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Thinking about HIV: the intersection of virus, neuroinflammation and cognitive dysfunction

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Abstract

It is estimated that half of HIV-infected adults and children will present at one time during their disease course with a neurologic disorder. The neurologic sequelae of HIV infection arise as a direct result of viral replication as well as from the subsequent neuroinflammatory processes. HIV enters the CNS early in infection and resides primarily in long-lived perivascular macrophages and microglia. CNS immunosurveillance is an integral part of normal brain function. Circulating lymphocytes play a vital role in support of brain plasticity under normal and traumatic circumstances. Malfunctions of this immunologic niche can impair brain homeostasis, resulting in neural impairment. Combination therapies that lower CNS viral load and improve immune homeostasis and neuroprotection will be required to address the neuropathogenesis of HIV infection.

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References

  1. WHO/UNAIDS. Report on the global AIDS epidemic; 2009.

  2. Kaul M, Zheng J, Okamoto S, Gendelman HE, Lipton SA. HIV-1 infection and AIDS: consequences for the central nervous system. Cell Death Differ. 2005;12(Suppl 1):878–92. 15832177.

    Article  PubMed  CAS  Google Scholar 

  3. Williams KC, Corey S, Westmoreland SV, Pauley D, Knight H, deBakker C, Alvarez X, Lackner AA. Perivascular macrophages are the primary cell type productively infected by simian immunodeficiency virus in the brains of macaques: implications for the neuropathogenesis of AIDS. J Exp Med. 2001;193(8):905–15.

    Article  PubMed  CAS  Google Scholar 

  4. Bissel SJ, Wiley CA. Human immunodeficiency virus infection of the brain: pitfalls in evaluating infected/affected cell populations. Brain Pathol. 2004;14(1):97–108.

    Article  PubMed  CAS  Google Scholar 

  5. Fischer-Smith T, Bell C, Croul S, Lewis M, Rappaport J. Monocyte/macrophage trafficking in acquired immunodeficiency syndrome encephalitis: lessons from human and nonhuman primate studies. J Neurovirol. 2008;14(4):318–26.

    Article  PubMed  CAS  Google Scholar 

  6. Cosenza MA, Zhao ML, Si Q, Lee SC. Human brain parenchymal microglia express CD14 and CD45 and are productively infected by HIV-1 in HIV-1 encephalitis. Brain Pathol. 2002;12(4):442–55.

    Article  PubMed  CAS  Google Scholar 

  7. Yi Y, Lee C, Liu QH, Freedman BD, Collman RG. Chemokine receptor utilization and macrophage signaling by human immunodeficiency virus type 1 gp120: implications for neuropathogenesis. J Neurovirol. 2004;10(Suppl 1):91–6. 14982745.

    PubMed  CAS  Google Scholar 

  8. Agrawal L, Louboutin JP, Marusich E, Reyes BA, Van Bockstaele EJ, Strayer DS. Dopaminergic neurotoxicity of HIV-1 gp120: reactive oxygen species as signaling intermediates. Brain Res. 2010;1306:116–30. Epub@2009 Oct 6.:116-30.

    Article  PubMed  CAS  Google Scholar 

  9. An SF, Groves M, Giometto B, Beckett AA, Scaravilli F. Detection and localisation of HIV-1 DNA and RNA in fixed adult AIDS brain by polymerase chain reaction/in situ hybridisation technique. Acta Neuropathol. 1999;98(5):481–7.

    Article  PubMed  CAS  Google Scholar 

  10. An SF, Groves M, Gray F, Scaravilli F. Early entry and widespread cellular involvement of HIV-1 DNA in brains of HIV-1 positive asymptomatic individuals. J Neuropathol Exp Neurol. 1999;58(11):1156–62.

    Article  PubMed  CAS  Google Scholar 

  11. Davis LE, Hjelle BL, Miller VE, et al. Early viral brain invasion in iatrogenic human immunodeficiency virus infection. Neurology. 1992;42(9):1736–9.

    PubMed  CAS  Google Scholar 

  12. Borjabad A, Brooks AI, Volsky DJ. Gene expression profiles of HIV-1-infected glia and brain: toward better understanding of the role of astrocytes in HIV-1-associated neurocognitive disorders. J Neuroimmune Pharmacol. 2010;5(1):44–62.

    Article  PubMed  Google Scholar 

  13. Ivey NS, MacLean AG, Lackner AA. Acquired immunodeficiency syndrome and the blood-brain barrier. J Neurovirol. 2009;15(2):111–22.

    Article  PubMed  Google Scholar 

  14. Dunfee R, Thomas ER, Gorry PR, Wang J, Ancuta P, Gabuzda D. Mechanisms of HIV-1 neurotropism. Curr HIV Res. 2006;4(3):267–78.

    Article  PubMed  CAS  Google Scholar 

  15. Adle-Biassette H, Levy Y, Colombel M, Poron F, Natchev S, Keohane C, Gray F. Neuronal apoptosis in HIV infection in adults. Neuropathol Appl Neurobiol. 1995;21(3):218–27.

    Article  PubMed  CAS  Google Scholar 

  16. Gray F, dle-Biassette H, Brion F, Ereau T, le MI, Levy V, Corcket G. Neuronal apoptosis in human immunodeficiency virus infection. J Neurovirol. 2000;6(Suppl 1):S38–43.

    PubMed  Google Scholar 

  17. Gray F, dle-Biassette H, Chretien F, de la Lorin GG, Force G, Keohane C. Neuropathology and neurodegeneration in human immunodeficiency virus infection. Pathogenesis of HIV-induced lesions of the brain, correlations with HIV-associated disorders and modifications according to treatments. Clin Neuropathol. 2001;20(4):146–55.

    PubMed  CAS  Google Scholar 

  18. Agrawal L, Louboutin JP, Reyes BA, Van Bockstaele EJ, Strayer DS. Antioxidant enzyme gene delivery to protect from HIV-1 gp120-induced neuronal apoptosis. Gene Ther. 2006;13(23):1645–56.

    Article  PubMed  CAS  Google Scholar 

  19. Louboutin JP, Reyes BA, Agrawal L, Maxwell CR, Van Bockstaele EJ, Strayer DS. Blood-brain barrier abnormalities caused by exposure to HIV-1 gp120–protection by gene delivery of antioxidant enzymes. Neurobiol Dis. 2010;38(2):313–25.

    Article  PubMed  CAS  Google Scholar 

  20. Louboutin JP, Reyes BA, Agrawal L, Van Bockstaele EJ, Strayer DS. HIV-1 gp120-induced neuroinflammation: relationship to neuron loss and protection by rSV40-delivered antioxidant enzymes. Exp Neurol. 2010;221(1):231–45.

    Article  PubMed  CAS  Google Scholar 

  21. Louboutin JP, Reyes BA, Agrawal L, Van BE, Strayer DS. Strategies for CNS-directed gene delivery: in vivo gene transfer to the brain using SV40-derived vectors. Gene Ther. 2007;14(12):939–49.

    Article  PubMed  CAS  Google Scholar 

  22. Chaudhuri A, Yang B, Gendelman HE, Persidsky Y, Kanmogne GD. STAT1 signaling modulates HIV-1-induced inflammatory responses and leukocyte transmigration across the blood-brain barrier. Blood. 2008;111(4):2062–72.

