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.
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References
Ances B, Ellis RJ (2007). Dementia and Neurocognitive Disorders Due to HIV-1 Infection. Semin Neurol 27: 86–92.
Anthony IC, Bell JE (2008). The Neuropathology of HIV/ AIDS. Int Rev Psychiatry 20: 15–24.
Arendt GvGH (2002). Antiretroviraltherapy regimes for neuro-AIDS. Curr Drug Targets Infects Disord 2: 187–192.
Bell JE (2004). An update on the neuropathology of HIV in the HAART era. Histopathology 45: 549–559.
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.
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.
Budka H (1991). Neuropathology of human immunodeficiency virus infection. Brain Pathol 1: 163–175.
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.
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.
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.
Centers for Disease Control and Prevention (2007). HIV/ AIDS Surveillance Report, 2005. Atlanta: U.S. Department of Health and Human Services.
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.
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.
Everall IP, Luthert PJ, Lantos PL (1991). Neuronal loss in the frontal cortex in HIV infection. Lancet 337: 1119–1121.
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.
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.
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.
Grant I (2008). Neurocognitive disturbances in HIV. Int Rev Psychiatry 20: 33–47.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Price RW, Spudich S (2008). Antiretroviral therapy and central nervous system HIV type 1 infection. J Infect Dis 197 (Suppl 3): S294-S306.
Thomas SA (2004). Anti-HIV drug distribution to the central nervous system. Curr Pharm Des 10: 1313–24.
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.
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.
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I.P.E. is supported by grants R01MH079881, R41MH079728, R25MH074508, R25MH081482, and P30 MH62512, R24MH59745, and U01MH083506. This publication was also made possible from NIH funding through the NIMH and NINDS Institutes by the following grants: Manhattan HIV Brain Bank (U01MH083501, R24MH59724), Texas NeuroAIDS Research Center (U01MH083507, R24NS45491), National Neurological AIDS Bank (U01MH083500, R24NS38841), California NeuroAIDS Tissue Network (U01MH083506, R24MH59745), Statistics and Data Coordinating Center (U01 MH083545-01). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NNTC or NIH. The authors report no conflicts of interest.
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Everall, I., Vaida, F., Khanlou, N. et al. Cliniconeuropathologic correlates of human immunodeficiency virus in the era of antiretroviral therapy. Journal of NeuroVirology 15, 360–370 (2009). https://doi.org/10.3109/13550280903131915
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DOI: https://doi.org/10.3109/13550280903131915