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Measurement of soluble inflammatory mediators in cerebrospinal fluid of human immunodeficiency virus-positive patients at distinct stages of infection by solid-phase protein array

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Abstract

The objective of this study was to evaluate immune cytokine expression in cerebrospinal fluid (CSF) of patients with human immunodeficiency virus-1 (HIV-1)-associated dementia (HAD) using a novel cytokine array assay. HIV-1 induces a condition resembling classical subcortical dementia, known as HAD. The immune mechanisms contributing to HAD have not been elucidated. Cytokine expression in CSF was determined by solid-phase protein array in 33 neurologically asymptomatic HIV-positive male patients and were compared to levels in non-HIV controls and patients with HAD. Neurological examinations and lumbar and venous punctures were conducted in all patients and controls. Interleukin (IL)-1, IL-4, and IL-10, were up-regulated in all treated acquired immunodeficiency syndrome (AIDS) patients independent of neurological status compared to controls. In contrast, interferon gamma (IFN-γ), IL-1α, IL-15, and tumor necrosis factor alpha (TNF-α) were highly expressed in patients with HAD compared to undemented HIV-positive patients. These results show that solid-phase protein array can detect immunological changes in patients infected with HIV. Cytokine expression levels differ in different disease stages and in patients on different treatment paradigms. Pending further validation on a larger number of patients, this method may be a useful tool in CSF diagnostics and the longitudinal evaluation of patient with HAD.

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References

  • Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J, Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE (2007). Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69: 1789–1799.

    Article  CAS  PubMed  Google Scholar 

  • Aquaro S, Ronga L, Pollicita M, Antinori A, Ranazzi A, Perno CF (2005). Human immunodeficiency virus infection and acquired immunodeficiency syndrome dementia complex: role of cells of monocyte-macrophage lineage. J NeuroVirol 11(Suppl 3): 58–66.

    Article  CAS  PubMed  Google Scholar 

  • Arendt G, Hefter H, Hilperath F, von Giesen HJ, Strohmeyer G, Freund HJ (1994). Motor analysis predicts progression in HIV-associated brain disease. J Neurol Sci 123: 180–185.

    Article  CAS  PubMed  Google Scholar 

  • Arendt G, Nolting T, Frisch C, Husstedt IW, Gregor N, Koutsilieri E, Maschke M, Angerer A, Obermann M, Neuen-Jacob E, Adams O, Loeffert S, Riederer P, ter Meulen V, Sopper S (2007). Intrathecal viral replication and cerebral deficits in different stages of human immunodeficiency virus disease. J NeuroVirol 13: 225–232.

    Article  PubMed  Google Scholar 

  • Arendt G, von Giesen HJ (2002). Human immunodeficiency virus dementia: evidence of a subcortical process from studies of fine finger movements. J NeuroVirol 8(Suppl 2): 27–32.

    Article  PubMed  Google Scholar 

  • Bangs SC, McMichael AJ, Xu XN (2006). Bystander T cell activation—implications for HIV infection and other diseases. Trends Immunol 27: 518–524.

    Article  CAS  PubMed  Google Scholar 

  • Buch S, Pinson D, King CL, Raghavan R, Hou Y, Li Z, Adany I, Hicks A, Villinger F, Kumar A, Narayan O (2001). Inhibitory and enhancing effects of IFN-gamma and IL-4 on SHIV(KU) replication in rhesus macaque macrophages: correlation between Th2 cytokines and productive infection in tissue macrophages during late-stage infection. Cytokine 13: 295–304.

    Article  CAS  PubMed  Google Scholar 

  • Clerici M, Shearer GM (1993). A TH1→TH2 switch is a critical step in the etiology of HIV infection. Immunol Today 14: 107–111.

    Article  CAS  PubMed  Google Scholar 

  • Cysique LA, Maruff P, Brew BJ (2004). Prevalence and pattern of neuropsychological impairment in human immunodeficiency virus-infected/acquired immunodeficiency syndrome (HIV/AIDS) patients across pre- and post-highly active antiretroviral therapy eras: a combined study of two cohorts. J NeuroVirol 10: 350–357.