    Article  PubMed  CAS  Google Scholar 

  23. Kanmogne GD, Schall K, Leibhart J, Knipe B, Gendelman HE, Persidsky Y. HIV-1 gp120 compromises blood-brain barrier integrity and enhances monocyte migration across blood-brain barrier: implication for viral neuropathogenesis. J Cereb Blood Flow Metab. 2007;27(1):123–34.

    Article  PubMed  CAS  Google Scholar 

  24. Mukhtar M, Pomerantz RJ. Development of an in vitro blood-brain barrier model to study molecular neuropathogenesis and neurovirologic disorders induced by human immunodeficiency virus type 1 infection. J Hum Virol. 2000;3(6):324–34.

    PubMed  CAS  Google Scholar 

  25. Persidsky Y, Zheng J, Miller D, Gendelman HE. Mononuclear phagocytes mediate blood-brain barrier compromise and neuronal injury during HIV-1-associated dementia. J Leukoc Biol. 2000;68(3):413–22.

    PubMed  CAS  Google Scholar 

  26. Harrington PR, Schnell G, Letendre SL, et al. Cross-sectional characterization of HIV-1 env compartmentalization in cerebrospinal fluid over the full disease course. AIDS. 2009;23(8):907–15.

    Article  PubMed  Google Scholar 

  27. Pillai SK, Pond SL, Liu Y, et al. Genetic attributes of cerebrospinal fluid-derived HIV-1 env. Brain. 2006;129(Pt 7):1872–83.

    Article  PubMed  Google Scholar 

  28. Strain MC, Letendre S, Pillai SK, et al. Genetic composition of human immunodeficiency virus type 1 in cerebrospinal fluid and blood without treatment and during failing antiretroviral therapy. J Virol. 2005;79(3):1772–88.

    Article  PubMed  CAS  Google Scholar 

  29. Ritola K, Pilcher CD, Fiscus SA, et al. Multiple V1/V2 env variants are frequently present during primary infection with human immunodeficiency virus type 1. J Virol. 2004;78(20):11208–18.

    Article  PubMed  CAS  Google Scholar 

  30. Ritola K, Robertson K, Fiscus SA, Hall C, Swanstrom R. Increased human immunodeficiency virus type 1 (HIV-1) env compartmentalization in the presence of HIV-1-associated dementia. J Virol. 2005;79(16):10830–4.

    Article  PubMed  CAS  Google Scholar 

  31. Robertson K, Fiscus S, Kapoor C, et al. CSF, plasma viral load and HIV associated dementia. J Neurovirol. 1998;4(1):90–4.

    Article  PubMed  CAS  Google Scholar 

  32. Brew BJ, Pemberton L, Cunningham P, Law MG. Levels of human immunodeficiency virus type 1 RNA in cerebrospinal fluid correlate with AIDS dementia stage. J Infect Dis. 1997;175(4):963–6.

    Article  PubMed  CAS  Google Scholar 

  33. Scourfield A, Waters L, Nelson M. Spectrum of neurological disease in patients with discordant HIV-1 RNA levels in plasma and cerebrospinal fluid. J Infect. 2010;60(3):251–2.

    Article  PubMed  CAS  Google Scholar 

  34. Christo PP, Greco DB, Aleixo AW, Livramento JA. Factors influencing cerebrospinal fluid, plasma HIV-1 RNA detection rate in patients with, without opportunistic neurological disease during the HAART era. BMC Infect Dis. 2007;7:147.

    Article  PubMed  CAS  Google Scholar 

  35. Christo PP, Vilela MC, Bretas TL, Domingues RB, Greco DB, Livramento JA, Teixeira AL. Cerebrospinal fluid levels of chemokines in HIV infected patients with and without opportunistic infection of the central nervous system. J Neurol Sci. 2009;287(1–2):79–83.

    Article  PubMed  CAS  Google Scholar 

  36. Schnell G, Spudich S, Harrington P, Price RW, Swanstrom R. Compartmentalized human immunodeficiency virus type 1 originates from long-lived cells in some subjects with HIV-1-associated dementia. PLoS Pathog. 2009;5(4):e1000395.

    Article  PubMed  CAS  Google Scholar 

  37. Staprans S, Marlowe N, Glidden D, et al. Time course of cerebrospinal fluid responses to antiretroviral therapy: evidence for variable compartmentalization of infection. AIDS. 1999;13(9):1051–61.

    Article  PubMed  CAS  Google Scholar 

  38. Caragounis EC, Gisslen M, Lindh M, Nordborg C, Westergren S, Hagberg L, Svennerholm B. Comparison of HIV-1 pol and env sequences of blood, CSF, brain and spleen isolates collected ante-mortem and post-mortem. Acta Neurol Scand. 2008;117(2):108–16.

    PubMed  CAS  Google Scholar 

  39. Ohagen A, Devitt A, Kunstman KJ, et al. Genetic and functional analysis of full-length human immunodeficiency virus type 1 env genes derived from brain and blood of patients with AIDS. J Virol. 2003;77(22):12336–45.

    Article  PubMed  CAS  Google Scholar 

  40. Schnell G, Price RW, Swanstrom R, Spudich S. Compartmentalization and clonal amplification of HIV-1 variants in the cerebrospinal fluid during primary infection. J Virol. 2010;84(5):2395–407.

    Article  PubMed  CAS  Google Scholar 

  41. Chang J, Jozwiak R, Wang B, et al. Unique HIV type 1 V3 region sequences derived from six different regions of brain: region-specific evolution within host-determined quasispecies. AIDS Res Hum Retrovir. 1998;14(1):25–30.

    Article  PubMed  CAS  Google Scholar 

  42. Di SM, Gray F, Leitner T, Chiodi F. Analysis of ENV V3 sequences from HIV-1-infected brain indicates restrained virus expression throughout the disease. J Med Virol. 1996;49(1):41–8.

    Article  Google Scholar 

  43. Di SM, Wilt S, Gray F, Dubois-Dalcq M, Chiodi F. HIV type 1 V3 sequences and the development of dementia during AIDS. AIDS Res Hum Retrovir. 1996;12(6):471–6.

    Article  Google Scholar 

  44. Di SM, Sabri F, Leitner T, Svennerholm B, Hagberg L, Norkrans G, Chiodi F. Reverse transcriptase sequence of paired isolates of cerebrospinal fluid and blood from patients infected with human immunodeficiency virus type 1 during zidovudine treatment. J Clin Microbiol. 1995;33(2):352–5.

    Google Scholar 

  45. Monno L, Di SM, Zimatore GB, et al. Measurement of viral sequences in cerebrospinal fluid of AIDS patients with cerebral white-matter lesions using polymerase chain reaction. AIDS. 1998;12(6):581–90.

    Article  PubMed  CAS  Google Scholar 

  46. Donaldson YK, Bell JE, Holmes EC, Hughes ES, Brown HK, Simmonds P. In vivo distribution and cytopathology of variants of human immunodeficiency virus type 1 showing restricted sequence variability in the V3 loop. J Virol. 1994;68(9):5991–6005.

    PubMed  CAS  Google Scholar 

  47. Gartner S, McDonald RA, Hunter EA, Bouwman F, Liu Y, Popovic M. Gp120 sequence variation in brain and in T-lymphocyte human immunodeficiency virus type 1 primary isolates. J Hum Virol. 1997;1(1):3–18.

