:51–55
Heyes MP, Brew B, Martin A, Markey SP, Price RW, Bhalla RB, Salazar A (1991) Cerebrospinal fluid quinolinic acid concentrations are increased in acquired immune deficiency syndrome. Adv Exp Med Biol 294:687–690
Huang JS, Letendre S, Marquie-Beck J, Cherner M, McCutchan JA, Grant I, Ellis R (2007) Low CSF leptin levels are associated with worse learning and memory performance in HIV-infected men. J Neuroimmune Pharmacol 2:352–358
Hult B, Chana G, Masliah E, Everall I (2008) Neurobiology of HIV. Int Rev Psychiatry 20:3–13
Husson I, Rangon CM, Lelievre V, Bemelmans AP, Sachs P, Mallet J, Kosofsky BE, Gressens P (2005) BDNF-induced white matter neuroprotection and stage-dependent neuronal survival following a neonatal excitotoxic challenge. Cereb Cortex 15:250–261
Johnston JB, Zhang K, Silva C, Shalinsky DR, Conant K, Ni W, Corbett D, Yong VW, Power C (2001) HIV-1 Tat neurotoxicity is prevented by matrix metalloproteinase inhibitors. Ann Neurol 49:230–241
Jostock T, Mullberg J, Ozbek S, Atreya R, Blinn G, Voltz N, Fischer M, Neurath MF, Rose-John S (2001) Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses. Eur J Biochem 268:160–167
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
Kilic E, Kilic U, Hermann DM (2005) TAT-GDNF in neurodegeneration and ischemic stroke. CNS Drug Rev 11:369–378
Kilic E, Kilic U, Wang Y, Bassetti CL, Marti HH, Hermann DM (2006) The phosphatidylinositol-3 kinase/Akt pathway mediates VEGF’s neuroprotective activity and induces blood brain barrier permeability after focal cerebral ischemia. FASEB J 20:1185–1187
Kistorp C, Faber J, Galatius S, Gustafsson F, Frystyk J, Flyvbjerg A, Hildebrandt P (2005) Plasma adiponectin, body mass index, and mortality in patients with chronic heart failure. Circulation 112:1756–1762
Koenig S, Gendelman HE, Orenstein JM, Dal Canto MC, Pezeshkpour GH, Yungbluth M, Janotta F, Aksamit A, Martin MA, Fauci AS (1986) Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 233:1089–1093
Kolson DL (2002) Neuropathogenesis of central nervous system HIV-1 infection. Clin Lab Med 22:703–717
Krabbe KS, Mortensen EL, Avlund K, Pedersen AN, Pedersen BK, Jorgensen T, Bruunsgaard H (2009) Brain-derived neurotrophic factor predicts mortality risk in older women. J Am Geriatr Soc 57:1447–1452
Leveque T, Le Pavec G, Boutet A, Tardieu M, Dormont D, Gras G (2004) Differential regulation of gelatinase A and B and TIMP-1 and -2 by TNF-alpha and HIV virions in astrocytes. Microbes Infect 6:157–163
Liuzzi GM, Mastroianni CM, Santacroce MP, Fanelli M, D’Agostino C, Vullo V, Riccio P (2000) Increased activity of matrix metalloproteinases in the cerebrospinal fluid of patients with HIV-associated neurological diseases. J Neurovirol 6:156–163
McCoig C, Castrejon MM, Saavedra-Lozano J, Castano E, Baez C, Lanier ER, Saez-Llorens X, Ramilo O (2004) Cerebrospinal fluid and plasma concentrations of proinflammatory mediators in human immunodeficiency virus-infected children. Pediatr Infect Dis J 23:114–118
Meeker RB, Robertson K, Barry T, Hall C (1999) Neurotoxicity of CSF from HIV-infected humans. J Neurovirol 5:507–518
Meeker RB, Boles JC, Robertson KR, Hall CD (2005) Cerebrospinal fluid from human immunodeficiency virus-infected individuals facilitates neurotoxicity by suppressing intracellular calcium recovery. J Neurovirol 11:144–156
Meisner F, Scheller C, Kneitz S, Sopper S, Neuen-Jacob E, Riederer P, Meulen VT, Koutsilieri E (2008) Memantine upregulates BDNF and prevents dopamine deficits in SIV-infected macaques: a novel pharmacological action of memantine. Neuropsychopharmacology 33:2228–2236