    Article  PubMed  Google Scholar 

  • Dhar A, Gardner J, Borgmann K, Wu L, Ghorpade A (2006). Novel role of TGF-beta in differential astrocyte-TIMP-1 regulation: implications for HIV-1-dementia and neuroinflammation. J Neurosci Res 83: 1271–1280.

    Article  CAS  PubMed  Google Scholar 

  • Ehl S, Hombach J, Aichele P, Hengartner H, Zinkernagel RM (1997). Bystander activation of cytotoxic T cells: studies on the mechanism and evaluation of in vivo significance in a transgenic mouse model. J Exp Med 185: 1241–1251.

    Article  CAS  PubMed  Google Scholar 

  • Faller EM, McVey MJ, Kakal JA, MacPherson PA (2006). Interleukin-7 receptor expression on CD8 T-cells is downregulated by the HIV Tat protein. J Acquir Immune Defic Syndr 43: 257–269.

    Article  CAS  PubMed  Google Scholar 

  • Galli G, Annunziato F, Cosmi L, Manetti R, Maggi E, Romagnani S (2001). Th1 and th2 responses, HIV-1 coreceptors, and HIV-1 infection. J Biol Regul Homeost Agents 15: 308–313.

    CAS  PubMed  Google Scholar 

  • Gallo P, Frei K, Rordorf C, Lazdins J, Tavolato B, Fontana A (1989). Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system: an evaluation of cytokines in cerebrospinal fluid. J Neuroimmunol 23: 109–116.

    Article  CAS  PubMed  Google Scholar 

  • Gallo P, Sivieri S, Rinaldi L, Yan XB, Lolli F, De Rossi A, Tavolato B (1994). Intrathecal synthesis of interleukin-10 (IL-10) in viral and inflammatory diseases of the central nervous system. J Neurol Sci 126: 49–53.

    Article  CAS  PubMed  Google Scholar 

  • Garin A, Tarantino N, Faure S, Daoudi M, Lecureuil C, Bourdais A, Debre P, Deterre P, Combadiere C (2003). Two novel fully functional isoforms of CX3CR1 are potent HIV coreceptors. J Immunol 171: 5305–5312.

    CAS  PubMed  Google Scholar 

  • Hammer SM, Saag MS, Schechter M, Montaner JS, Schooley RT, Jacobsen DM, Thompson MA, Carpenter CC, Fischl MA, Gazzard BG, Gatell JM, Hirsch MS, Katzenstein DA, Richman DD, Vella S, Yeni PG, Volberding PA (2006). Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel. JAMA 296: 827–843.

    Article  CAS  PubMed  Google Scholar 

  • Heeney JL, Plotkin SA (2006). Immunological correlates of protection from HIV infection and disease. Nat Immunol 7: 1281–1284.

    Article  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.

    Article  CAS  PubMed  Google Scholar 

  • Killebrew DA, Troelstrup D, Valcour V, Williams A, Aguon J, Sapalo D, Shikuma C, Ratto-Kim S, Shiramizu B (2005). Discordant plasma and cerebral spinal fluid cytokines/chemokines in relation to HIV-1-associated dementia. Cell Mol Biol (Noisy-le-grand) 51(Suppl): OL745-OL754.

    CAS  Google Scholar 

  • Lane BR, Strieter RM, Coffey MJ, Markovitz DM (2001). Human immunodeficiency virus type 1 (HIV-1)-induced GRO-alpha production stimulates HIV-1 replication in macrophages and T lymphocytes. J Virol 75: 5812–5822.

    Article  CAS  PubMed  Google Scholar 

  • Lojek E, Bornstein RA (2005). The stability of neurocognitive patterns in HIV infected men: classification considerations. J Clin Exp Neuropsychol 27: 665–682.

    Article  PubMed  Google Scholar 

  • Malaspina A, Moir S, Ho J, Wang W, Howell ML, O’Shea MA, Roby GA, Rehm CA, Mican JM, Chun TW, Fauci AS (2006). Appearance of immature/transitional B cells in HIV-infected individuals with advanced disease: correlation with increased IL-7. Proc Natl Acad Sci U S A 103: 2262–227.