    PubMed  CAS  Google Scholar 

  48. Hughes ES, Bell JE, Simmonds P. 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. 1997;71(2):1272–80.

    PubMed  CAS  Google Scholar 

  49. Korber BT, Kunstman KJ, Patterson BK, Furtado M, McEvilly MM, Levy R, Wolinsky SM. Genetic differences between blood- and brain-derived viral sequences from human immunodeficiency virus type 1-infected patients: evidence of conserved elements in the V3 region of the envelope protein of brain-derived sequences. J Virol. 1994;68(11):7467–81.

    PubMed  CAS  Google Scholar 

  50. Morris A, Marsden M, Halcrow K, Hughes ES, Brettle RP, Bell JE, Simmonds P. Mosaic structure of the human immunodeficiency virus type 1 genome infecting lymphoid cells and the brain: evidence for frequent in vivo recombination events in the evolution of regional populations. J Virol. 1999;73(10):8720–31.

    PubMed  CAS  Google Scholar 

  51. Pang S, Vinters HV, Akashi T, O’Brien WA, Chen IS. HIV-1 env sequence variation in brain tissue of patients with AIDS-related neurologic disease. J Acquir Immune Defic Syndr. 1991;4(11):1082–92.

    PubMed  CAS  Google Scholar 

  52. Power C, McArthur JC, Johnson RT, Griffin DE, Glass JD, Perryman S, Chesebro B. Demented and nondemented patients with AIDS differ in brain-derived human immunodeficiency virus type 1 envelope sequences. J Virol. 1994;68(7):4643–9.

    PubMed  CAS  Google Scholar 

  53. van’t Wout AB, Ran LJ, Kuiken CL, Kootstra NA, Pals ST, Schuitemaker H. Analysis of the temporal relationship between human immunodeficiency virus type 1 quasispecies in sequential blood samples and various organs obtained at autopsy. J Virol. 1998;72(1):488–96.

    PubMed  Google Scholar 

  54. Wang TH, Donaldson YK, Brettle RP, Bell JE, Simmonds P. Identification of shared populations of human immunodeficiency virus type 1 infecting microglia and tissue macrophages outside the central nervous system. J Virol. 2001;75(23):11686–99.

    Article  PubMed  CAS  Google Scholar 

  55. Wong JK, Ignacio CC, Torriani F, Havlir D, Fitch NJ, Richman DD. In vivo compartmentalization of human immunodeficiency virus: evidence from the examination of pol sequences from autopsy tissues. J Virol. 1997;71(3):2059–71.

    PubMed  CAS  Google Scholar 

  56. Sheehy N, Desselberger U, Whitwell H, Ball JK. Concurrent evolution of regions of the envelope and polymerase genes of human immunodeficiency virus type 1 during zidovudine (AZT) therapy. J Gen Virol. 1996;77(Pt 5):1071–81.

    Article  PubMed  CAS  Google Scholar 

  57. Shapshak P, Segal DM, Crandall KA, et al. Independent evolution of HIV type 1 in different brain regions. AIDS Res Hum Retrovir. 1999;15(9):811–20.

    Article  PubMed  CAS  Google Scholar 

  58. Smit TK, Brew BJ, Tourtellotte W, Morgello S, Gelman BB, Saksena NK. Independent evolution of human immunodeficiency virus (HIV) drug resistance mutations in diverse areas of the brain in HIV-infected patients, with and without dementia, on antiretroviral treatment. J Virol. 2004;78(18):10133–48.

    Article  PubMed  CAS  Google Scholar 

  59. Smit TK, Wang B, Ng T, Osborne R, Brew B, Saksena NK. Varied tropism of HIV-1 isolates derived from different regions of adult brain cortex discriminate between patients with and without AIDS dementia complex (ADC): evidence for neurotropic HIV variants. Virology. 2001;279(2):509–26.

    Article  PubMed  CAS  Google Scholar 

  60. Gorry PR, Bristol G, Zack JA, et al. Macrophage tropism of human immunodeficiency virus type 1 isolates from brain and lymphoid tissues predicts neurotropism independent of coreceptor specificity. J Virol. 2001;75(21):10073–89.

    Article  PubMed  CAS  Google Scholar 

  61. Olivieri KC, Agopian KA, Mukerji J, Gabuzda D. Evidence for adaptive evolution at the divergence between lymphoid and brain HIV-1 nef genes. AIDS Res Hum Retrovir. 2010;26(4):495–500.

    Article  PubMed  CAS  Google Scholar 

  62. Thomas ER, Dunfee RL, Stanton J, Bogdan D, Kunstman K, Wolinsky SM, Gabuzda D. High frequency of defective vpu compared with tat and rev genes in brain from patients with HIV type 1-associated dementia. AIDS Res Hum Retrovir. 2007;23(4):575–80.

    Article  PubMed  CAS  Google Scholar 

  63. Thomas ER, Dunfee RL, Stanton J, et al. Macrophage entry mediated by HIV Envs from brain and lymphoid tissues is determined by the capacity to use low CD4 levels and overall efficiency of fusion. Virology. 2007;360(1):105–19.

    Article  PubMed  CAS  Google Scholar 

  64. Dunfee RL, Thomas ER, Wang J, Kunstman K, Wolinsky SM, Gabuzda D. Loss of the N-linked glycosylation site at position 386 in the HIV envelope V4 region enhances macrophage tropism and is associated with dementia. Virology. 2007;367(1):222–34.

    Article  PubMed  CAS  Google Scholar 

  65. Kuiken CL, Goudsmit J, Weiller GF, Armstrong JS, Hartman S, Portegies P, Dekker J, Cornelissen M. Differences in human immunodeficiency virus type 1 V3 sequences from patients with and without AIDS dementia complex. J Gen Virol. 1995;76(Pt 1):175–80.

    Article  PubMed  CAS  Google Scholar 

  66. Reddy RT, Achim CL, Sirko DA, Tehranchi S, Kraus FG, Wong-Staal F, Wiley CA. Sequence analysis of the V3 loop in brain and spleen of patients with HIV encephalitis. AIDS Res Hum Retrovir. 1996;12(6):477–82.

    Article  PubMed  CAS  Google Scholar 

  67. Zink MC, Brice AK, Kelly KM, et al. 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 Infect Dis. 2010;202(1):161–70. 20497048.

    Article  PubMed  CAS  Google Scholar 

  68. Zink MC, Laast VA, Helke KL, Brice AK, Barber SA, Clements JE, Mankowski JL. From mice to macaques–animal models of HIV nervous system disease. Curr HIV Res. 2006;4(3):293–305.

    Article  PubMed  CAS  Google Scholar 

  69. Zink MC, Clements JE. A novel simian immunodeficiency virus model that provides insight into mechanisms of human immunodeficiency virus central nervous system disease. J Neurovirol. 2002;8(Suppl 2):42–8.

    Article  PubMed  CAS  Google Scholar 

  70. Zink MC, Suryanarayana K, Mankowski JL, et al. High viral load in the cerebrospinal fluid and brain correlates with severity of simian immunodeficiency virus encephalitis. J Virol. 1999;73(12):10480–8.

