Journal of NeuroVirology

, Volume 12, Issue 2, pp 100–107 | Cite as

Relationship of antiretroviral treatment to postmortem brain tissue viral load in human immunodeficiency virus-infected patients

  • Dianne Langford
  • Jennifer Marquie-Beck
  • Sergio de Almeida
  • Deborah Lazzaretto
  • Scott Letendre
  • Igor Grant
  • J. Allen McCutchan
  • Eliezer Masliah
  • Ronald J. Ellis
  • the HIV Neurobehavioral Research Center (HNRC) group
Article

Abstract

Human immunodeficiency virus (HIV)-1 invades the central nervous system (CNS) soon after infection and is partially protected there from host immunity and antiretroviral drugs (ARVs). Sanctuary from highly active antiretroviral therapy (HAART) in the CNS could result in ongoing viral replication, promoting the development of drug resistance and neurological disease. Despite the importance of these risks, no previous study has directly assessed HAART’s effects on brain tissue viral load (VL). The authors evaluated 61 HIV-infected individuals for whom both histories of HAART treatment and postmortem brain tissue VL measurements were available. Two groups were defined based on HAART use in the 3 months prior to death: HAART(+) subjects had received HAART, and HAART(−) subjects had not received HAART. HIV RNA was quantified in postmortem brain tissue (log10 copies/10 μg total tissue RNA) and antemortem plasma (log10 copies/ml) by reverse transcriptase—polymerase chain reaction (RT-PCR). Brain tissue VLs were significantly lower among HAART(+) subjects compared to HAART(−) subjects (median 2.6 versus 4.1; P = .0007). These findings suggest that despite the limited CNS penetration of many antiretroviral medications, HAART is at least partially effective in suppressing CNS viral replication. Because some HAART regimens may be better than others in this regard, regimen selection strategies could be used to impede CNS viral activity, limit neuronal dysfunction, and prevent or treat clinical neurocognitive disorders in HIV-infected patients. Furthermore, such strategies might help to prevent the development of ARV resistance.

