Journal of NeuroVirology

, Volume 20, Issue 1, pp 28–38 | Cite as

Brain viral burden, neuroinflammation and neurodegeneration in HAART-treated HIV positive injecting drug users

  • Donald B. Smith
  • Peter Simmonds
  • Jeanne E. Bell


The long-term impact of chronic human immunodeficiency virus (HIV) infection on brain status in injecting drug users (IDU) treated with highly active antiretroviral therapy (HAART) is unknown. Viral persistence in the brain with ongoing neuroinflammation may predispose to Alzheimer-like neurodegeneration. In this study, we investigated the brains of ten HAART-treated individuals (six IDU and four non-DU), compared with ten HIV negative controls (six IDU and four non-DU). HIV DNA levels in brain tissue were correlated with plasma and lymphoid tissue viral loads, cognitive status, microglial activation and Tau protein and amyloid deposition. Brain HIV proviral DNA levels were low in most cases but higher in HIV encephalitis (n = 2) and correlated significantly with levels in lymphoid tissue (p = 0.0075), but not with those in plasma. HIV positive subjects expressed more Tau protein and amyloid than HIV negative controls (highest in a 58 year old), as did IDU, but brain viral loads showed no relation to Tau and amyloid. Microglial activation linked significantly to HIV positivity (p = 0.001) and opiate abuse accentuated these microglial changes (p = 0.05). This study confirms that HIV DNA persists in brains despite HAART and that opiate abuse adds to the risk of brain damage in HIV positive subjects. Novel findings in this study show that (1) plasma levels are not a good surrogate indicator of brain status, (2) viral burden in brain and lymphoid tissues is related, and (3) while Tau and amyloid deposition is increased in HIV positive IDU, this is not specifically related to increased HIV burden within the brain.


HIV HAART Brain viral burden Microglia Tau protein Amyloid 



The Edinburgh HIV Brain Bank is funded by the UK Medical Research Council. We thank the clinicians who looked after these subjects including Drs R Brettle and R Robertson and Professor C Leen, the clinical database manager Alan Wilson, and staff members who have assisted with the investigation of the tissue samples including Frances Carnie and Dr I Anthony. Lastly, this study would not have been possible without the generous trust and support of the donors and their families.

Conflict of interest

All three authors, Dr Donald Smith and Professors Peter Simmonds and Jeanne Bell, declare that they have no conflict of interest with the UK Medical Research Council.