    PubMed  CAS  Google Scholar 

  71. Reeve AB, Pearce NC, Patel K, Augustus KV, Novembre FJ. Neuropathogenic SIVsmmFGb genetic diversity and selection-induced tissue-specific compartmentalization during chronic infection and temporal evolution of viral genes in lymphoid tissues and regions of the central nervous system. AIDS Res Hum Retrovir. 2010;26(6):663–79.

    Article  PubMed  CAS  Google Scholar 

  72. Witwer KW, Gama L, Li M, et al. Coordinated regulation of SIV replication and immune responses in the CNS. PLoS One. 2009;4(12):e8129.

    Article  PubMed  CAS  Google Scholar 

  73. Clements JE, Li M, Gama L, Bullock B, Carruth LM, Mankowski JL, Zink MC. The central nervous system is a viral reservoir in simian immunodeficiency virus–infected macaques on combined antiretroviral therapy: a model for human immunodeficiency virus patients on highly active antiretroviral therapy. J Neurovirol. 2005;11(2):180–9.

    PubMed  CAS  Google Scholar 

  74. Clements JE, Babas T, Mankowski JL, Suryanarayana K, Piatak M Jr, Tarwater PM, Lifson JD, Zink MC. The central nervous system as a reservoir for simian immunodeficiency virus (SIV): steady-state levels of SIV DNA in brain from acute through asymptomatic infection. J Infect Dis. 2002;186(7):905–13.

    Article  PubMed  CAS  Google Scholar 

  75. Witwer KW, Sisk JM, Gama L, Clements JE. MicroRNA regulation of IFN-beta protein expression: rapid and sensitive modulation of the innate immune response. J Immunol. 2010;184(5):2369–76.

    Article  PubMed  CAS  Google Scholar 

  76. O’Brien WA. HIV-1 entry and reverse transcription in macrophages. J Leukoc Biol. 1994;56(3):273–7.

    PubMed  Google Scholar 

  77. O’Brien WA, Mao SH, Cao Y, Moore JP. Macrophage-tropic and T-cell line-adapted chimeric strains of human immunodeficiency virus type 1 differ in their susceptibilities to neutralization by soluble CD4 at different temperatures. J Virol. 1994;68(8):5264–9.

    PubMed  Google Scholar 

  78. Barber SA, Herbst DS, Bullock BT, Gama L, Clements JE. Innate immune responses and control of acute simian immunodeficiency virus replication in the central nervous system. J Neurovirol. 2004;10(Suppl 1):15–20.

    PubMed  CAS  Google Scholar 

  79. Barber SA, Gama L, Dudaronek JM, Voelker T, Tarwater PM, Clements JE. Mechanism for the establishment of transcriptional HIV latency in the brain in a simian immunodeficiency virus-macaque model. J Infect Dis. 2006;193(7):963–70.

    Article  PubMed  CAS  Google Scholar 

  80. Dudaronek JM, Barber SA, Clements JE. CUGBP1 is required for IFNbeta-mediated induction of dominant-negative CEBPbeta and suppression of SIV replication in macrophages. J Immunol. 2007;179(11):7262–9.

    PubMed  CAS  Google Scholar 

  81. Barber SA, Gama L, Li M, et al. Longitudinal analysis of simian immunodeficiency virus (SIV) replication in the lungs: compartmentalized regulation of SIV. J Infect Dis. 2006;194(7):931–8.

    Article  PubMed  CAS  Google Scholar 

  82. Sodora DL, Allan JS, Apetrei C, et al. Toward an AIDS vaccine: lessons from natural simian immunodeficiency virus infections of African nonhuman primate hosts. Nat Med. 2009;15(8):861–5. 19661993.

    Article  PubMed  CAS  Google Scholar 

  83. Broussard SR, Staprans SI, White R, Whitehead EM, Feinberg MB, Allan JS. Simian immunodeficiency virus replicates to high levels in naturally infected African green monkeys without inducing immunologic or neurologic disease. J Virol. 2001;75(5):2262–75.

    Article  PubMed  CAS  Google Scholar 

  84. Taaffe J, Chahroudi A, Engram J, et al. A five-year longitudinal analysis of sooty mangabeys naturally infected with simian immunodeficiency virus reveals a slow but progressive decline in CD4 + T-cell count whose magnitude is not predicted by viral load or immune activation. J Virol. 2010;84(11):5476–84.

    Article  PubMed  CAS  Google Scholar 

  85. Paiardini M, Pandrea I, Apetrei C, Silvestri G. Lessons learned from the natural hosts of HIV-related viruses. Ann Rev Med. 2009;60:485–95.

    Article  PubMed  CAS  Google Scholar 

  86. Pandrea I, Silvestri G, Apetrei C. AIDS in African nonhuman primate hosts of SIVs: a new paradigm of SIV infection. Curr HIV Res. 2009;7(1):57–72.

    Article  PubMed  CAS  Google Scholar 

  87. Silvestri G. AIDS pathogenesis: a tale of two monkeys. J Med Primatol. 2008;37(Suppl 2):6–12.

    Article  PubMed  Google Scholar 

  88. Silvestri G. Immunity in natural SIV infections. J Intern Med. 2009;265(1):97–109.

    Article  PubMed  CAS  Google Scholar 

  89. Jacquelin B, Mayau V, Targat B, et al. Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response. J Clin Invest. 2009;119(12):3544–55.

    PubMed  CAS  Google Scholar 

  90. Cumont MC, Diop O, Vaslin B, et al. Early divergence in lymphoid tissue apoptosis between pathogenic and nonpathogenic simian immunodeficiency virus infections of nonhuman primates. J Virol. 2008;82(3):1175–84.

    Article  PubMed  CAS  Google Scholar 

  91. Ziv Y, Ron N, Butovsky O, et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci. 2006;9(2):268–75. 16415867.

    Article  PubMed  CAS  Google Scholar 

  92. Lewitus GM, Cohen H, Schwartz M. Reducing post-traumatic anxiety by immunization. Brain Behav Immun. 2008;22(7):1108–14. 18562161.

    Article  PubMed  CAS  Google Scholar 

  93. Kipnis J, Cohen H, Cardon M, Ziv Y, Schwartz M. T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc Natl Acad Sci USA. 2004;101(21):8180–5. 15141078.

    Article  PubMed  CAS  Google Scholar 

  94. Lewitus GM, Wilf-Yarkoni A, Ziv Y, Shabat-Simon M, Gersner R, Zangen A, Schwartz M. Vaccination as a novel approach for treating depressive behavior. Biol Psychiatry. 2009;65(4):283–8. 18722594.

    Article  PubMed  Google Scholar 

  95. Moalem G, Leibowitz-Amit R, Yoles E, Mor F, Cohen IR, Schwartz M. Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat Med. 1999;5(1):49–55. 9883839.

    Article  PubMed  CAS  Google Scholar 

  96. Rapalino O, Lazarov-Spiegler O, Agranov E, et al. Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat Med. 1998;4(7):814–21. 9662373.

    Article  PubMed  CAS  Google Scholar 

  97. Hauben E, Agranov E, Gothilf A, Nevo U, Cohen A, Smirnov I, Steinman L, Schwartz M. Posttraumatic therapeutic vaccination with modified myelin self-antigen prevents complete paralysis while avoiding autoimmune disease. J Clin Invest. 2001;108(4):591–9. 11518733.

