Journal of NeuroVirology

, Volume 15, Issue 5–6, pp 360–370 | Cite as

Cliniconeuropathologic correlates of human immunodeficiency virus in the era of antiretroviral therapy

  • I. Everall
  • F. Vaida
  • N. Khanlou
  • D. Lazzaretto
  • C. Achim
  • S. Letendre
  • D. Moore
  • R. Ellis
  • M. Cherner
  • B. Gelman
  • S. Morgello
  • E. Singer
  • I. Grant
  • E. Masliah
  • National NeuroAIDS Tissue Consortium (NNTC)
Article

Abstract

The objective of this study was to examine the spectrum of human immunodeficiency virus (HIV) brain pathology and its clinical correlates in the antiretroviral era. We carried out a cross-sectional survey, analyzing prospective clinical and neuropathological data collected by the National NeuroAIDS Tissue Consortium (NNTC), comprising 589 brain samples from individuals with advanced HIV disease collected from 1999 onwards. We assessed gender, ethnicity/race, mode of transmission, age, year of death, nadir CD4, plasma viral load, last antiretroviral regimen, presence of parenchymal HIV brain pathology, HIV-associated neurocognitive disorder, and major depressive disorder. We compared cohort demographic variables with Centers for Disease Control and Prevention US HIV/AIDS statistics and examined associations of parenchymal HIV brain pathology with demographic, clinical, and HIV disease factors. With regard to Centers for Disease Control and Prevention US data, the NNTC was similar in age distribution, but had fewer females and African Americans and more Hispanics and men who have sex with men. Only 22% of the brains examined were neuropathologically normal. Opportunistic infections occurred in 1% to 5% of the cohort. Parenchymal HIV brain pathology was observed in 17.5% of the cohort and was associated with nadir CD4 and plasma viral load. Brains without parenchymal HIV brain pathology often had other noninfectious findings or minimal nondiagnostic abnormalities that were associated with HIV-associated neurocognitive disorder. Clinically, 60% of the cohort reported a lifetime episode of major depressive disorder and 88% had a HIV-associated neurocognitive disorder. No pathological finding correlated with major depressive disorder. Both antiretroviral treatment regimen and elevated plasma HIV viral load were associated with presence of parenchymal HIV brain pathology; however, multivariate analyses suggest a stronger association with plasma viral load. The frequency of HIV brain pathology was lower than previous pre-antiretroviral reports, and was predicted by lower nadir CD4 and higher plasma viral load. Noninfectious pathologies and minimal changes correlated with HIV-associated neurocognitive disorder, suggesting a shift in pathogenesis from florid HIV replication to other, diverse mechanisms.