  1. Andras IE, Toborek M (2013) Amyloid beta accumulation in HIV-1-infected brain: the role of the blood–brain barrier. IUBMB Life 65:43–49. doi: 10.1002/iub.1106 PubMedCentralPubMedCrossRefGoogle Scholar
  2. Anthony IC, Ramage SN, Carnie FW, Simmonds P, Bell JE (2005) Does drug abuse alter microglial phenotype and cell turnover in the context of advancing HIV infection. Neuropathol Appl Neurobiol 31:325–338. doi: 10.1111/j.1365-2990.00648.x PubMedCrossRefGoogle Scholar
  3. Anthony IC, Ramage SN, Carnie FW, Simmonds P, Bell JE (2006) 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. Acta Neuropathol 111:529–538. doi: 10.1007/s00401-006-0037-0 PubMedCrossRefGoogle Scholar
  4. Anthony IC, Norrby KE, Dingwall T, Carnie FW, Millar T, Arango JC, Robertson R, Bell JE (2010) Predisposition to accelerated Alzheimer-related changes in the brains of human immunodeficiency virus negative opiate abusers. Brain 133:3685–3698. doi: 10.1093/brain/awq263 PubMedCrossRefGoogle Scholar
  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 10:493–499PubMedCrossRefGoogle Scholar
  6. Borjabad A, Morgello S, Chao W, Kim SY, Brooks AI, Murray J, Potash MJ, Volsky DJ (2011) Significant effects of antiretroviral therapy on global gene expression in brain tissues of patients with HIV-1-associated neurocognitive disorders. PLoS Pathog. doi: 10.1371/journal.ppat. 1002213 PubMedCentralPubMedGoogle Scholar
  7. Brew BJ, Crowe SM, Landay A, Cysique LA, Guillemin G (2009) Neurodegeneration and ageing in the HAART era. J Neuroimmune Pharmacol 4:163–174. doi: 10.1007/s11481-008-9143-1 PubMedCrossRefGoogle Scholar
  8. Byrd D, Murray J, Safdieh G, Morgello S (2012) Impact of opiate addiction on neuroinflammation in HIV. J Neurovirol 18:364–373. doi: 10.1007/s13365-012-0118-x PubMedCentralPubMedCrossRefGoogle Scholar
  9. Clements JE, Gama L, Graham DR, Mankowski JL, Zink MC (2011) An SIV macaque model of HAART: viral latency in the periphery and the central nervous system. Curr Opin HIV AIDS 6:37–42. doi: 10.1097/COH.0b03e3283412413 PubMedCentralPubMedCrossRefGoogle Scholar
  10. Cysique LA, Waters EK, Brew BJ (2011) Central nervous system antiretroviral efficacy in HIV infection: a qualitative and quantitative review and implications for future research. BMC Neurol 11:148. doi: 10.1186/1471-2377-11-148 PubMedCentralPubMedCrossRefGoogle Scholar
  11. Dutta R, Roy S (2012) Mechanism(s) involved in opioid drug abuse modulation of HAND. Curr HIV Res 10:469–477. doi: 10.2174/157016212802138805 PubMedCentralPubMedCrossRefGoogle Scholar
  12. Eisfeld C, Reichelt D, Evers S, Husstedt I (2013) CSF penetration by antiretroviral drugs. CNS Drugs 27:31–55. doi: 10.1007/s40263-012-0018-x PubMedCrossRefGoogle Scholar
  13. Ersche KD, Clark L, London M, Robbins TW, Sahakian BJ (2006) Profile of executive and memory function associated with amphetamine and opiate dependence. Neuropsychopharmacology 31:1036–1047. doi: 10.1038/si.nnp.1300889 PubMedCentralPubMedCrossRefGoogle Scholar
  14. Everall I, Vaida F, Khanlou N, Lazzaretto D, Achim C, Letendre S, Moore D, Ellis R, Cherner M, Gelman B, Morgello S, Singer E, Grant I, Masliah E, National NeuroAIDS Tissue Consortium (NNTC) (2009) Cliniconeuropathologic correlates of human immunodeficiency virus in the era of antiretroviral therapy. J Neurovirol 15:360–370. doi: 10.3109/13550280903131915 PubMedCentralPubMedCrossRefGoogle Scholar
  15. Gelman BB, Chen T, Lisinicchia JG, Soukup VM, Carmical JR, Starkey JM, Masliah E, Commins DL, Brandt D, Grant I, Singer EJ, Levine AJ, Miller J, Winkler JM, Fox HS, Luxon BA, Morgello S, National NeuroAIDS Tissue Consortium (2012) The National NeuroAIDS Tissue Consortium brain gene array: two types of HIV-associated neurocognitive impairment. PLoS One. doi: 10.1371/journal pone. 0046178 PubMedCentralPubMedGoogle Scholar
