Skip to main content

Advertisement

SpringerLink
Log in

Identification of T lymphocytes in simian immunodeficiency virus encephalitis: Distribution of CD8+ T cells in association with central nervous system vessels and virus

  • Published:
Journal of NeuroVirology Aims and scope Submit manuscript

Abstract

T lymphocytes are found within brains infected with human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) where they are a minor, but consistently identified, population. However, little analysis of their phenotypes has been done, and questions concerning whether or not they are viral antigen specific has not been thoroughly examined. We investigated the central nervous system (CNS) of SIV-infected rhesus macaques to identify T-lymphocyte subsets in relation to virus-infected cells and brain microvessels. We have found that a sensitive antigen-retrieval technique greatly enhanced immunohistochemical detection of CD4+ and CD8+ T lymphocytes in control studies. In encephalitic brains of SIV-infected monkeys with acquired immunodeficiency syndrome (AIDS), we found a significant accumulation of CD8+ T lymphocytes but little-to-no accumulation of CD4+ T lymphocytes. CD4+ cells, when detected, were mostly monocyte/macrophages closely associated with CNS vessels. Using a combination of in situ hybridization for SIV RNA, and immunohistochemistry for CD8+ T lymphocytes and/or Glut-1 for endothelial cells on brain microvessels, we found CD8+ T lymphocytes with an angiocentric distribution often adjacent to virus-infected cells. In the CNS of animals with SIV encephalitis, there was a trend of CD8+ T lymphocytes that were not directly juxtaposed with CNS vessels. These data suggest that in brains of SIV-infected monkeys and HIV-infected humans, CD8+ T lymphocytes traffic to and are retained in the CNS in an angiocentric and possibly antigen-specific manner.

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

  • Babbe H, Roers A, Waisman A, Lassmann H, Goebels N, Hohlfeld R, Friese M, Schröder R, Deckert M, Schmidt S, Ravid R, Rajewsky K (2000). Clonal expansions of CD8+ T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J Exp Med 192: 393–404.

    Article  CAS  PubMed  Google Scholar 

  • Bauer J, Rauschka H, Lassmann H (2001). Inflammation in the nervous system: the human perspective. Glia 36: 235–243.

    Article  CAS  PubMed  Google Scholar 

  • Bell JE, Busuttil A, Ironside JW, Rebus S, Donaldson YK, Simmonds P, Peutherer JF (1993). Human immunodeficiency virus and the brain: investigation of virus load and neuropathologic changes in pre-AIDS subjects. J Infect Dis 168: 818–824.

    CAS  PubMed  Google Scholar 

  • Bien CG, Bauer J, Deckwerth TL, Wiendl H, Deckert M, Wiestler OD, Schramm J, Elger CE, Lassmann H (2002). Destruction of neurons by cytotoxic T cells: a new pathogenic mechanism in Rasmussen’s encephalitis. Ann Neurol 51: 311–318.

    Article  CAS  PubMed  Google Scholar 

  • Boche D, Khatissian E, Gray F, Falanga P, Montagnier L, Hurtrel B (1999). Viral load and neuropathology in the SIV model. J NeuroVirol 5: 232–240.

    Article  CAS  PubMed  Google Scholar 

  • Broadwell RD, Charlton HM, Ebert P, Hickey WF, Villegas JC, Wolf AL (1990). Angiogenesis and the blood-brain barrier in solid and dissociated cell grafts within the CNS. Prog Brain Res 82: 95–101.

    Article  CAS  PubMed  Google Scholar 

  • Chakrabarti L, Hurtrel M, Maire MA, Vazeux R, Dormont D, Montagnier L, Hurtrel B (1991). Early viral replication in the brain of SIV-infected rhesus monkeys. Am J Pathol 139: 1273–1280.

