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Expression of Inflammatory Cytokines and Inducible Nitric Oxide Synthase in Brains of SIV-Infected Rhesus Monkeys: Applications to HIV-Induced Central Nervous System Disease

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Abstract

Background

Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) can lead to severe impairments in cognition, behavior, and motor skills. The mechanism(s) by which HIV-1 induces CNS disease are not well understood. Recent evidence suggests that expression of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) may contribute to HIV-1-induced neurologic disease. We sought to determine if these factors were present in the CNS of rhesus monkeys with simian immunodeficiency virus (SIV)-induced CNS disease.

Materials and Methods

Total NO production in cerebral spinal fluid (CSF) from infected monkeys was determined by measuring nitrite (NO2−) and nitrate (NO3−) (stable NO degradation products) utilizing Greiss reagents. In situ hybridization revealed iNOS, interferon-γ (IFNγ), and interleukin 1β (IL-1β) mRNA in the brains of SIV-infected monkeys. Microglia were isolated from animals infected with SIV. Following stimulation with LPS, induction of iNOS mRNA in isolated microglia was analyzed by reverse transcriptase-polymerase chain reaction.

Results

Serial CSF samples from an SIV-infected monkey reveal increased levels of NO2−/NO3−. In situ hybridization demonstrated iNOS, IFNγ, and DL-1β mRNAs in post-mortem brain tissue of SIV-infected monkeys. Furthermore, stimulated microglia from an SIV-infected monkey could produce iNOS mRNA.

Conclusions

The presence of iNOS in the brain and NO2−/NO3− in the CSF indicates that NO is produced in the CNS of SIV-infected monkeys. The data suggest that iNOS and NO may be contributing to SIV-induced CNS disease.

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References

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

    Article  CAS  Google Scholar 

  2. Rao C, Anzil AP, Sher JH. (1993) The neuropathology of AIDS: A review. Adv. Neuwimm. 3: 1–15.

    Article  CAS  Google Scholar 

  3. Sharer L. (1992) Pathology of HIV-1 infection of the central nervous system: A review. J. Neuropath. Exp. Neurol. 51: 3–11.

    Article  CAS  Google Scholar 

  4. Desrosiers R. (1990) The simian immunodeficiency viruses. Annu. Rev. Immunol. 8: 557–578.

    Article  CAS  Google Scholar 

  5. Kestler H, Kodama T, Ringler D, et al. (1990) Induction of AIDS in rhesus monkeys by molecularly cloned simian immunodeficiency virus. Science 248: 1109–1112.

    Article  CAS  Google Scholar 

  6. Hurtrel B, Chakrabarti L, Hurtrel M, Maire M, Dormont D, Montagnier L. (1991) Early SIV encephalopathy. J. Med. Primatol. 20: 159–166.

    CAS  PubMed  Google Scholar 

  7. Sharer L, Baskin G, Cho E, Murphey-Corb M, Blumberg B, Epstein L. (1988) Comparison of simian immunodeficiency virus and human immunodeficiency virus encephalitides in the immature host. Ann. Neurol 23: S108–S112.

    Article  Google Scholar 

  8. Kindt T, Hirsch V, Johnson P, Sawasdikosol S. (1992) Animal models for acquired immunodeficiency syndrome. Adv. Immunol. 52: 425–473.

    Article  CAS  Google Scholar 

  9. Brinkmann R, Schwinn A, Muller J, et al. (1993) In vitro and in vivo infection of Rhesus monkey microglial cells by simian immunodeficiency virus. Virology 195: 561–568.

    Article  CAS  Google Scholar 

  10. Brinkmann R, Schwinn A, Narayan O, et al. (1992) Human immunodeficiency virus infection in microglia: Correlation between cells infected in the brain and cells cultured from infectious brain tissue. Ann. Neurol. 31: 361–365.

    Article  CAS  Google Scholar 

  11. Hurtrel B, Chakrabarti L, Hurtrel M, Montagnier L. (1993) Target cells during early SIV encephalopathy. Res. Virol. 144: 41–46.

    Article  CAS  Google Scholar 

  12. Lackner AA, Smith MO, Munn RJ, et al. (1991) Localization of simian immunodeficiency virus in the central nervous system of rhesus monkeys. Am. J. Pathol. 139: 609–619.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. O’Brien WA. (1994) Genetic and biologic basis of HIV-1 neurotropism. In: Price RW, Perry SW (eds). HIV AIDS and the Brain. Raven Press, New York pp. 47–69.

    Google Scholar 

  14. Benos D, Hahn B, Bubien J, et al. (1994) Envelope glycoprotein gp120 of human immunodeficiency virus type 1 alters ion transport in astrocytes: Implications for AIDS dementia complex. Proc. Natl. Acad. Sci. USA 91: 494–498.