  16. Gelman BB, Lisinicchia JG, Morgello S, Masliah E, Commins D, Achim CL, Fox HS, Kolson DL, Grant I, Singer E, Yiannoutsos CT, Sherman S, Gensler G, Moore DJ, Chen T, Soukup VM (2013) Neurovirological correlation with HIV-associated neurocognitive disorders and encephalitis in a HAART-era cohort. J Acquir Immune Defic Syndr 62:487–495. doi: 10.1097/QAI.0b013e31827f1bdb PubMedCrossRefGoogle Scholar
  17. Gisslen M, Krut J, Andreasson U, Blennow K, Cinque P, Brew BJ, Spudich S, Hagberg L, Rosengren L, Price RW, Zetterberg H (2009) Amyloid and tau cerebrospinal fluid biomarkers in HIV infection. BMC Neurol 9:63. doi: 10.1186/1471-2377-9-63 PubMedCentralPubMedCrossRefGoogle Scholar
  18. Green DA, Masliah E, Vinters HV, Beizai P, Moore DJ, Achim CL (2005) Brain deposition of beta-amyloid is a common feature in HIV positive patients. AIDS 19:407–411PubMedCrossRefGoogle Scholar
  19. Gupta S, Knight AG, Losso BY, Ingram DK, Keller JN, Bruce-Keller AJ (2012) Brain injury caused by HIV protease inhibitors: role of lipodystrophy and insulin resistance. Antiviral Res 95:19–29. doi: 10.1016/j.antiviral.2012.04.010 PubMedCentralPubMedCrossRefGoogle Scholar
  20. Harezlak J, Buchthal S, Taylor M, Schifitto G, Zhong J, Daar E, Alger J, Singer E, Campbell T, Yiannoutsos C, Cohen R, Navia B, HIV Neuroimaging Consortium (2011) Persistence of HIV-associated cognitive impairment, inflammation and neuronal injury in era of highly active antiretroviral treatment. AIDS 25:625–633. doi: 10.1097/QAD.0b013e3283427da7 PubMedCrossRefGoogle Scholar
  21. Hauser KF, Fitting S, Dever SM, Podhaizer EM, Knapp PE (2012) Opiate drug use and the pathophysiology of neuro-AIDS. Curr HIV Res 10:435–452. doi: 10.2174/157016212802138779 PubMedCentralPubMedCrossRefGoogle Scholar
  22. Heaton RK, Franklin DR, Ellis RJ, McCutchan JA, Letendre SL, Leblanc S, Corkran SH, Duarte NA, Clifford DB, Woods SP, Collier AC, Marra CM, Morgello S, Mindt MR, Taylor MJ, Marcotte TD, Atkinson JH, Wolfson T, Gelman BB, McArthur JC, Simpson DM, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I, CHARTER Group, HNRC Group (2011) HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature and predictors. J Neurovirol 17:3–16. doi: 10.1007/s13365-010-0006-1 PubMedCentralPubMedCrossRefGoogle Scholar
  23. Hughes ES, Bell JE, Simmonds P (1997) Investigation of the dynamics of the spread of human immunodeficiency virus to brain and other tissues by evolutionary analysis of sequences from the p17gag and env genes. J Virol 71:1272–1280PubMedCentralPubMedGoogle Scholar
  24. Kaul M (2009) HIV-1 associated dementia: update on pathological mechanisms and therapeutic approaches. Curr Opin Neurol 22:315–320. doi: 10.1097/WCO.0b013e328329cf3c PubMedCentralPubMedCrossRefGoogle Scholar
  25. Lamers SL, Salemi M, Galligan DC, Morris A, Gray R, Fogel G, Zhao L, McGrath MS (2010) Human immunodeficiency virus-1 evolutionary patterns associated with pathogenic processes in the brain. J Neurovirol 16:230–241. doi: 10.3109/13550281003735709 PubMedCentralPubMedCrossRefGoogle Scholar
  26. Lamers SL, Gray RR, Salemi M, Huysentruyt LC, McGrath MS (2011) HIV-1 phylogenetic analysis shows HIV-1 transits through the meninges to brain and peripheral tissues. Infect Genet Evol 11:31–37. doi: 10.1016/j.meegid. 2010.10.016 PubMedCentralPubMedCrossRefGoogle Scholar
  27. Langford D, Marquie-Beck J, de Almeida S, Lazzaretto D, Letendre S, Grant I, McCutchan JA, Masliah E, Ellis RJ, HIV Neurobehavioural Research Centre (HNRC) group (2006) Relationship of antiretroviral treatment to post mortem brain tissue viral load in human immunodeficiency virus-infected patients. J Neurovirol 12:100–107. doi: 10.1080/13550280600713932 PubMedCrossRefGoogle Scholar
  28. Letendre SL, Ellis RJ, Everall I, Ances B, Bharti A, McCutchan JA (2009) Neurologic complications of HIV disease and their treatment. Top HIV Med 17:46–56PubMedCentralPubMedGoogle Scholar