    Article  CAS  PubMed  Google Scholar 

  • Marchetti G, Gori A, Casabianca A, Magnani M, Franzetti F, Clerici M, Perno CF, Monforte A, Galli M, Meroni L (2006). Comparative analysis of T-cell turnover and homeostatic parameters in HIV-infected patients with discordant immune-virological responses to HAART. AIDS 20: 1727–1736.

    Article  PubMed  Google Scholar 

  • McArthur JC (2004). HIV dementia: an evolving disease. J Neuroimmunol 157: 3–10.

    Article  CAS  PubMed  Google Scholar 

  • McArthur JC, Brew BJ, Nath A (2005). Neurological complications of HIV infection. Lancet Neurol 4: 543–555.

    Article  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 NeuroVirol 9: 205–221.

    CAS  PubMed  Google Scholar 

  • Navia BA, Rostasy K (2005). The AIDS dementia complex: clinical and basic neuroscience with implications for novel molecular therapies. Neurotox Res 8: 3–24.

    Article  CAS  PubMed  Google Scholar 

  • Nielsen UB, Geierstanger BH (2004). Multiplexed sandwich assays in microarray format. J Immunol Methods 290: 107–120.

    Article  CAS  PubMed  Google Scholar 

  • Nolting T, Arendt G (2008). Cytokine findings in the CSF of HIV-positive patients. Future HIV Therapy 2: 59–67.

    Article  CAS  Google Scholar 

  • Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW (2006). A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354: 899–910.

    Article  CAS  PubMed  Google Scholar 

  • Romagnani S (2006). Regulation of the T cell response. Clin Exp Allergy 36: 1357–1366.

    Article  CAS  PubMed  Google Scholar 

  • Rouse BT, Sarangi PP, Suvas S (2006). Regulatory T cells in virus infections. Immunol Rev 212: 272–286.

    Article  CAS  PubMed  Google Scholar 

  • Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, Lublin FD, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA, Sandrock AW (2006). Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 354: 911–923.

    Article  CAS  PubMed  Google Scholar 

  • Schutzer SE, Brunner M, Fillit HM, Berger JR (2003). Autoimmune markers in HIV-associated dementia. J Neuroimmunol 138: 156–161.

    Article  CAS  PubMed  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.

    CAS  PubMed  Google Scholar 

  • Valcour V, Shikuma C, Shiramizu B, Watters M, Poff P, Selnes O, Holck P, Grove J, Sacktor N (2004). Higher frequency of dementia in older HIV-1 individuals: the Hawaii Aging with HIV-1 Cohort. Neurology 63: 822–827.

    CAS  PubMed  Google Scholar 

  • Villard J, Dayer-Pastore F, Hamacher J, Aubert JD, Schlegel-Haueter S, Nicod LP (1995). GRO alpha and interleukin-8 in Pneumocystis carinii or bacterial pneumonia and adult respiratory distress syndrome. Am J Respir Crit Care Med 152: 1549–1554.

    CAS  PubMed  Google Scholar 

  • Wahl SM, Allen JB, McCartney-Francis N, Morganti-Kossmann MC, Kossmann T, Ellingsworth L, Mai UE, Mergenhagen SE, Orenstein JM (1991). Macrophage- and astrocyte-derived transforming growth factor beta as a mediator of central nervous system dysfunction in acquired immune deficiency syndrome. J Exp Med 173: 981–991.

    Article  CAS  PubMed  Google Scholar 

  • Yonekawa K, Harlan JM (2005). Targeting leukocyte integrins in human diseases. J Leukoc Biol 77: 129–140.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Thorsten Nolting.

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This work was the supported by the German “Bundesministerium fuer Bildung und Forschung” (Federal Ministry of Education and Research; BMBF); grant 01KI0211.

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Nolting, T., Lindecke, A., Koutsilieri, E. et al. Measurement of soluble inflammatory mediators in cerebrospinal fluid of human immunodeficiency virus-positive patients at distinct stages of infection by solid-phase protein array. Journal of NeuroVirology 15, 390–400 (2009). https://doi.org/10.3109/13550280903350192

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  • DOI: https://doi.org/10.3109/13550280903350192

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