    Article  CAS  Google Scholar 

  15. Dawson V, Dawson T, Uhl G, Snyder S. (1993) Human immunodeficiency virus type 1 coat protein neurotoxicity mediated by nitric oxide in primary cortical cultures. Proc. Natl. Acad. Sci. USA 90: 3256–3259.

    Article  CAS  Google Scholar 

  16. Genis P, Jett M, Bernton EW, et al. (1992) Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)-infected macrophage-astroglia interactions: Implications for the neuropathogenesis of HIV disease. J. Exp. Med. 176: 1703–1718.

    Article  CAS  Google Scholar 

  17. Merrill J, Chen I. (1991) HIV-1, macrophages, glial cells, and cytokines in AIDS nervous system disease. FASEB J. 5: 2391–2397.

    Article  CAS  Google Scholar 

  18. Poli G, Fauci A. (1992) The role of monocyte/macrophages and cytokines in the pathogenesis of HIV infection. Pathobiology 60: 246–251.

    Article  CAS  Google Scholar 

  19. Heyes M, Rubinow D, Lane C, Markey S. (1989) Cerebrospinal fluid quinolinic acid concentrations are increased in acquired immune deficiency syndrome. Ann. Neurol. 26: 275–277.

    Article  CAS  Google Scholar 

  20. Heyes M, Saito K, Crowley J, et al. (1992) Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. Brain 115: 1249–1273.

    Article  Google Scholar 

  21. Marietta MA, Yoon PS, Iyengar R, Leaf CD, Wishnok JS. (1988) Macrophage oxidation of L-arginine to nitrite and nitrate: Nitric oxide is an intermediate. Biochemistry 27: 8706–8711.

    Article  Google Scholar 

  22. Nathan C, Xie Q. (1994) Nitric oxide synthases: Roles, tolls, and controls. Cell 78: 915–918.

    Article  CAS  Google Scholar 

  23. Zhang J, Dawson VL, Dawson TM, Snyder SH. (1994) Nitric oxide activation of poly-(ADP-ribose) synthetase in neurotoxicity. Science 263: 687–689.

    Article  CAS  Google Scholar 

  24. Nathan CF, Hibbs JB. (1991) Role of nitric oxide synthase in macrophage antimicrobial activity. Curr. Opin. Immunol. 3: 65–70.

    Article  CAS  Google Scholar 

  25. Lancaster JR, Hibbs JB. (1990) EPR demonstration of iron-nitrosyl complex formation by cytotoxic activated macrophages. Proc. Natl. Acad. Sci. USA 87: 1223–1227.

    Article  CAS  Google Scholar 

  26. Sarih M, Souvannavong V, Adam A. (1993) Nitric oxide synthase induces macrophage death by apoptosis. Biochem. Biophys. Res. Commun. 191: 503–508.

    Article  CAS  Google Scholar 

  27. Beckman JS. (1991) The double-edged role of nitric oxide in brain function and superoxidemediated injury. J. Dev. Physiol 15: 53–59.

    CAS  PubMed  Google Scholar 

  28. Beckman JS, Ye YZ, Anderson PG, et al. (1994) Extensive nitration of protein tyrosines in human atherosclerosis detected by immunohistochemistry. Biol. Chem. Hoppe-Seyler 375: 81–88.

    Article  Google Scholar 

  29. Bo L, Dawson TM, Wesselingh S, et al. (1994) Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains. Ann. Neurol. 36: 778–786.

    Article  CAS  Google Scholar 

  30. Bukrinsky MI, Nottet HSLM, Schmidtmayerova H, et al. (1995) Regulation of nitric oxide synthase activity in human immunodeficiency virus type 1 (HIV-1)-infected monocytes: Implications for HIV-associated neurological disease. J. Exp. Med. 181: 735–745.

    Article  CAS  Google Scholar 

  31. Morgan MJ, Kimes AS, London ED. (1991) Possible roles for nitric oxide in AIDS and associated pathology. Med. Hypoth. 38: 189–193.

    Article  Google Scholar 

  32. Watry DD, Lane TE, Streb M, Fox HS. (1995) Transfer of neuropathogenic SIV with naturally infected microglia. Am. J. Pathol. 146: 914–923.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Sambrook J. (1989) In: Fritsch EF, Maniatis T (eds). Molecular Cloning: A Laboratory Manual. 2nd Ed. Cold Spring Harbor Press: Cold Spring Harbor, NY pp. 7.3–7.25.

  34. Griffin DE, McArthur JC, Cornblath DR. (1991) Neopterin and interferon-gamma in serum and cerebrospinal fluid of patients with HIV-associated neurologic disease. Neurology 41: 69–74.