Keywords

all infections HIV dementia risk factors in epidemiology 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ances B, Ellis RJ (2007). Dementia and Neurocognitive Disorders Due to HIV-1 Infection. Semin Neurol 27: 86–92.CrossRefPubMedGoogle Scholar
  2. Anthony IC, Bell JE (2008). The Neuropathology of HIV/ AIDS. Int Rev Psychiatry 20: 15–24.CrossRefPubMedGoogle Scholar
  3. Arendt GvGH (2002). Antiretroviraltherapy regimes for neuro-AIDS. Curr Drug Targets Infects Disord 2: 187–192.CrossRefGoogle Scholar
  4. Bell JE (2004). An update on the neuropathology of HIV in the HAART era. Histopathology 45: 549–559.CrossRefPubMedGoogle Scholar
  5. Bell JE, Donaldson YK, Lowrie S, et al (1996). Influence of risk group and zidovudine therapy on the development of HIV encephalitis and cognitive impairment in AIDS patients. AIDS 10: 493–499.CrossRefPubMedGoogle Scholar
  6. Bing EG, Burnam MA, Longshore D, Fleishman JA, Sherbourne CD, London AS, Turner BJ, Eggan F, Beckman R, Vitiello B, Morton SC, Orlando M, Bozzette SA, Ortiz-Barron L, Shapiro M (2001). Psychiatric disorders and drug use among human immunodeficiency virus-infected adults in the United States. Arch Gen Psychiatry 58: 721–728.CrossRefPubMedGoogle Scholar
  7. Budka H (1991). Neuropathology of human immunodeficiency virus infection. Brain Pathol 1: 163–175.CrossRefPubMedGoogle Scholar
  8. Budka H, Wiley CA, Kleihues P, Artigas J, Asbury AK, Cho ES, Cornblath DR, Dal Canto MC, DeGirolami U, Dickson D (1991). HIV-associated disease of the nervous system: review of nomenclature and proposal for neuropathology-based terminology. Brain Pathol 1: 143–152.CrossRefPubMedGoogle Scholar
  9. Carey CL, Woods SP, Rippeth JD, Gonzalez R, Moore DJ, Marcotte TD, Grant I, Heaton RK (2004). Initial validation of a screening battery for the detection of HIV-associated cognitive impairment. Clin Neuropsychol 18: 234–248.CrossRefPubMedGoogle Scholar
  10. Cherner M, Masliah E, Ellis RJ, Marcotte TD, Moore DJ, Grant I, Heaton RK (2002). Neurocognitive dysfunction predicts postmortem findings of HIV encephalitis. Neurology 59: 1563–1567.PubMedGoogle Scholar
  11. Centers for Disease Control and Prevention (2007). HIV/ AIDS Surveillance Report, 2005. Atlanta: U.S. Department of Health and Human Services.Google Scholar
  12. Davies J, Everall IP, Weich S, McLaughlin J, Scaravilli F, Lantos PL (1997). HIV-associated brain pathology in the United Kingdom: an epidemiological study. AIDS 11: 1145–1150.CrossRefPubMedGoogle Scholar
  13. Everall IP, Heaton RK, Marcotte TD, Ellis RJ, McCutchan JA, Atkinson JH, Grant I, Mallory M, Masliah E (1999). Cortical synaptic density is reduced in mild to moderate human immunodeficiency virus neurocognitive disorder. HNRC Group. HIV Neurobehavioral Research Center. Brain Pathol 9: 209–217.CrossRefPubMedGoogle Scholar
  14. Everall IP, Luthert PJ, Lantos PL (1991). Neuronal loss in the frontal cortex in HIV infection. Lancet 337: 1119–1121.CrossRefPubMedGoogle Scholar
  15. Everall IP, Salaria S, Atkinson JH, Young C, Corbeil J, Grant I, Masliah E (2006). Diminished somatostatin gene expression in individuals with HIV and major depressive disorder. Neurology 67: 1867–1869.CrossRefPubMedGoogle Scholar
  16. Gibbs JE, Gaffen Z, Thomas SA (2006). Nevirapine uptake into the central nervous system of the Guinea pig: an in situ brain perfusion study. J Pharmacol Exp Ther 317: 746–751.CrossRefPubMedGoogle Scholar
  17. Glass JD, Fedor H, Wesselingh SL, McArthur JC (1995). Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlations with dementia. Ann Neurol 38: 755–762.CrossRefPubMedGoogle Scholar
  18. Grant I (2008). Neurocognitive disturbances in HIV. Int Rev Psychiatry 20: 33–47.CrossRefPubMedGoogle Scholar
  19. Heaton RK, Grant I, Butters N, White DA, Kirson D, Atkinson JH, McCutchan JA, Taylor MJ, Kelly MD, Ellis RJ, et al (1995). The HNRC 500—neuropsychology of HIV infection at different disease stages. HIV Neurobehavioral Research Center. J Int Neuropsychol Soc 1: 231–51.CrossRefPubMedGoogle Scholar
  20. Judd F, Komiti A, Chua P, Mijch A, Hoy J, Grech P, Street A, Lloyd J, Williams B (2005). Nature of depression in patients with HIV/AIDS. Aust N Z J Psychiatry 39: 826–832.PubMedGoogle Scholar
  21. Langford TD, Letendre SL, Larrea GJ, Masliah E (2003). Changing patterns in the neuropathogenesis of HIV during the HAART era. Brain Pathol 13: 195–210.CrossRefPubMedGoogle Scholar
  22. Letendre S, Marquie-Beck J, Capparelli E, Best B, Clifford D, Collier AC, Gelman BB, McArthur JC, McCutchan JA, Morgello S, Simpson D, Grant I, Ellis RJ, for the CHARTER Group (2008). Validation of the CNS Penetration-Effectiveness Rank for Quantifying Antiretroviral Penetration Into the Central Nervous System. Arch Neurol 65: 65–70.CrossRefPubMedGoogle Scholar
  23. Letendre S, Marquie-Beck J, Capparelli E, Best B, Clifford D, Collier AC, Gelman BB, McArthur JC, McCutchan JA, Morgello S, Simpson D, Grant I, Ellis RJ (2008). Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol 65: 65–70.CrossRefPubMedGoogle Scholar
  24. Masliah E, DeTeresa RM, Mallory ME, Hansen LA (2000). Changes in pathological findings at autopsy in AIDS cases for the last 15 years. AIDS 14: 69–74.CrossRefPubMedGoogle Scholar
  25. Masliah E, Heaton RK, Marcotte TD, Ellis RJ, Wiley CA, Mallory M, Achim CL, McCutchan JA, Nelson JA, Atkinson JH, Grant I (1997). Dendritic injury is a pathological substrate for human immunodeficiency virus-related cognitive disorders. Ann Neurol 42: 963–972.CrossRefPubMedGoogle Scholar
  26. Moore DJ, Masliah E, Rippeth JD, Gonzalez R, Carey CL, Cherner M, Ellis RJ, Achim CL, Marcotte TD, Heaton RK, Grant I (2006). Cortical and subcortical neurodegeneration is associated with HIV neurocognitive impairment. AIDS 20: 879–887.CrossRefPubMedGoogle Scholar
  27. Morgello S, Gelman BB, Kozlowski PB, Vinters HV, Masliah E, Cornford M, Cavert W, Marra C, Grant I, Singer EJ (2001). The National NeuroAIDS Tissue Consortium: a new paradigm in brain banking with an emphasis on infectious disease. Neuropathol Appl Neurobiol 27: 326–335.CrossRefPubMedGoogle Scholar
  28. Morgello S, Holzer CE 3rd, Ryan E, Young C, Naseer M, Castellon SA, Frol AB, Atkinson JH, Gelman BB, Grant I, Singer EJ (2006). Interrater reliability of the Psychiatric Research Interview for Substance and Mental Disorders in an HIV-infected cohort: experience of the National NeuroAIDS Tissue Consortium. Int J Methods Psychiatr Res 15: 131–138.CrossRefPubMedGoogle Scholar
  29. Morgello S, Mahboob R, Yakoushina T, Khan S, Hague K (2002). Autopsy findings in a human immunodeficiency virus-infected population over 2 decades: influences of gender, ethnicity, risk factors, and time. Arch Pathol Lab Med 126: 182–190.PubMedGoogle Scholar
  30. Price RW, Spudich S (2008). Antiretroviral therapy and central nervous system HIV type 1 infection. J Infect Dis 197 (Suppl 3): S294-S306.CrossRefPubMedGoogle Scholar
  31. Thomas SA (2004). Anti-HIV drug distribution to the central nervous system. Curr Pharm Des 10: 1313–24.CrossRefPubMedGoogle Scholar
  32. Wittchen HU, Robins LN, Cottler LB, Sartorius N, Burke JD, Regier D (1991). Cross-cultural feasibility, reliability and sources of variance of the Composite International Diagnostic Interview (CIDI). The Multicentre WHO/ ADAMHA Field Trials. Br J Psychiatry 159: 645–53, 658.CrossRefPubMedGoogle Scholar
  33. Woods SP, Rippeth JD, Frol AB, Levy JK, Ryan E, Soukup VM, Hinkin CH, Lazzaretto D, Cherner M, Marcotte TD, Gelman BB, Morgello S, Singer EJ, Grant I, Heaton RK (2004). Interrater reliability of clinical ratings and neurocognitive diagnoses in HIV. J Clin Exp Neuropsychol 26: 759–778.CrossRefPubMedGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2009