Mocchetti I, Bachis A (2004) Brain-derived neurotrophic factor activation of TrkB protects neurons from HIV-1/gp120-induced cell death. Crit Rev Neurobiol 16:51–57
Nakagawa T, Suga S, Kawase T, Toda M (2006) Intracarotid injection of granulocyte-macrophage colony-stimulating factor induces neuroprotection in a rat transient middle cerebral artery occlusion model. Brain Res 1089:179–185
Nawashiro H, Martin D, Hallenbeck JM (1997) Neuroprotective effects of TNF binding protein in focal cerebral ischemia. Brain Res 778:265–271
Nosheny RL, Mocchetti I, Bachis A (2005) Brain-derived neurotrophic factor as a prototype neuroprotective factor against HIV-1-associated neuronal degeneration. Neurotox Res 8:187–198
Nosheny RL, Ahmed F, Yakovlev A, Meyer EM, Ren K, Tessarollo L, Mocchetti I (2007) Brain-derived neurotrophic factor prevents the nigrostriatal degeneration induced by human immunodeficiency virus-1 glycoprotein 120 in vivo. Eur J Neurosci 25:2275–2284
Novikova LN, Novikov LN, Kellerth JO (2000) Survival effects of BDNF and NT-3 on axotomized rubrospinal neurons depend on the temporal pattern of neurotrophin administration. Eur J Neurosci 12:776–780
Padberg F, Feneberg W, Schmidt S, Schwarz MJ, Korschenhausen D, Greenberg BD, Nolde T, Muller N, Trapmann H, Konig N, Moller HJ, Hampel H (1999) CSF and serum levels of soluble interleukin-6 receptors (sIL-6R and sgp130), but not of interleukin-6 are altered in multiple sclerosis. J Neuroimmunol 99:218–223
Pemberton LA, Brew BJ (2001) Cerebrospinal fluid S-100beta and its relationship with AIDS dementia complex. J Clin Virol 22:249–253
Perrella O, Guerriero M, Izzo E, Soscia M, Carrieri PB (1992) Interleukin-6 and granulocyte macrophage-CSF in the cerebrospinal fluid from HIV infected subjects with involvement of the central nervous system. Arq Neuropsiquiatr 50:180–182
Poluektova L, Gorantla S, Faraci J, Birusingh K, Dou H, Gendelman HE (2004) Neuroregulatory events follow adaptive immune-mediated elimination of HIV-1-infected macrophages: studies in a murine model of viral encephalitis. J Immunol 172:7610–7617
Price RW, Sidtis JJ (1990) Evaluation of the AIDS dementia complex in clinical trials. J Acquir Immune Defic Syndr 3(Suppl 2):S51–S60
Qi Y, Takahashi N, Hileman SM, Patel HR, Berg AH, Pajvani UB, Scherer PE, Ahima RS (2004) Adiponectin acts in the brain to decrease body weight. Nat Med 10:524–529
Robertson KR, Kapoor C, Robertson WT, Fuscus S, Ford S, Hall C (2004) No gender differences in the progression of nervous system disease of HIV infection. J Acquir Immune Defic Syndr 36:817–822
Sabri F, de Milito A, Pirskanen R, Elovaara I, Hagberg L, Cinque P, Price R, Chiodi F (2001) Elevated levels of soluble Fas and Fas ligand in cerebrospinal fluid of patients with AIDS dementia complex. J Neuroimmunol 114:197–206
Schnydrig S, Korner L, Landweer S, Ernst B, Walker G, Otten U, Kunz D (2007) Peripheral lipopolysaccharide administration transiently affects expression of brain-derived neurotrophic factor, corticotropin and proopiomelanocortin in mouse brain. Neurosci Lett 429:69–73
Sidenius N, Nebuloni M, Sala S, Zerbi P, Price RW, Gisslen M, Hagberg L, Vago L, Lazzarin A, Blasi F, Cinque P (2004) Expression of the urokinase plasminogen activator and its receptor in HIV-1-associated central nervous system disease. J Neuroimmunol 157:133–139
Soontornniyomkij V, Wang G, Pittman CA, Wiley CA, Achim CL (1998) Expression of brain-derived neurotrophic factor protein in activated microglia of human immunodeficiency virus type 1 encephalitis. Neuropathol Appl Neurobiol 24:453–460