    Article  CAS  Google Scholar 

  35. Grimaldi LME, Martino GV, Franciotta DM, et al. (1991) Elevated alpha-tumor necrosis factor levels in spinal fluid from HIV-1-infected patients with central nervous system involvement. Ann. Neurol. 29: 21–25.

    Article  CAS  Google Scholar 

  36. Visser JJ, Scholten RJPM, Hoekman K. (1994) Nitric oxide synthesis in meningococcal meningitis. Ann. Intern. Med. 120: 345–346.

    Article  CAS  Google Scholar 

  37. Milstien S, Sakai N, Brew BJ, et al. (1994) Cerebrospinal fluid nitrite/nitrate levels in neurologic diseases. J. Neurochem. 63: 1178–1180.

    Article  CAS  Google Scholar 

  38. Asano K, Chee CBE, Gaston B, et al. (1994) Constitutive and inducible nitric oxide synthase gene expression, regulation, and activity in human lung epithelial cells. Proc. Natl. Acad. Sci. USA 91: 10089–10093.

    Article  CAS  Google Scholar 

  39. Geller D, Lowenstein C, Shapiro R, et al. (1993) Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes. Proc. Natl. Acad. Sci. USA 90: 3491–3495.

    Article  CAS  Google Scholar 

  40. Lee SC, Dickson DW, Liu W, Brosnan CF. (1993) Induction of nitric oxide synthase activity in human astrocytes by interleukin-1 beta and interferon-gamma. J. Neuroimmunol. 46: 19–24.

    Article  CAS  Google Scholar 

  41. Reiling N, Ulmer AJ, Duchrow M, Ernst M, Flad HD, Hauschildt S. (1994) Nitric oxide synthase: mRNA expression of different iso-forms in human monocytes/macrophages. Eur. J. Immunol. 24: 1941–1944.

    Article  CAS  Google Scholar 

  42. Pietraforte D, Tritarelli E, Testa U, Minetti M. (1994) gp120 HIV envelope glycoprotein increases the production of nitric oxide in human monocyte-derived macrophages. J. Leukoc. Biol. 55: 175–182.

    Article  CAS  Google Scholar 

  43. Campbell IL, Samimi A, Chiang CS. (1994) Expression of the inducible nitric oxide synthase: Correlation with neuropathology and clinical features in mice with lymphocytic choriomeningitis. J. Immunol. 153: 3622–3629.

    CAS  PubMed  Google Scholar 

  44. Zheng Y, Schafer M, Weihe E, et al. (1993) Severity of neurological signs and degree of inflammatory lesions in the brains of rats with borna disease correlate with the induction of nitric oxide synthase. J. Virol. 67: 5786–5791.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Chakrabarti L, Hurtrel M, Maire M-A, et al. (1991) Early viral replication in the brain of SIV-infected Rhesus monkeys. Am. J. Pathol. 139: 1273–1280.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Merrill JE, Ignarro LJ, Sherman MP, Melinek J, Lane TE. (1993) Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. J. Immunol. 151: 2132–2141.

    CAS  PubMed  Google Scholar 

  47. Peterson PK, Hu S, Anderson WR, Chao CC. (1994) Nitric oxide production and neurotoxicity mediated by activated microglia from human versus mouse brain. J. Infect. Dis. 170: 457–460.

    Article  CAS  Google Scholar 

  48. Lairmore MD, Post AA, Goldsmith CS, Folks TM. (1991) Cytokine enhancement of simian immunodeficiency virus (SIV/mac) from a chronically infected cloned T-cell line (HuT-78). Arch. Virol. 121: 43–53.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  50. von Herrath M, Oldstone MBA, Fox HS. (1995) Simian immunodeficiency virus (SlV)-specific CTL in cerebrospinal fluid and brains of SIV-infected rhesus macaques. J. Immunol. 154: 5582–5589.

    Google Scholar 

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Acknowledgments

We thank Dr. Floyd Bloom for advice and support and Michelle Zandonatti for excellent technical assistance. This is Scripps Research Institute Manuscript Number 9451-NP. This work was supported by NIMH AIDS Center Grant MH 47680 and National Institutes of Health (NIH) Grant AR40981. TEL was supported (in part) by Postdoctoral Fellowship Grant FA 1163A1 from the National Multiple Sclerosis Society and NIH Training Grant MH 19185.

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  1. Department of Neuropharmacology, The Scripps Research Institute, 10666 N. Torrey Pines Road, CVN 8, La Jolla, California, 92037, USA

    Thomas E. Lane, Michael J. Buchmeier, Debbie D. Watry & Howard S. Fox

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  1. Thomas E. Lane
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  2. Michael J. Buchmeier
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Contributed by F. E. Bloom on September 11, 1995.

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Lane, T.E., Buchmeier, M.J., Watry, D.D. et al. 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 (1996). https://doi.org/10.1007/BF03402200

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