    CAS  PubMed  Google Scholar 

  • Desrosiers RC, Hansen-Moosa A, Mori K, Bouvier DP, King NW, Daniel MD, Ringler DJ (1991). Macrophage-tropic variants of SIV are associated with specific AIDS-related lesions but are not essential for the development of AIDS. Am J Pathol 139: 29–35.

    CAS  PubMed  Google Scholar 

  • Fischer-Smith T, Croul S, Sverstiuk AE, Capini C, L’Heureux D, Regulier EG, Richardson MW, Amini S, Morgello S, Khalili K, Rappaport J (2001). CNS invasion by CD14+/CD16+ peripheral blood-derived monocytes in HIV dementia: perivascular accumulation and reservoir of HIV infection. J NeuroVirol 7: 528–541.

    Article  CAS  PubMed  Google Scholar 

  • Gartner S (2000). HIV infection and dementia. Science 287: 602–604.

    Article  CAS  PubMed  Google Scholar 

  • Griffin DE, Levine B, Tyor WR, Irani DN (1992). The immune response in viral encephalitis. Sem Immunol 4: 111–119.

    CAS  Google Scholar 

  • Hickey WF (1991). Migration of hematogenous cells through the blood-brain barrier and the initiation of CNS inflammation. Brain Pathol 1: 97–105.

    Article  CAS  PubMed  Google Scholar 

  • Hirsch VM, Adger-Johnson D, Campbell B, Goldstein S, Brown C, Elkins WR, Montefiori DC (1997). A molecularly cloned, pathogenic, neutralization-resistant simian immunodeficiency virus, SIVsmE543-3. J Virol 71: 1608–1620.

    CAS  PubMed  Google Scholar 

  • Hu J, Pope M, Brown C, O’Doherty U, Miller CJ (1998). Immunophenotypic characterization of simian immunodeficiency virus-infected dendritic cells in cervix, vagina, and draining lymph nodes of rhesus monkeys. Lab Invest 78: 435–451.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Iwasaki Y, Sako K, Tsunoda I, Ohara Y (1993). Phenotypes of mononuclear cell infiltrates in human central nervous system. Acta Neuropathol (Berl) 85: 653–657.

    Article  CAS  Google Scholar 

  • Jassoy C, Johnson RP, Navia BA, Worth J, Walker BD (1992). Detection of a vigorous HIV-1-specific cytotoxic T lymphocyte response in cerebrospinal fluid from infected persons with AIDS dementia complex. J Immunol 149: 3113–3119.

    CAS  PubMed  Google Scholar 

  • Katsetos CD, Fincke JE, Legido A, Lischner HW, de Chadarevian JP, Kaye EM, Platsoucas CD, Oleszak EL (1999). Angiocentric CD3+ T-cell infiltrates in human immunodeficiency virus type 1-associated central nervous system disease in children. Clin Diagn Lab Immunol 6: 105–114.

    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.

    Article  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 AIDS. J Virol 67: 6522–6534.

    CAS  PubMed  Google Scholar 

  • Lackner AA (1994). Pathology of simian immunodeficiency virus induced disease. Curr Top Microbiol Immunol 188: 35–64.

    CAS  PubMed  Google Scholar 

  • Lackner AA, Smith MO, Munn RJ, Martfeld DJ, Gardner MB, Marx PA, Dandekar S (1991). Localization of simian immunodeficiency virus in the central nervous system of rhesus monkeys. Am J Pathol 139: 609–621.

    CAS  PubMed  Google Scholar 

  • Lane JH, Sasseville VG, Smith MO, Vogel P, Pauley DR, Heyes MP, Lackner AA (1996). Neuroinvasion by simian immunodeficiency virus coincides with increased numbers of perivascular macrophages/microglia and intrathecal immune activation. J NeuroVirol 2: 423–432.

    Article  CAS  PubMed  Google Scholar 

  • Lellouch-Tubiana A, Fohlen M, Robain O, Rozenberg F (2000). Immunocytochemical characterization of long-term persistent immune activation in human brain after herpes simplex encephalitis. Neuropathol Appl Neurobiol 26: 285–294.