  29. Marra CM, Zhao Y, Clifford DB, Letendre S, Evans S, Henry K, Ellis RJ, Rodriguez B, Coombs RW, Schifitto G, McArthur JC, Robertson K, AIDS Clinical Trials Group 736 Study Team (2009) Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS 23:1359–1366. doi: 10.1097/QAD.0b013e32832c4152 PubMedCentralPubMedCrossRefGoogle Scholar
  30. Patrick C, Crews L, Desplats P, Dumaop W, Rockenstein E, Achim CL, Everall I, Masliah E (2011) Increased CDK5 expression in HIV encephalitis contributes to neurodegeneration via Tau phosphorylation and is reversed with Roscovitine. Am J Pathol 178:1646–1661. doi: 10.1016/j.ajpath.2010.12.033 PubMedCrossRefGoogle Scholar
  31. Paulino AD, Ubhi K, Rockenstein E, Adame A, Crews L, Letendre S, Ellis R, Everall IP, Grant I, Masliah E (2011) Neurotoxic effects of the HCV core protein are mediated by sustained activation of ERK via TLR2 signalling. J Neurovirol 17:327–340. doi: 10.1007/s13365-011-0039-0 PubMedCentralPubMedCrossRefGoogle Scholar
  32. 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 31:439–448. doi: 10.1111/j.1365-2990.2005.007670.x PubMedCrossRefGoogle Scholar
  33. Reddy PV, Pilakka-Kanthikeel S, Saxena SK, Saiyed Z, Nair MP (2012) Interactive effects of morphine on HIV infection: role in HIV-associated neurocognitive disorder. AIDS Res Treat. doi: 10.1155/2012/953678 PubMedCentralPubMedGoogle Scholar
  34. Robbins TW, Ersche KD, Everitt BJ (2008) Drug addiction and the memory systems of the brain. Ann NY Acad Sci 1141:1–21. doi: 10.1196/annals.1441.020 PubMedCrossRefGoogle Scholar
  35. Schouten J, Cinque P, Gisslen M, Reiss P, Portegies P (2011) HIV-1 infection and cognitive impairment in the cART era: a review. AIDS 25:561–575. doi: 10.1097/QAD.0b013e3283437f9a PubMedCrossRefGoogle Scholar
  36. Tomlinson GS, Simmonds P, Busuttil A, Chiswick A, Bell JE (1999) Upregulation of microglia in drug users with and without pre-symptomatic HIV infection. Neuropathol Appl Neurobiol 25:369–379. doi: 10.1046/j.1365-2990.1999.00197.x PubMedCrossRefGoogle Scholar
  37. 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. doi: 10.1128/JVI.75.23.11686-11699.2001 PubMedCentralPubMedCrossRefGoogle Scholar
  38. Weed M, Adams RJ, Hienz RD, Meulendyke KA, Linde ME, Clements JE, Mankowski JL, Zink MC (2012) SIV/macaque model of HIV infection in cocaine users: minimal effects of cocaine on behaviour, virus replication and CNS inflammation. J Neuroimmune Pharmacol 7:401–411PubMedCentralPubMedCrossRefGoogle Scholar
  39. Xu J, Ikezu T (2009) The comorbidity of HIV-associated neurocognitive disorders and Alzheimer's disease: a foreseeable medical challenge in post-HAART era. J Neuroimmune Pharmacol 4:200–212. doi: 10.1007/s11481-008-9136-0 PubMedCentralPubMedCrossRefGoogle Scholar
  40. Zhao L, Galligan DC, Lamers SL, Yu S, Shagrun L, Salemi M, McGrath MS (2009) High level of HIV-1 DNA concentrations in brain tissues differentiate patients with post-HAART AIDS dementia complex or cardiovascular disease from those with AIDS. Sci China C Life Sci 52:651–656. doi: 10.1007/s11427-009-0085-5 PubMedCrossRefGoogle Scholar
  41. Zink MC, Brice AK, Kelly KM, Queen SE, Gama L, Li M, Adams RJ, Bartizal C, Varrone J, Rahi A, Graham DR, Tarwater PM, Mankowski JL, Clements JE (2010) Simian immunodeficiency virus-infected macaques treated with highly active antiretroviral therapy have reduced central nervous system viral replication and inflammation but persistence of viral DNA. J Inf Dis 202:161–170. doi: 10.1086/653213 CrossRefGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2014

Authors and Affiliations

  • Donald B. Smith
    • 1
  • Peter Simmonds
    • 1
  • Jeanne E. Bell
    • 2
    • 3
  1. 1.Centre for Immunity, Infection and Immunity, Ashworth LaboratoriesUniversity of EdinburghEdinburghUK
  2. 2.NeuropathologyUniversity of EdinburghEdinburghUK
  3. 3.CJD Surveillance UnitWestern General HospitalEdinburghUK

Personalised recommendations