Acta Neuropathologica

, Volume 111, Issue 6, pp 529–538 | Cite as

Accelerated Tau deposition in the brains of individuals infected with human immunodeficiency virus-1 before and after the advent of highly active anti-retroviral therapy

  • Iain C. Anthony
  • Stephen N. Ramage
  • Frances W. Carnie
  • Peter Simmonds
  • Jeanne E. Bell
Original Paper


This study aims to investigate the influence of human immunodeficiency virus (HIV) infection on the neurodegenerative processes normally associated with ageing. We have looked for evidence of beta amyloid and hyperphosphorylated Tau deposition in HIV-infected subjects before and after the advent of highly active anti-retroviral therapy (HAART). In addition we have looked for evidence of axonal damage. We have compared these HIV-positive cases with age-matched controls and with older non-demented controls. We find no evidence of significant premature beta amyloid deposition in HIV-infected cases; however, we do observe elevated levels of hyperphosphorylated Tau in the hippocampus of many HIV-infected subjects, compared with age-matched controls. The greatest levels of hyperphosphorylated Tau are noted in HAART-treated subjects. Axonal damage marked by expression of beta amyloid pre-cursor protein (BAPP) was highly variable in all groups including control subjects. We surmise that HIV infection and/or the use of anti-retroviral therapy may predispose to accelerated neuroageing in the form of hyperphosphorylated Tau deposition in the hippocampus. Within the age groups studied these significant neuropathological changes remained subclinical and were not yet associated with cognitive impairment.


HIV HAART Neurodegeneration Hyperphosphorylated Tau Brain 



This work was supported by NIH grants R01-13840, R01-13127, SHERT grant F6/05 and MRC grant 9708080. We would like to thank Mr. Alan Wilson for his help in retrieving archived case information.