Keywords

antiretroviral therapy brain CNS dementia HIV 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Chun TW, Carruth L, Finzi D, Shen X, DiGiuseppe JA, Taylor H, Hermankova M, Chadwick K, Margolick J, Quinn TC, Kuo YH, Brookmeyer R, Zeiger MA, Barditch-Crovo P, Siliciano RF (1997). Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387: 183–188.PubMedCrossRefGoogle Scholar
  2. De Luca A, Ciancio BC, Larussa D, Murri R, Cingolani A, Rizzo MG, Giancola ML, Ammassari A, Ortona L (2002). Correlates of independent HIV-1 replication in the CNS and of its control by antiretrovirals. Neurology 59: 342–347.PubMedGoogle Scholar
  3. 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: 1249–1253.PubMedCrossRefGoogle Scholar
  4. Ellis RJ, Gamst AC, Capparelli E, Spector SA, Hsia K, Wolfson T, Abramson I, Grant I, McCutchan JA (2000). Cerebrospinal fluid HIV RNA originates from both local CNS and systemic sources. Neurology 54: 927–936.PubMedGoogle Scholar
  5. Fagard C, Oxenius A, Gunthard H, Garcia F, Le Braz M, Mestre G, Battegay M, Furrer H, Vernazza P, Bernasconi E, Telenti A, Weber R, Leduc D, Yerly S, Price D, Dawson SJ, Klimkait T, Perneger TV, McLean A, Clotet B, Gatell JM, Perrin L, Plana M, Phillips R, Hirschel B (2003). A prospective trial of structured treatment interruptions in human immunodeficiency virus infection. Arch Intern Med 163: 1220–1226.PubMedCrossRefGoogle Scholar
  6. Foudraine NA, Hoetelmans RM, Lange JM, de Wolf F, van Benthem BH, Maas JJ, Keet IP, Portegies P (1998). Cerebrospinal-fluid HIV-1 RNA and drug concentrations after treatment with lamivudine plus zidovudine or stavudine. Lancet 351: 1547–1551.PubMedCrossRefGoogle Scholar
  7. Gartner S (2000). HIV infection and dementia. Science 287: 602–604.PubMedCrossRefGoogle Scholar
  8. 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: 429–440.PubMedGoogle Scholar
  9. Gray F, Geny C, Dournon E, Fenelon F, Lionnet F, Gherardi R (1991). Neuropathological evidence that zidovudine reduces incidence of HIV infection of brain. Lancet 337: 852–853.PubMedCrossRefGoogle Scholar
  10. Haas DW, Johnson BW, Spearman P, Raffanti S, Nicotera J, Schmidt D, Hulgan T, Shepard R, Fiscus SA (2003). Two phases of HIV RNA decay in CSF during initial days of multidrug therapy. Neurology 61: 1391–1396.PubMedGoogle Scholar
  11. Heilek-Snyder G, Bean P (2002). Role of HIV phenotypic assays in the management of HIV infection. Am Clin Lab 21: 40–43.PubMedGoogle Scholar
  12. Huisman M, Smit J, Hoetelmans RM, Wiltshire H, Beijnen JH, Schninkel A (2000). The role of P-glycoprotein in oral bioavailability, brain and fetal penetration of the HIV protease inhibitor saquinavir. In: Proceedings of the Fifth International Congress on Drug Therapy in HIV Infection. Glasgow, United Kingdom, 22–26 October.Google Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. Langford TD, Letendre SL, Marcotte TD, Ellis RJ, McCutchan JA, Grant I, Mallory ME, Hansen LA, Archibald S, Jernigan T, Masliah E (2002). Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy. AIDS 16: 1019–1029.PubMedCrossRefGoogle Scholar
  15. Letendre SL, Childers ME, McCutchan JA, Woods SP, Lazzaretto D, Heaton RK, Grant I, Ellis RJ, Group TH (2004). Predictors of improvement in HIV-associated neurocognitive disorders during antiretroviral therapy. Annals of Neurology 56: 416–423.PubMedCrossRefGoogle Scholar
  16. Lipton SA (1992). Requirement for macrophages in neuronal injury induced by HIV envelope protein gp120. Neuroreport 3: 913–915.PubMedCrossRefGoogle Scholar
  17. Major EO, Rausch D, Marra C, Clifford D (2000). HIV-associated dementia. Science 288: 440–442.PubMedCrossRefGoogle Scholar
  18. Masliah E, De Teresa RM, Mallory ME, Hansen LA (2000). Changes in pathological findings at autopsy in AIDS cases for the last 15 years. AIDS 14: 69–74.PubMedCrossRefGoogle Scholar
  19. McClernon DR, Lanier R, Gartner S, Feaser P, Pardo CA, St Clair M, Liao Q, McArthur JC (2001). HIV in the brain: RNA levels and patterns of zidovudine resistance. Neurology 57: 1396–1401.PubMedGoogle Scholar
  20. Nath A (2002). Human immunodeficiency virus (HIV) proteins in neuropathogenesis of HIV dementia. J Infect Dis 186 (Suppl 2): S193-S198.PubMedCrossRefGoogle Scholar
  21. Neuenburg JK, Brodt HR, Herndier BG, Bickel M, Bacchetti P, Price RW, Grant RM, Schlote W (2002). HIV-related neuropathology, 1985 to 1999: rising prevalence of HIV encephalopathy in the era of highly active antiretroviral therapy. J Acquir Immune Defic Syndr 31: 171–177.PubMedCrossRefGoogle Scholar