    Article  CAS  PubMed  Google Scholar 

  • Li SL, Kaaya EE, Feichtinger H, Putkonen P, Parravicini C, Bottiger D, Biberfeld G, Biberfeld P (1991). Monocyte/macrophage giant cell disease in SIV-infected cynomolgus monkeys. Res Virol 142: 173–182.

    Article  CAS  PubMed  Google Scholar 

  • Mankowski JL, Clements JE, Zink MC (2002a). Searching for clues: tracking the pathogenesis of human immunodeficiency virus central nervous system disease by use of an accelerated, consistent simian immunodeficiency virus macaque model. J Infect Dis 186(Suppl 2): S199-S208.

    Article  PubMed  Google Scholar 

  • Mankowski JL, Queen SE, Tarwater PM, Fox KJ, Perry VH (2002b). Accumulation of beta-amyloid precursor protein in axons correlates with CNS expression of SIV gp41. J Neuropathol Exp Neurol 61: 85–90.

    CAS  PubMed  Google Scholar 

  • Marcondes MC, Phillipson CA, Fox HS (2003). Distinct clonal repertoire of brain CD8+ cells in simian immunodeficiency virus infection. AIDS 17: 1605–1611.

    Article  CAS  PubMed  Google Scholar 

  • Mason DY, Cordell JL, Gaulard P, Tse AGD, Brown MH (1992). Immunohistological detection of human cytotoxic/suppressor T cells using antibodies to a CD8 peptide sequence. J Clin Pathol 45: 1084–1088.

    Article  CAS  PubMed  Google Scholar 

  • Miller RF, Isaacson PG, Hall-Craggs M, Lucas S, Gray F, Scaravilli F, An SF (2004). Cerebral CD8+ lymphocytosis in HIV-1 infected patients with immune restoration induced by HAART. Acta Neuropathol (Berl) 108: 17–23.

    Article  Google Scholar 

  • Parravicini CL, Petrén AL, Vago L, Costanzi G, Gluckman JC, Gallo RC, Biberfeld P (1989). HIV encephalopathy and lymphadenopathy: cells associated with viral antigens. APMIS Suppl 8: 33–39.

    CAS  PubMed  Google Scholar 

  • Petito CK, Adkins B, McCarthy M, Roberts B, Khamis I (2003). CD4+ and CD8+ cells accumulate in the brains of acquired immunodeficiency syndrome patients with human immunodeficiency virus encephalitis. J NeuroVirol 9: 36–44.

    CAS  PubMed  Google Scholar 

  • Peudenier S, Hery C, Ng KH, Tardieu M (1991). HIV receptors within the brain: a study of CD4 and MHC-II on human neurons, astrocytes and microglial cells. Res Virol 142: 145–149.

    Article  CAS  PubMed  Google Scholar 

  • Porwit A, Parravicini C, Petren AL, Barkhem T, Costanzi G, Josephs S, Biberfeld P (1989). Cell association of HIV in AIDS-related encephalopathy and dementia. APMIS 97: 79–90.

    Article  CAS  PubMed  Google Scholar 

  • Pumarola-Sune T, Navia BA, Cordon-Cardo C, Cho ES, Price RW (1987). HIV antigen in the brains of patients with the AIDS dementia complex. Ann Neurol 21: 490–496.

    Article  CAS  PubMed  Google Scholar 

  • Reinhart TA, Rogan MJ, Huddleston D, Rausch DM, Eiden LE, Haase AT (1997). Simian immunodeficiency virus burden in tissues and cellular compartments during clinical latency and AIDS. J Infect Dis 176: 1198–1208.

    Article  CAS  PubMed  Google Scholar 

  • Sethi KK, Naher H, Stroehmann I (1988). Phenotypic heterogeneity of cerebrospinal fluid-derived HIV-specific and HLA-restricted cytotoxic T-cell clones. Nature 335: 178–181.