    PubMed  CAS  Google Scholar 

  98. Thompson PM, Dutton RA, Hayashi KM, Toga AW, Lopez OL, Aizenstein HJ, Becker JT. Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4 + T lymphocyte decline. Proc Natl Acad Sci USA. 2005;102(43):15647–52. 16227428.

    Article  PubMed  CAS  Google Scholar 

  99. Anthony IC, Ramage SN, Carnie FW, Simmonds P, Bell JE. Influence of HAART on HIV-related CNS disease and neuroinflammation. J Neuropathol Exp Neurol. 2005;64(6):529–36. 15977645.

    PubMed  CAS  Google Scholar 

  100. Eden A, Price RW, Spudich S, Fuchs D, Hagberg L, Gisslen M. Immune activation of the central nervous system is still present after >4 years of effective highly active antiretroviral therapy. J Infect Dis. 2007;196(12):1779–83. 18190258.

    Article  PubMed  CAS  Google Scholar 

  101. Ellis R, Langford D, Masliah E. HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci. 2007;8(1):33–44. 17180161.

    Article  PubMed  CAS  Google Scholar 

  102. Sacktor N, Lyles RH, Skolasky R, et al. HIV-associated neurologic disease incidence changes: Multicenter AIDS Cohort Study, 1990–1998. Neurology. 2001;56(2):257–60. 11160967.

    PubMed  CAS  Google Scholar 

  103. Sacktor N, Tarwater PM, Skolasky RL, McArthur JC, Selnes OA, Becker J, Cohen B, Miller EN. CSF antiretroviral drug penetrance and the treatment of HIV-associated psychomotor slowing. Neurology. 2001;57(3):542–4. 11502933.

    PubMed  CAS  Google Scholar 

  104. Marra CM, Lockhart D, Zunt JR, Perrin M, Coombs RW, Collier AC. Changes in CSF and plasma HIV-1 RNA and cognition after starting potent antiretroviral therapy. Neurology. 2003;60(8):1388–90. 12707454.

    PubMed  CAS  Google Scholar 

  105. Cysique LA, Maruff P, Brew BJ. Antiretroviral therapy in HIV infection: are neurologically active drugs important? Arch Neurol. 2004;61(11):1699–704. 15534181.

    Article  PubMed  Google Scholar 

  106. Shelburne SA 3rd, Hamill RJ, Rodriguez-Barradas MC, et al. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine (Baltimore). 2002;81(3):213–27. 11997718.

    Article  Google Scholar 

  107. McCombe JA, Auer RN, Maingat FG, Houston S, Gill MJ, Power C. Neurologic immune reconstitution inflammatory syndrome in HIV/AIDS: outcome and epidemiology. Neurology. 2009;72(9):835–41. 19255411.

    Article  PubMed  CAS  Google Scholar 

  108. Kaul M, Garden GA, Lipton SA. Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature. 2001;410(6831):988–94. 11309629.

    Article  PubMed  CAS  Google Scholar 

  109. Power C, Gill MJ, Johnson RT. Progress in clinical neurosciences: the neuropathogenesis of HIV infection: host-virus interaction and the impact of therapy. Can J Neurol Sci. 2002;29(1):19–32. 11858531.

    PubMed  CAS  Google Scholar 

  110. The neurology of AIDS, Second edn. London: Oxford University Press; 2005.

  111. Ellis RJ, Deutsch R, Heaton RK, et al. Neurocognitive impairment is an independent risk factor for death in HIV infection. San Diego HIV Neurobehavioral Research Center Group. Arch Neurol. 1997;54(4):416–24. 9109743.

    PubMed  CAS  Google Scholar 

  112. Budka H. Neuropathology of human immunodeficiency virus infection. Brain Pathol. 1991;1(3):163–75. 1669705.

    Article  PubMed  CAS  Google Scholar 

  113. Spencer DC, Price RW. Human immunodeficiency virus and the central nervous system. Annu Rev Microbiol. 1992;46:655–93. 1444270.

    Article  PubMed  CAS  Google Scholar 

  114. McArthur JC, Hoover DR, Bacellar H, et al. Dementia in AIDS patients: incidence and risk factors Multicenter AIDS Cohort Study. Neurology. 1993;43(11):2245–52. 8232937.

    PubMed  CAS  Google Scholar 

  115. Gendelman HE, Lipton SA, Tardieu M, Bukrinsky MI, Nottet HS. The neuropathogenesis of HIV-1 infection. J Leukoc Biol. 1994;56(3):389–98. 8083614.

    PubMed  CAS  Google Scholar 

  116. Lipton SA, Gendelman HE. Seminars in medicine of the Beth Israel Hospital, Boston. Dementia associated with the acquired immunodeficiency syndrome. N Engl J Med. 1995;332(14):934–40. 7877652.

    Article  PubMed  CAS  Google Scholar 

  117. Bell JE. The neuropathology of adult HIV infection. Rev Neurol (Paris). 1998;154(12):816–29. 9932303.

    CAS  Google Scholar 

  118. Nath A. Pathobiology of human immunodeficiency virus dementia. Semin Neurol. 1999;19(2):113–27. 10718533.

    Article  PubMed  CAS  Google Scholar 

  119. McArthur JC, Haughey N, Gartner S, Conant K, Pardo C, Nath A, Sacktor N. Human immunodeficiency virus-associated dementia: an evolving disease. J Neurovirol. 2003;9(2):205–21. 12707851.

    PubMed  CAS  Google Scholar 

  120. Cunningham PH, Smith DG, Satchell C, Cooper DA, Brew B. Evidence for independent development of resistance to HIV-1 reverse transcriptase inhibitors in the cerebrospinal fluid. AIDS. 2000;14(13):1949–54. 10997399.

    Article  PubMed  CAS  Google Scholar 

  121. Welch K, Morse A. The clinical profile of end-stage AIDS in the era of highly active antiretroviral therapy. AIDS Patient Care STDS. 2002;16(2):75–81. 11874639.

    Article  PubMed  Google Scholar 

  122. Lipton SA. Treating AIDS dementia. Science. 1997;276(5319):1629–30. 9206820.

    Article  PubMed  CAS  Google Scholar 

  123. Kramer-Hammerle S, Rothenaigner I, Wolff H, Bell JE, Brack-Werner R. Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus. Virus Res. 2005;111(2):194–213. 15885841.

    Article  PubMed  CAS  Google Scholar 

  124. Jones G, Power C. Regulation of neural cell survival by HIV-1 infection. Neurobiol Dis. 2006;21(1):1–17. 16298136.

    Article  PubMed  CAS  Google Scholar 

  125. Bansal AK, Mactutus CF, Nath A, Maragos W, Hauser KF, Booze RM. Neurotoxicity of HIV-1 proteins gp120 and Tat in the rat striatum. Brain Res. 2000;879(1–2):42–9. 11011004.

    Article  PubMed  CAS  Google Scholar 

  126. Agrawal L, Louboutin JP, Strayer DS. Preventing HIV-1 Tat-induced neuronal apoptosis using antioxidant enzymes: mechanistic and therapeutic implications. Virology. 2007;363(2):462–72. 17336361.