  22. Papasavvas E, Kostman JR, Mounzer K, Grant RM, Gross R, Gallo C, Azzoni L, Foulkes A, Thiel B, Pistilli M, Mackiewicz A, Shull J, Montaner LJ (2004). Randomized, controlled trial of therapy interruption in chronic HIV-1 infection. PLoS Med 1: e64.PubMedCrossRefGoogle Scholar
  23. Petito CK, Cash KS (1992). Blood-brain barrier abnormalities in the acquired immunodeficiency syndrome: immunohistochemical localization of serum proteins in postmortem brain. Ann Neurol 32: 658–666.PubMedCrossRefGoogle Scholar
  24. Pomerantz RJ (1999). Residual HIV-1 disease in the era of highly active antiretroviral therapy. N Engl J Med 340: 1672–1674.PubMedCrossRefGoogle Scholar
  25. Power C, Kong PA, Crawford TO, Wesselingh S, Glass JD, McArthur JC, Trapp BD (1993). Cerebral white matter changes in acquired immunodeficiency syndrome dementia: alterations of the blood-brain barrier. Ann Neurol 34: 339–350.PubMedCrossRefGoogle Scholar
  26. Rohr O, Marban C, Aunis D, Schaeffer E (2003). Regulation of HIV-1 gene transcription: from lymphocytes to microglial cells. J Leukoc Biol 74: 736–749.PubMedCrossRefGoogle Scholar
  27. Saito Y, Sharer LR, Epstein LG, Michaels J, Mintz M, Louder M, Golding K, Cvetkovich TA, Blumberg BM (1994). Overexpression of nef as a marker for restricted HIV-1 infection of astrocytes in postmortem pediatric central nervous tissues. Neurology 44: 474–481.PubMedGoogle Scholar
  28. Schrager LK, D’Souza MP (1998). Cellular and anatomical reservoirs of HIV-1 in patients receiving potent antiretroviral combination therapy. JAMA 280: 67–71.PubMedCrossRefGoogle Scholar
  29. Shapshak P, Segal DM, Crandall KA, Fujimura RK, Zhang BT, Xin KQ, Okuda K, Petito CK, Eisdorfer C, Goodkin K (1999). Independent evolution of HIV type 1 in different brain regions. AIDS Res Hum Retroviruses 15: 811–820.PubMedCrossRefGoogle Scholar
  30. Smith TW, DeGirolami U, Henin D, Bolgert F, Hauw JJ (1990). Human immunodeficiency virus (HIV) leukoencephalopathy and the microcirculation. J Neuropathol Exp Neurol 49: 357–370.PubMedCrossRefGoogle Scholar
  31. Staprans S, Marlowe N, Glidden D, Novakovic-Agopian T, Grant RM, Heyes M, Aweeka F, Deeks S, Price RW (1999). Time course of cerebrospinal fluid responses to antiretroviral therapy: evidence for variable compartmentalization of infection. AIDS 13: 1051–1061.PubMedCrossRefGoogle Scholar
  32. Tyler KL, McArthur JC (2002). Through a glass, darkly: cerebrospinal fluid viral load measurements and the pathogenesis of human immunodeficiency virus infection of the central nervous system. Arch Neurol 59: 909–912.PubMedCrossRefGoogle Scholar
  33. Wendel KA, McArthur JC (2003). Acute meningoencephalitis in chronic human immunodeficiency virus (HIV) infection: putative central nervous system escape of HIV replication. Clin Infect Dis 37: 1107–1111.PubMedCrossRefGoogle Scholar
  34. Wiley CA, Baldwin M, Achim CL (1996). Expression of HIV regulatory and structural mRNA in the central nervous system. AIDS 10: 843–847.PubMedCrossRefGoogle Scholar
  35. Wiley CA, Soontornniyomkij V, Radhakrishnan L, Masliah E, Mellors J, Hermann SA, Dailey P, Achim CL (1998). Distribution of brain HIV load in AIDS. Brain Pathol 8: 277–284.PubMedCrossRefGoogle Scholar
  36. Wong JK, Ignacio CC, Torriani F, Havlir D, Fitch NJ, Richman DD (1997). In vivo compartmentalization of human immunodeficiency virus: evidence from the examination of pol sequences from autopsy tissues. J Virol 71: 2059–2071.PubMedGoogle Scholar
  37. Wu M, Nie SQ (1998). [Research advances on fusion peptide and mechanisms about virus penetration into membrane]. Sheng Li Ke Xue Jin Zhan 29: 221–225.PubMedGoogle Scholar
  38. Xu Y, Kulkosky J, Acheampong E, Nunnari G, Sullivan J, Pomerantz RJ (2004). HIV-1-mediated apoptosis of neuronal cells: Proximal molecular mechanisms of HIV-1-induced encephalopathy. Proc Natl Acad Sci USA 101: 7070–7075.PubMedCrossRefGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2006

Authors and Affiliations

  • Dianne Langford
    • 1
  • Jennifer Marquie-Beck
    • 2
  • Sergio de Almeida
    • 2
  • Deborah Lazzaretto
    • 3
  • Scott Letendre
    • 4
  • Igor Grant
    • 3
  • J. Allen McCutchan
    • 4
  • Eliezer Masliah
    • 1
    • 2
  • Ronald J. Ellis
    • 2
  • the HIV Neurobehavioral Research Center (HNRC) group
  1. 1.Department of Pathology, School of MedicineUniversity of California San DiegoLa JollaUSA
  2. 2.Department of NeurosciencesUniversity of California, San DiegoLa JollaUSA
  3. 3.Department of PsychiatryUniversity of California, San DiegoLa JollaUSA
  4. 4.Department of MedicineUniversity of California, San DiegoLa JollaUSA

Personalised recommendations