Sporer B, Koedel U, Goebel FD, Pfister HW (2000) Increased levels of soluble Fas receptor and Fas ligand in the cerebrospinal fluid of HIV-infected patients. AIDS Res Hum Retroviruses 16:221–226
Sporer B, Koedel U, Popp B, Paul R, Pfister HW (2005) Evaluation of cerebrospinal fluid uPA, PAI-1, and soluble uPAR levels in HIV-infected patients. J Neuroimmunol 163:190–194
Stadelmann C, Kerschensteiner M, Misgeld T, Bruck W, Hohlfeld R, Lassmann H (2002) BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? Brain 125:75–85
Storkebaum E, Lambrechts D, Carmeliet P (2004) VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection. Bioessays 26:943–954
Streit WJ (2005) Microglia and neuroprotection: implications for Alzheimer’s disease. Brain Res Brain Res Rev 48:234–239
Suryadevara R, Holter S, Borgmann K, Persidsky R, Labenz-Zink C, Persidsky Y, Gendelman HE, Wu L, Ghorpade A (2003) Regulation of tissue inhibitor of metalloproteinase-1 by astrocytes: links to HIV-1 dementia. Glia 44:47–56
Szczepanik AM, Funes S, Petko W, Ringheim GE (2001) IL-4, IL-10 and IL-13 modulate A beta(1-42)-induced cytokine and chemokine production in primary murine microglia and a human monocyte cell line. J Neuroimmunol 113:49–62
Towfighi A, Skolasky RL, St Hillaire C, Conant K, McArthur JC (2004) CSF soluble Fas correlates with the severity of HIV-associated dementia. Neurology 62:654–656
Tsiodras S, Mantzoros C (2006) Leptin and adiponectin in the HIV associated metabolic syndrome: physiologic and therapeutic implications. Am J Infect Dis 2:141–152
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
Turrin NP, Rivest S (2006) Molecular and cellular immune mediators of neuroprotection. Mol Neurobiol 34:221–242
Verkauskiene R, Dollfus C, Levine M, Faye A, Deghmoun S, Houang M, Chevenne D, Bresson JL, Blanche S, Levy-Marchal C (2006) Serum adiponectin and leptin concentrations in HIV-infected children with fat redistribution syndrome. Pediatr Res 60:225–230
Wang Y, Kilic E, Kilic U, Weber B, Bassetti CL, Marti HH, Hermann DM (2005) VEGF overexpression induces post-ischaemic neuroprotection, but facilitates haemodynamic steal phenomena. Brain 128:52–63
Wong ML, Bongiorno PB, Rettori V, McCann SM, Licinio J (1997) Interleukin (IL) 1beta, IL-1 receptor antagonist, IL-10, and IL-13 gene expression in the central nervous system and anterior pituitary during systemic inflammation: pathophysiological implications. Proc Natl Acad Sci USA 94:227–232
Wu D (2005) Neuroprotection in experimental stroke with targeted neurotrophins. NeuroRx 2:120–128
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 Neurovirol 6(Suppl 1):S14–S23
Yabe T, Samuels I, Schwartz JP (2002) Bone morphogenetic proteins BMP-6 and BMP-7 have differential effects on survival and neurite outgrowth of cerebellar granule cell neurons. J Neurosci Res 68:161–168
Yasuhara T, Shingo T, Kobayashi K, Takeuchi A, Yano A, Muraoka K, Matsui T, Miyoshi Y, Hamada H, Date I (2004) Neuroprotective effects of vascular endothelial growth factor (VEGF) upon dopaminergic neurons in a rat model of Parkinson’s disease. Eur J Neurosci 19:1494–1504
Zheng J, Gendelman HE (1997) The HIV-1 associated dementia complex: a metabolic encephalopathy fueled by viral replication in mononuclear phagocytes. Curr Opin Neurol 10:319–325
Acknowledgments
This work was supported by NIH Grants MH079726 and MH085606.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Meeker, R.B., Poulton, W., Markovic-Plese, S. et al. Protein changes in CSF of HIV-infected patients: evidence for loss of neuroprotection. J. Neurovirol. 17, 258–273 (2011). https://doi.org/10.1007/s13365-011-0034-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13365-011-0034-5