  1. 1.
    Anthony IC, Ramage SN, Carnie FW, Simmonds P, Bell JE (2005) Influence of HAART on HIV-related CNS disease and neuroinflammation. J Neuropathol Exp Neurol 64:529–536PubMedGoogle Scholar
  2. 2.
    Bancher C, Brunner C, Lassmann H, Budka H, Jellinger K, Wiche G, Seitelberger F, Grundke-Iqbal I, Iqbal K, Wisniewski HM (1989) Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer’s disease. Brain Res 477:90–99CrossRefPubMedGoogle Scholar
  3. 3.
    Band GP, Ridderinkhof KR, Segalowitz S (2002) Explaining neurocognitive aging: is one factor enough? Brain Cogn 49:259–267CrossRefPubMedGoogle Scholar
  4. 4.
    Bell JE (1998) The neuropathology of adult HIV infection. Rev Neurol (Paris) 154:816–829Google Scholar
  5. 5.
    Bell JE, Donaldson YK, Lowrie S, McKenzie CA, Elton RA, Chiswick A, Brettle RP, Ironside JW, Simmonds P (1996) Influence of risk group and zidovudine therapy on the development of HIV encephalitis and cognitive impairment in AIDS patients. AIDS 10:493–499PubMedGoogle Scholar
  6. 6.
    Boven LA (2000) Macrophages and HIV-1-associated dementia. Arch Immunol Ther Exp (Warsz) 48:273–279Google Scholar
  7. 7.
    Boven LA, Middel J, Verhoef J, De Groot CJ, Nottet HS (2000) Monocyte infiltration is highly associated with loss of the tight junction protein zonula occludens in HIV-1-associated dementia. Neuropathol Appl Neurobiol 26:356–360CrossRefPubMedGoogle Scholar
  8. 8.
    Braak H, Braak E (1997) Diagnostic criteria for neuropathologic assessment of Alzheimer’s disease. Neurobiol Aging 18:S85–S88CrossRefPubMedGoogle Scholar
  9. 9.
    Braak H, Braak E (1997) Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 18:351–357CrossRefPubMedGoogle Scholar
  10. 10.
    Brew BJ (2004) Evidence for a change in AIDS dementia complex in the era of highly active antiretroviral therapy and the possibility of new forms of AIDS dementia complex. AIDS 18(Suppl 1):S75–S8CrossRefPubMedGoogle Scholar
  11. 11.
    Buee Scherrer V, Hof PR, Buee L, Leveugle B, Vermersch P, Perl DP, Olanow CW, Delacourte A (1996) Hyperphosphorylated tau proteins differentiate corticobasal degeneration and Pick’s disease. Acta Neuropathol (Berl) 91:351–359CrossRefGoogle Scholar
  12. 12.
    Cohen RA, Boland R, Paul R, Tashima KT, Schoenbaum EE, Celentano DD, Schuman P, Smith DK, Carpenter CC (2001) Neurocognitive performance enhanced by highly active antiretroviral therapy in HIV-infected women. AIDS 15:341–345CrossRefPubMedGoogle Scholar
  13. 13.
    Cysique LA, Maruff P, Brew BJ (2004) Antiretroviral therapy in HIV infection: are neurologically active drugs important? Arch Neurol 61:1699–1704CrossRefPubMedGoogle Scholar
  14. 14.
    Delacourte A, Sergeant N, Wattez A, Maurage CA, Lebert F, Pasquier F, David JP (2002) Tau aggregation in the hippocampal formation: an ageing or a pathological process? Exp Gerontol 37:1291–1296CrossRefPubMedGoogle Scholar
  15. 15.
    Dore GJ, Correll PK, Li Y, Kaldor JM, Cooper DA, Brew BJ (1999) Changes to AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS 13:1249–1253CrossRefPubMedGoogle Scholar
  16. 16.
    Dore GJ, McDonald A, Li Y, Kaldor JM, Brew BJ (2003) Marked improvement in survival following AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS 17:1539–1545CrossRefPubMedGoogle Scholar
  17. 17.
    D’Souza I, Poorkaj P, Hong M, Nochlin D, Lee VM, Bird TD, Schellenberg GD (1999) Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc Natl Acad Sci USA 96:5598–5603CrossRefPubMedGoogle Scholar
  18. 18.
    Esiri MM, Biddolph SC, Morris CS (1998) Prevalence of Alzheimer plaques in AIDS. J Neurol Neurosurg Psychiatry 65:29–33PubMedCrossRefGoogle Scholar
  19. 19.
    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 7:528–541CrossRefPubMedGoogle Scholar
  20. 20.
    Forton DM, Allsop JM, Main J, Foster GR, Thomas HC, Taylor-Robinson SD (2001) Evidence for a cerebral effect of the hepatitis C virus. Lancet 358:38–39CrossRefPubMedGoogle Scholar
  21. 21.
    Gartner S, Liu Y (2002) Insights into the role of immune activation in HIV neuropathogenesis. J Neurovirol 8:69–75CrossRefPubMedGoogle Scholar
  22. 22.
    Gelman BB, Schuenke K (2004) Brain aging in acquired immunodeficiency syndrome: increased ubiquitin-protein conjugate is correlated with decreased synaptic protein but not amyloid plaque accumulation. J Neurovirol 10:98–108CrossRefPubMedGoogle Scholar
  23. 23.
    Glass JD, Fedor H, Wesselingh SL, McArthur JC (1995) Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlations with dementia. Ann Neurol 38:755–762CrossRefPubMedGoogle Scholar
  24. 24.
    Gray F, Keohane C (2003) The neuropathology of HIV infection in the era of highly active antiretroviral therapy (HAART). Brain Pathol 13:79–83PubMedGoogle Scholar