    Article  PubMed  CAS  Google Scholar 

  127. Corasaniti MT, Strongoli MC, Piccirilli S, et al. Apoptosis induced by gp120 in the neocortex of rat involves enhanced expression of cyclooxygenase type 2 and is prevented by NMDA receptor antagonists and by the 21-aminosteroid U-74389G. Biochem Biophys Res Commun. 2000;274(3):664–9.

    Article  PubMed  CAS  Google Scholar 

  128. Kaul M, Lipton SA. Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis. Proc Natl Acad Sci USA. 1999;96(14):8212–6.

    Article  PubMed  CAS  Google Scholar 

  129. Meucci O, Fatatis A, Simen AA, Bushell TJ, Gray PW, Miller RJ. Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity. Proc Natl Acad Sci USA. 1998;95(24):14500–5.

    Article  PubMed  CAS  Google Scholar 

  130. Shi B, De GU, He J, Wang S, Lorenzo A, Busciglio J, Gabuzda D. Apoptosis induced by HIV-1 infection of the central nervous system. J Clin Invest. 1996;98(9):1979–90.

    Article  PubMed  CAS  Google Scholar 

  131. Hu S, Sheng WS, Lokensgard JR, Peterson PK, Rock RB. Preferential sensitivity of human dopaminergic neurons to gp120-induced oxidative damage. J Neurovirol. 2009;15(5–6):401–10.

    Article  PubMed  CAS  Google Scholar 

  132. Itoh K, Mehraein P, Weis S. Neuronal damage of the substantia nigra in HIV-1 infected brains. Acta Neuropathol. 2000;99(4):376–84.

    Article  PubMed  CAS  Google Scholar 

  133. Brenneman DE, Westbrook GL, Fitzgerald SP, Ennist DL, Elkins KL, Ruff MR, Pert CB. Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide. Nature. 1988;335(6191):639–42. 2845276.

    Article  PubMed  CAS  Google Scholar 

  134. Dong J, Xiong H. Human immunodeficiency virus type 1 gp120 inhibits long-term potentiation via chemokine receptor CXCR4 in rat hippocampal slices. J Neurosci Res. 2006;83(3):489–96. 16400660.

    Article  PubMed  CAS  Google Scholar 

  135. Foster JL, Garcia JV. HIV-1 Nef: at the crossroads. Retrovirology. 2008;5:84. 18808677.

    Article  PubMed  CAS  Google Scholar 

  136. Trillo-Pazos G, McFarlane-Abdulla E, Campbell IC, Pilkington GJ, Everall IP. Recombinant nef HIV-IIIB protein is toxic to human neurons in culture. Brain Res. 2000;864(2):315–26. 10802040.

    Article  PubMed  CAS  Google Scholar 

  137. van Marle G, Henry S, Todoruk T, et al. Human immunodeficiency virus type 1 Nef protein mediates neural cell death: a neurotoxic role for IP-10. Virology. 2004;329(2):302–18. 15518810.

    PubMed  Google Scholar 

  138. Sporer B, Koedel U, Paul R, Kohleisen B, Erfle V, Fontana A, Pfister HW. Human immunodeficiency virus type-1 Nef protein induces blood-brain barrier disruption in the rat: role of matrix metalloproteinase-9. J Neuroimmunol. 2000;102(2):125–30. 10636480.

    Article  PubMed  CAS  Google Scholar 

  139. Anthony IC, Ramage SN, Carnie FW, Simmonds P, Bell JE. 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. 2006;111(6):529–38. 16718349.

    Article  PubMed  CAS  Google Scholar 

  140. Fagan AM, Mintun MA, Mach RH, et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol. 2006;59(3):512–9. 16372280.

    Article  PubMed  CAS  Google Scholar 

  141. Brew BJ, Pemberton L, Blennow K, Wallin A, Hagberg L. CSF amyloid beta42 and tau levels correlate with AIDS dementia complex. Neurology. 2005;65(9):1490–2. 16275845.

    Article  PubMed  CAS  Google Scholar 

  142. Clifford DB, Fagan AM, Holtzman DM, Morris JC, Teshome M, Shah AR, Kauwe JS. CSF biomarkers of Alzheimer disease in HIV-associated neurologic disease. Neurology. 2009;73(23):1982–7. 19907013.

    Article  PubMed  CAS  Google Scholar 

  143. Pulliam L. HIV regulation of amyloid beta production. J Neuroimmune Pharmacol. 2009;4(2):213–7. 19288202.

    Article  PubMed  Google Scholar 

  144. Xu J, Ikezu T. The comorbidity of HIV-associated neurocognitive disorders and Alzheimer’s disease: a foreseeable medical challenge in post-HAART era. J Neuroimmune Pharmacol. 2009;4(2):200–12. 19016329.

    Article  PubMed  CAS  Google Scholar 

  145. Behnisch T, Francesconi W, Sanna PP. HIV secreted protein Tat prevents long-term potentiation in the hippocampal CA1 region. Brain Res. 2004;1012(1–2):187–9. 15158177.

    Article  PubMed  CAS  Google Scholar 

  146. Xiong H, Zeng YC, Zheng J, Thylin M, Gendelman HE. Soluble HIV-1 infected macrophage secretory products mediate blockade of long-term potentiation: a mechanism for cognitive dysfunction in HIV-1-associated dementia. J Neurovirol. 1999;5(5):519–28. 10568889.

    Article  PubMed  CAS  Google Scholar 

  147. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002;416(6880):535–9. 11932745.

    Article  PubMed  CAS  Google Scholar 

  148. Aksenov MY, Aksenova MV, Mactutus CF, Booze RM. HIV-1 protein-mediated amyloidogenesis in rat hippocampal cell cultures. Neurosci Lett. 2010;475(3):174–8. 20363291.

    Article  PubMed  CAS  Google Scholar 

  149. Harris-White ME, Chu T, Balverde Z, Sigel JJ, Flanders KC, Frautschy SA. Effects of transforming growth factor-beta (isoforms 1–3) on amyloid-beta deposition, inflammation, and cell targeting in organotypic hippocampal slice cultures. J Neurosci. 1998;18(24):10366–74. 9852574.

    PubMed  CAS  Google Scholar 

  150. Harris-White ME, Balverde Z, Lim GP, Kim P, Miller SA, Hammer H, Galasko D, Frautschy SA. Role of LRP in TGFbeta2-mediated neuronal uptake of Abeta and effects on memory. J Neurosci Res. 2004;77(2):217–28. 15211588.

    Article  PubMed  CAS  Google Scholar 

  151. Eslami P, Johnson MF, Terzakaryan E, Chew C, Harris-White ME. TGF beta2-induced changes in LRP-1/T beta R-V and the impact on lysosomal A beta uptake and neurotoxicity. Brain Res. 2008;1241:176–87. 18804458.

    Article  PubMed  CAS  Google Scholar 

  152. Hall JR, Short SC. Management of glioblastoma multiforme in HIV patients: a case series and review of published studies. Clin Oncol (R Coll Radiol). 2009;21(8):591–7. 19589665.

    CAS  Google Scholar 

  153. Rosenblum ML, Levy RM, DE Bredesen, So YT, Wara W, Ziegler JL. Primary central nervous system lymphomas in patients with AIDS. Ann Neurol. 1988;23(Suppl):S13–6. 2894803.