    Article  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 

  • Streilein JW (1995). Unraveling immune privilege. Science 270: 1158–1159.

    Article  CAS  PubMed  Google Scholar 

  • Togo T, Akiyama H, Iseki E, Kondo H, Ikeda K, Kato M, Oda T, Tsuchiya K, Kosaka K (2002). Occurrence of T cells in the brain of Alzheimer’s disease and other neurological diseases. J Neuroimmunol 124: 83–92.

    Article  CAS  PubMed  Google Scholar 

  • Tyor WR, Glass JD, Griffin JW, Becker PS, McArthur JC, Bezman L, Griffin DE (1992). Cytokine expression in the brain during the acquired immunodeficiency syndrome. Ann Neurol 31: 349–360.

    Article  CAS  PubMed  Google Scholar 

  • Vazeux R, Brousse N, Jarry A, Henin D, Marche C, Vedrenne C, Mikol J, Wolff M, Michon C, Rozenbaum W, Bureau JF, Montagnier L, Brahic M (1987). AIDS subacute encephalitis. Identification of HIV-infected cells. Am J Pathol 126: 403–410.

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  • Wang TH, Donaldson YK, Brettle RP, Bell JE, Simmonds P (2001). Identification of shared populations of human immunodeficiency virus type 1 infecting microglia and tissue macrophages outside the central nervous system. J Virol 75: 11686–11699.

    Article  CAS  PubMed  Google Scholar 

  • Weidenheim KM, Epshteyn I, Lyman WD (1993). Immunocytochemical identification of T-cells in HIV-1 encephalitis: implications for pathogenesis of CNS disease. Mod Pathol 6: 167–174.

    CAS  PubMed  Google Scholar 

  • Williams K, Hickey WF (1995). Traffic of lymphocytes into the CNS during inflammation and HIV infection. J Neuro-Aids 1: 31–55.

    Article  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.

    Article  CAS  PubMed  Google Scholar 

  • Williamson SLH, Steward M, Milton I, Parr A, Piggott NH, Krajewski AS, Angus B, Horne CHW (1998). New monoclonal antibodies to the T cell antigens CD4 and CD8. Production and characterization in formalin-fixed paraffin-embedded tissue. Am J Pathol 152: 1421–1426.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Viral Pathogenesis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Woong-Ki Kim, Sarah Corey, Gillian Chesney, Christian Wüthrich, Norman L. Letvin, Igor J. Koralnik & Kenneth Williams

  2. Division of Viral Pathogenesis, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Igor J. Koralnik

  3. Department of Comparative Pathology, Harvard Medical School, New England Regional Primate Research Center, Southborough, Massachusetts, USA

    Heather Knight & Sherry Klumpp

  4. Tulane Regional Primate Research Center, Tulane University Health Sciences Center, Covington, Louisiana, USA

    Andrew Lackner & Ronald S. Veasey

Authors
  1. Woong-Ki Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sarah Corey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gillian Chesney
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Heather Knight
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sherry Klumpp
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christian Wüthrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Norman L. Letvin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Igor J. Koralnik
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Andrew Lackner
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ronald S. Veasey
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kenneth Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenneth Williams.

Additional information

This work was supported by Public Health Service grants AI49080 (R.S.V.), NS37654 (K.W.), NS40237 (K.W.), NS04709 (I.J.K.), NS/AI O 41198 (I.J.K.), NS35732 (A.A.L.), RR07000 (A.A.L.), and RR00168 (A.A.L.).

Andrew Lackner is a recipient of an Elizabeth Glaser Scientist Award.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, WK., Corey, S., Chesney, G. et al. Identification of T lymphocytes in simian immunodeficiency virus encephalitis: Distribution of CD8+ T cells in association with central nervous system vessels and virus. Journal of NeuroVirology 10, 315–325 (2004). https://doi.org/10.1080/13550280490505382

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1080/13550280490505382

Keywords

Search

Navigation