Authors and Affiliations

  • I. Everall
    • 1
    • 2
  • F. Vaida
    • 1
  • N. Khanlou
    • 1
    • 2
  • D. Lazzaretto
    • 1
  • C. Achim
    • 1
    • 2
  • S. Letendre
    • 1
    • 3
  • D. Moore
    • 1
    • 2
  • R. Ellis
    • 1
    • 4
  • M. Cherner
    • 1
    • 2
  • B. Gelman
    • 5
    • 6
  • S. Morgello
    • 7
    • 8
  • E. Singer
    • 9
  • I. Grant
    • 1
    • 2
  • E. Masliah
    • 1
    • 4
  • National NeuroAIDS Tissue Consortium (NNTC)
  1. 1.HIV Neurobehavioral Research Center (HNRC)University of California, San DiegoLa JollaUSA
  2. 2.Department of PsychiatryUniversity of California, San DiegoLa JollaUSA
  3. 3.Department of MedicineUniversity of California, San DiegoLa JollaUSA
  4. 4.Department of NeuroscienceUniversity of California, San DiegoLa JollaUSA
  5. 5.Department of PathologyUniversity of Texas Medical BranchGalvestonUSA
  6. 6.Department of Neuroscience and Cell BiologyUniversity of Texas Medical BranchGalvestonUSA
  7. 7.Department of PathologyMount Sinai Medical CenterNew YorkUSA
  8. 8.Department of NeuroscienceMount Sinai Medical CenterNew YorkUSA
  9. 9.Department of NeurologyUniversity of CaliforniaLos AngelesUSA

Personalised recommendations