    Article  PubMed  Google Scholar 

  154. Welch K, Finkbeiner W, Alpers CE, Blumenfeld W, Davis RL, Smuckler EA, Beckstead JH. Autopsy findings in the acquired immune deficiency syndrome. JAMA. 1984;252(9):1152–9. 6471338.

    Article  PubMed  CAS  Google Scholar 

  155. Sparano JA, Anand K, Desai J, Mitnick RJ, Kalkut GE, Hanau LH. Effect of highly active antiretroviral therapy on the incidence of HIV-associated malignancies at an urban medical center. J Acquir Immune Defic Syndr. 1999;21(Suppl 1):S18–22. 10430213.

    PubMed  CAS  Google Scholar 

  156. Inungu J, Melendez MF, Montgomery JP. AIDS-related primary brain lymphoma in Michigan, January 1990 to December 2000. AIDS Patient Care STDS. 2002;16(3):107–12. 11945206.

    Article  PubMed  Google Scholar 

  157. Tanner JE, Alfieri C. The Epstein-Barr virus and post-transplant lymphoproliferative disease: interplay of immunosuppression, EBV, and the immune system in disease pathogenesis. Transpl Infect Dis. 2001;3(2):60–9. 11395971.

    Article  PubMed  CAS  Google Scholar 

  158. Gasser O, Bihl FK, Wolbers M, et al. HIV patients developing primary CNS lymphoma lack EBV-specific CD4+T cell function irrespective of absolute CD4+T cell counts. PLoS Med. 2007;4(3):e96. 17388662.

    Article  PubMed  CAS  Google Scholar 

  159. Blumenthal DT, Raizer JJ, Rosenblum MK, Bilsky MH, Hariharan S, Abrey LE. Primary intracranial neoplasms in patients with HIV. Neurology. 1999;52(8):1648–51. 10331693.

    PubMed  CAS  Google Scholar 

  160. Moulignier A, Mikol J, Pialoux G, Eliaszewicz M, Thurel C, Thiebaut JB. Cerebral glial tumors and human immunodeficiency virus-1 infection. More than a coincidental association. Cancer. 1994;74(2):686–92. 8033048.

    Article  PubMed  CAS  Google Scholar 

  161. Tacconi L, Stapleton S, Signorelli F, Thomas DG. Acquired immune deficiency syndrome (AIDS) and cerebral astrocytoma. Clin Neurol Neurosurg. 1996;98(2):149–51. 8836588.

    Article  PubMed  CAS  Google Scholar 

  162. Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, Smyth MJ, Schreiber RD. Adaptive immunity maintains occult cancer in an equilibrium state. Nature. 2007;450(7171):903–7. 18026089.

    Article  PubMed  CAS  Google Scholar 

  163. Salvati M, Frati A, Caroli E, Russo N, Polli FM, Domenicucci M, Delfini R. Glioblastoma in kidney transplant recipients. Report of five cases. J Neurooncol. 2003;63(1):33–7. 12814252.

    Article  PubMed  Google Scholar 

  164. Schiff D, O’Neill B, Wijdicks E, Antin JH, Wen PY. Gliomas arising in organ transplant recipients: an unrecognized complication of transplantation? Neurology. 2001;57(8):1486–8. 11673595.

    PubMed  CAS  Google Scholar 

  165. Hajjar M, Lacoste D, Brossard G, Morlat P, Dupon M, Salmi LR, Dabis F. Non-acquired immune deficiency syndrome-defining malignancies in a hospital-based cohort of human immunodeficiency virus-infected patients: Bordeaux, France, 1985–1991. Groupe d’Epidemiologie Clinique du SIDA en Aquitaine. J Natl Cancer Inst. 1992;84(20):1593–5. 1404453.

    Article  PubMed  CAS  Google Scholar 

  166. Geleziunas R, Schipper HM, Wainberg MA. Pathogenesis and therapy of HIV-1 infection of the central nervous system. AIDS. 1992;6(12):1411–26. 1337255.

    Article  PubMed  CAS  Google Scholar 

  167. Taylor JP, Cupp C, Diaz A, Chowdhury M, Khalili K, Jimenez SA, Amini S. Activation of expression of genes coding for extracellular matrix proteins in Tat-producing glioblastoma cells. Proc Natl Acad Sci USA. 1992;89(20):9617–21. 1409674.

    Article  PubMed  CAS  Google Scholar 

  168. Wahl SM, Allen JB, Hines KL, Imamichi T, Wahl AM, Furcht LT, McCarthy JB. Synthetic fibronectin peptides suppress arthritis in rats by interrupting leukocyte adhesion and recruitment. J Clin Invest. 1994;94(2):655–62. 8040319.

    Article  PubMed  CAS  Google Scholar 

  169. Selmaj KW, Farooq M, Norton WT, Raine CS, Brosnan CF. Proliferation of astrocytes in vitro in response to cytokines. A primary role for tumor necrosis factor. J Immunol. 1990;144(1):129–35. 2104886.

    PubMed  CAS  Google Scholar 

  170. Maxwell M, Galanopoulos T, Neville-Golden J, Antoniades HN. Effect of the expression of transforming growth factor-beta 2 in primary human glioblastomas on immunosuppression and loss of immune surveillance. J Neurosurg. 1992;76(5):799–804. 1373442.

    Article  PubMed  CAS  Google Scholar 

  171. Emdad L, Sarkar D, Su ZZ, Lee SG, Kang DC, Bruce JN, Volsky DJ, Fisher PB. Astrocyte elevated gene-1: recent insights into a novel gene involved in tumor progression, metastasis and neurodegeneration. Pharmacol Ther. 2007;114(2):155–70. 17397930.

    Article  PubMed  CAS  Google Scholar 

  172. Sarkar D, Emdad L, Lee SG, Yoo BK, Su ZZ, Fisher PB. Astrocyte elevated gene-1: far more than just a gene regulated in astrocytes. Cancer Res. 2009;69(22):8529–35. 19903854.

    Article  PubMed  CAS  Google Scholar 

  173. Kang DC, Su ZZ, Sarkar D, Emdad L, Volsky DJ, Fisher PB. Cloning and characterization of HIV-1-inducible astrocyte elevated gene-1, AEG-1. Gene. 2005;353(1):8–15. 15927426.

    Article  PubMed  CAS  Google Scholar 

  174. Lee SG, Jeon HY, Su ZZ, Richards JE, Vozhilla N, Sarkar D, Van Maerken T, Fisher PB. Astrocyte elevated gene-1 contributes to the pathogenesis of neuroblastoma. Oncogene. 2009;28(26):2476–84. 19448665.

    Article  PubMed  CAS  Google Scholar 

  175. Liu H, Song X, Liu C, Xie L, Wei L, Sun R. Knockdown of astrocyte elevated gene-1 inhibits proliferation and enhancing chemo-sensitivity to cisplatin or doxorubicin in neuroblastoma cells. J Exp Clin Cancer Res. 2009;28:19. 19216799.

    Article  PubMed  CAS  Google Scholar 

  176. Ranki A, Nyberg M, Ovod V, Haltia M, Elovaara I, Raininko R, Haapasalo H, Krohn K. Abundant expression of HIV Nef and Rev proteins in brain astrocytes in vivo is associated with dementia. AIDS. 1995;9(9):1001–8. 8527071.