  25. 25.
    Gray F, Chretien F, Vallat-Decouvelaere AV, Scaravilli F (2003) The changing pattern of HIV neuropathology in the HAART era. J Neuropathol Exp Neurol 62:429–440PubMedGoogle Scholar
  26. 26.
    Green DA, Masliah E, Vinters HV, Beizai P, Moore DJ, Achim CL (2005) Brain deposition of beta-amyloid is a common pathologic feature in HIV positive patients. AIDS 19:407–411CrossRefPubMedGoogle Scholar
  27. 27.
    Kandanearatchi A, Williams B, Everall IP (2003) Assessing the efficacy of highly active antiretroviral therapy in the brain. Brain Pathol 13:104–110PubMedGoogle Scholar
  28. 28.
    McGeer PL, McGeer EG (2002) Local neuroinflammation and the progression of Alzheimer’s disease. J Neurovirol 8:529–538CrossRefPubMedGoogle Scholar
  29. 29.
    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) 108:17–23CrossRefGoogle Scholar
  30. 30.
    Mitchell TW, Mufson EJ, Schneider JA, Cochran EJ, Nissanov J, Han LY, Bienias JL, Lee VM, Trojanowski JQ, Bennett DA, Arnold SE (2002) Parahippocampal tau pathology in healthy aging, mild cognitive impairment, and early Alzheimer’s disease. Ann Neurol 51:182–189CrossRefPubMedGoogle Scholar
  31. 31.
    Nath A, Haughey NJ, Jones M, Anderson C, Bell JE, Geiger JD (2000) Synergistic neurotoxicity by human immunodeficiency virus proteins Tat and gp120: protection by memantine. Ann Neurol 47:186–194CrossRefPubMedGoogle Scholar
  32. 32.
    Navia BA, Cho ES, Petito CK, Price RW (1986) The AIDS dementia complex: II. Neuropathology. Ann Neurol 19:525–535CrossRefPubMedGoogle Scholar
  33. 33.
    Navia BA, Jordan BD, Price RW (1986) The AIDS dementia complex: I. Clinical features. Ann Neurol 19:517–524CrossRefPubMedGoogle Scholar
  34. 34.
    Perry VH (2004) The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease. Brain Behav Immun 18:407–413CrossRefPubMedGoogle Scholar
  35. 35.
    Pollock NJ, Mirra SS, Binder LI, Hansen LA, Wood JG (1986) Filamentous aggregates in Pick’s disease, progressive supranuclear palsy, and Alzheimer’s disease share antigenic determinants with microtubule-associated protein, tau. Lancet 2:1211CrossRefPubMedGoogle Scholar
  36. 36.
    Price RW, Sidtis JJ, Brew BJ (1991) AIDS dementia complex and HIV-1 infection: a view from the clinic. Brain Pathol 1:155–162PubMedCrossRefGoogle Scholar
  37. 37.
    Ramage SN, Anthony IC, Carnie FW, Busuttil A, Robertson R, Bell JE (2005) Hyperphosphorylated tau and amyloid precursor protein deposition is increased in the brains of young drug abusers. Neuropathol Appl Neurobiol 31:439–448CrossRefPubMedGoogle Scholar
  38. 38.
    Robertson KR, Robertson WT, Ford S, Watson D, Fiscus S, Harp AG, Hall CD (2004) Highly active antiretroviral therapy improves neurocognitive functioning. J Acquir Immune Defic Syndr 36:562–566PubMedCrossRefGoogle Scholar
  39. 39.
    Rudelli RD, Ambler MW, Wisniewski HM (1984) Morphology and distribution of Alzheimer neuritic (senile) and amyloid plaques in striatum and diencephalon. Acta Neuropathol (Berl) 64:273–281CrossRefGoogle Scholar
  40. 40.
    Ryan EL, Morgello S, Isaacs K, Naseer M, Gerits P (2004) Neuropsychiatric impact of hepatitis C on advanced HIV. Neurology 62:957–962PubMedGoogle Scholar
  41. 41.
    Sacktor N, McDermott MP, Marder K, Schifitto G, Selnes OA, McArthur JC, Stern Y, Albert S, Palumbo D, Kieburtz K, De Marcaida JA, Cohen B, Epstein L (2002) HIV-associated cognitive impairment before and after the advent of combination therapy. J Neurovirol 8:136–142PubMedGoogle Scholar
  42. 42.
    Sato-Harada R, Okabe S, Umeyama T, Kanai Y, Hirokawa N (1996) Microtubule-associated proteins regulate microtubule function as the track for intracellular membrane organelle transports. Cell Struct Funct 21:283–295PubMedCrossRefGoogle Scholar
  43. 43.
    Tozzi V, Balestra P, Galgani S, Narciso P, Ferri F, Sebastiani G, D’Amato C, Affricano C, Pigorini F, Pau FM, De Felici A, Benedetto A (1999) Positive and sustained effects of highly active antiretroviral therapy on HIV-1-associated neurocognitive impairment. AIDS 13:1889–1897CrossRefPubMedGoogle Scholar
  44. 44.
    Witman GB, Cleveland DW, Weingarten MD, Kirschner MW (1976) Tubulin requires tau for growth onto microtubule initiating sites. Proc Natl Acad Sci USA 73:4070–4074PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Iain C. Anthony
    • 1
  • Stephen N. Ramage
    • 1
  • Frances W. Carnie
    • 1
  • Peter Simmonds
    • 2
  • Jeanne E. Bell
    • 1
  1. 1.Department of Pathology (Neuropathology)University of Edinburgh, Western General HospitalEdinburghUK
  2. 2.Basic & Clinical Virology LaboratoryUniversity of Edinburgh, Royal (Dick) Veterinary SchoolEdinburghUK

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