    Article  PubMed  CAS  Google Scholar 

  177. Kramer-Hammerle S, Kohleisen B, Hohenadl C, Shumay E, Becker I, Erfle V, Schmidt J. HIV type 1 Nef promotes neoplastic transformation of immortalized neural cells. AIDS Res Hum Retrovir. 2001;17(7):597–602. 11375055.

    Article  PubMed  CAS  Google Scholar 

  178. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994;331(18):1173–80.

    Article  PubMed  CAS  Google Scholar 

  179. Van Rie A, Mupuala A, Dow A. Impact of the HIV/AIDS epidemic on the neurodevelopment of preschool-aged children in Kinshasa, Democratic Republic of the Congo. Pediatrics. 2008;122(1):e123–8. 18595957.

    Article  PubMed  Google Scholar 

  180. Diamond GW, Kaufman J, Belman AL, Cohen L, Cohen HJ, Rubinstein A. Characterization of cognitive functioning in a subgroup of children with congenital HIV infection. Arch Clin Neuropsychol. 1987;2(3):245–56. 14589616.

    PubMed  CAS  Google Scholar 

  181. Epstein LG, Sharer LR, Oleske JM, Connor EM, Goudsmit J, Bagdon L, Robert-Guroff M, Koenigsberger MR. Neurologic manifestations of human immunodeficiency virus infection in children. Pediatrics. 1986;78(4):678–87. 2429248.

    PubMed  CAS  Google Scholar 

  182. Van RA, Harrington PR, Dow A, Robertson K. Neurologic and neurodevelopmental manifestations of pediatric HIV/AIDS: a global perspective. Eur J Paediatr Neurol. 2007;11(1):1–9.

    Article  Google Scholar 

  183. Belman AL. Pediatric neuro-AIDS. Update. Neuroimaging Clin N Am. 1997;7(3):593–613.

    PubMed  CAS  Google Scholar 

  184. Chase C, Vibbert M, Pelton SI, Coulter DL, Cabral H. Early neurodevelopmental growth in children with vertically transmitted human immunodeficiency virus infection. Arch Pediatr Adolesc Med. 1995;149(8):850–5.

    PubMed  CAS  Google Scholar 

  185. Smith R, Malee K, Leighty R, Brouwers P, Mellins C, Hittelman J, Chase C, Blasini I. Effects of perinatal HIV infection and associated risk factors on cognitive development among young children. Pediatrics. 2006;117(3):851–62.

    Article  PubMed  Google Scholar 

  186. Chase C, Ware J, Hittelman J, et al. Early cognitive and motor development among infants born to women infected with human immunodeficiency virus. Women and Infants Transmission Study Group. Pediatrics. 2000;106(2):E25.

    Article  PubMed  CAS  Google Scholar 

  187. Thorne C, Newell ML. Safety of agents used to prevent mother-to-child transmission of HIV: is there any cause for concern? Drug Saf. 2007;30(3):203–13.

    Article  PubMed  CAS  Google Scholar 

  188. Bulterys M, Nesheim S, Abrams EJ, Palumbo P, Farley J, Lampe M, Fowler MG. Lack of evidence of mitochondrial dysfunction in the offspring of HIV-infected women. Retrospective review of perinatal exposure to antiretroviral drugs in the Perinatal AIDS Collaborative Transmission Study. Ann NY Acad Sci. 2000;918:212–21.

    Article  PubMed  CAS  Google Scholar 

  189. Williams PL, Marino M, Malee K, Brogly S, Hughes MD, Mofenson LM. Neurodevelopment and in utero antiretroviral exposure of HIV-exposed uninfected infants. Pediatrics. 2010;125(2):e250–60. 20083530.

    Article  PubMed  Google Scholar 

  190. Boksa P. Effects of prenatal infection on brain development and behavior: a review of findings from animal models; 2010; (1090–2139 (Electronic)).

  191. Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12(12):1365–71.

    Article  PubMed  CAS  Google Scholar 

  192. Ancuta P, Kamat A, Kunstman KJ, et al. Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients. PLoS One. 2008;3(6):e2516. 18575590.

    Article  PubMed  CAS  Google Scholar 

  193. Teeling JL, Perry VH. Systemic Infection and inflammation in acute CNS injury and chronic neurodegeneration: underlying mechanisms. Neuroscience. 2009;158:1062–73.

    Article  PubMed  CAS  Google Scholar 

  194. Ahrne S, Lonnermark E, Wold AE, et al. Lactobacilli in the intestinal microbiota of Swedish infants. Microbes Infect. 2005;7(11–12):1256–62.

    Article  PubMed  Google Scholar 

  195. Wold AE, Adlerberth I. Breast feeding and the intestinal microflora of the infant–implications for protection against infectious diseases. Adv Exp Med Biol. 2000;478:77–93.

    Article  PubMed  CAS  Google Scholar 

  196. Qing G, Howlett S, Bortolussi R. Lipopolysaccharide binding proteins on polymorphonuclear leukocytes: comparison of adult and neonatal cells. Infect Immun. 1996;64(11):4638–42.

    PubMed  CAS  Google Scholar 

  197. Wallet MA, Rodriguez CA, Yin L, Saporta S, Chinratanapisit S, Hou W, Sleasman JW, Goodenow MM. Microbial translocation induces persistent macrophage activation unrelated to HIV-1 levels or T-cell activation following therapy. AIDS. 2010;24(9):1281–90.

    Article  PubMed  CAS  Google Scholar 

  198. Ho DD, Rota TR, Schooley RT, et al. Isolation of HTLV-III from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related to the acquired immunodeficiency syndrome. N Engl J Med. 1985;313(24):1493–7. 2999591.

    Article  PubMed  CAS  Google Scholar 

  199. Gonzalez-Scarano F, Martin-Garcia J. The neuropathogenesis of AIDS. Nat Rev Immunol. 2005;5(1):69–81. 15630430.

    Article  PubMed  CAS  Google Scholar 

  200. Gartner S. HIV infection and dementia. Science. 2000;287(5453):602–4. 10691542.

    Article  PubMed  CAS  Google Scholar 

  201. Schwartz M, Shechter R. Protective autoimmunity functions by intracranial immunosurveillance to support the mind: the missing link between health and disease. Mol Psychiatry. 2010;15:342–54.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was funded by VA Merit Reviews (K.G.-F. and M.E.H.-W.), an NIH R01 AG022080 (M.E.H.-W.) and The Macy’s Foundation (K.G.F.).

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  1. UCLA Department of Medicine, Los Angeles, CA, USA

    K. Grovit-Ferbas & M. E. Harris-White

  2. UCLA AIDS Institute, 11301 Wilshire Blvd. (111Q), Bldg. 114, Room 217, Los Angeles, CA, 90073, USA

    K. Grovit-Ferbas

  3. Veterans Administration, Greater Los Angeles Healthcare System, Los Angeles, CA, USA

    K. Grovit-Ferbas & M. E. Harris-White

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Grovit-Ferbas, K., Harris-White, M.E. Thinking about HIV: the intersection of virus, neuroinflammation and cognitive dysfunction. Immunol Res 48, 40–58 (2010). https://doi.org/10.1007/s12026-010-8166-x

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