Abstract
Human immunodeficiency virus type 1 (HIV-1) central nervous system (CNS) infection in children is associated with impaired brain growth and neurodevelopmental delays. Neural progenitors are critical for neurogenesis. Human multipotential neural progenitors grown in culture are permissive for HIV-1 infection, but it is not known if infection of these cells occurs in vivo. Brain tissue from pre-highly active antiretroviral therapy (HAART) era pediatric acquired immunodeficiency syndrome (AIDS) patients was examined for evidence of HIV-1 infection of nestin-positive neural progenitors by in situ hybridization; or after laser microdissection harvest, DNA extraction, and polymerase chain reaction (PCR). HIV-1 or viral DNA was identified in nestin-positive cells in four of seven HIV-1-infected children, suggesting in vivo infection of neural progenitors.
References
Adachi A, Gendelman HE, Koenig S, Folks T, Willey R, Rabson A, Martin MA (1986). Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. J Virol 59: 284–291.
Belman Al, Ultmann MH, Horoupian D, Novick B, Spiro AJ, Rubinstein A, Kurtzberg D, Cone-Wesson B (1985). Neurological complications in infants and children with acquired immunodeficiency syndrome. Ann Neurol 18: 560–566.
Bhat S, Spitalnik SL, Gonzalez-Scarano F, Silberberg DH (1991). Galactosyl ceremide or a derivative is an essential component of the neural receptor for human immunodeficiency virus type 1 envelope glycoprotein gp120. Proc Natl Acad Sci U S A 88: 7131–7134.
Biber K, de Jong EK, van Weering HRJ, Boddeke HWGM (2006). Chemokines and their receptors in central nervous system disease. Curr Drug Targets 7: 29–46.
Blumcke I, Schewe J-C, Normann S, Brüstle O, Schramm J, Elger CE, Weistler OD (2001). Increase in nestinimmunoreactive neural precursor cells in the dentate gyrus of pediatric patients with early-onset temporal lobe epilepsy. Hippocampus 11: 311–321.
Boutet A, Salim H, Taoufik Y, Lledo P-M, Vincent J-D, Delfraissy J-F, Tardieu M (2001). Isolated human astrocytes are not susceptible to infection by M- and T-tropic strains despite functional expression of the chemokine receptors CCR5 and CXCR4. Glia 34: 165–177.
Brack-Werner R (1999). Astrocytes: HIV cellular reservoirs and important participants in neuropathogenesis. AIDS 13: 1–22.
Churchill MJ, Gorry PR, Cowley D, Lal L, Sonza S, Purcell DFJ, Thompson KA, Gabuzda D, McArthur JC, Pardo CA, Wesselingh SL (2006). Use of laser capture microdissection to detect integrated HIV-1 DNA in macrophages and astrocytes from autopsy brain tissues. J NeuroVirol 12: 146–152.
Conant K, Garzino-Demo A, Nath A, McArthur JC, Halliday W, Power C, Gallo RC, Major EO (1998). Induction of monocyte chemoattractant protein-1 in HIV-1 tat-stimulated astrocytes and elevation in AIDS dementia. Proc Natl Acad Sci U S A 95: 3117–3121.
Deshpande M, Zheng J, Borgmann K, Persidsky R, Wu L, Schellpeper C, Ghorpade A (2005). Role of activated astrocytes in neuronal damage: potential links to HIV-1 associated dementia. Neurotoxicol Res 7: 183–192.
Epstein LG, Sharer LR, Oleske JM, Connor EM, Goudsmit J, Bagdon L, Robert-Guroff M, Koenigsberger MR (1986). Neurologic manifestations of human immunodeficiency virus infection in children. Pediatrics 78: 678–687.
Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn A-M, Nordborg C, Peterson DA, Gage FH (1998). Neurogenesis in the adult hippocampus. Nat Med 4: 1313–1317.
Frisen J, Johansson CB, Török C, Risling M, Lendahl U (1995). Rapid, widespread, and long lasting induction of nestin contributes to the generation of glial scar tissue after CNS injury. J Cell Biol 131: 453–464.
Glass JD, Wesselingh SL (2001). Microglia in HIV-associated neurological diseases. Microsc Res Tech 54: 5–105.
Gu H, Wang S, Messam CA, Yao Z (2002). Distribution of nestin immunoreactivity in normal adult human forebrain. Brain Res 943: 174–180.
Haase AT, Henry K, Zupancic M, Sedgewick G, Faust RA, Melroe H, Cavert W, Gebhard K, Staskus K, Zhang ZQ, Dailey PJ, Balfour HH Jr, Erice A, Perelson AS (1996). Quantitative image analysis of HIV-1 infection in lymphoid tissue. Science 274: 985–989.
Hockfield S, McKay RD (1985). Identification of major cell classes in the developing mammalian nervous system. J Neurosci 5: 3310–3328.
Holmin S, Almqvist P, Lendahl U, Mathiesen T (1997). Adult nestin-expressing subependymal cells differentiate to astrocytes in response to brain injury. Eur J Neurosci 9: 65–75.
Hsia K, Spector DH, Spector SA (1997). Molecular analysis of the differential expression of human immunodeficiency virus type 1 replication in neuronal cell lines. J Gen Virol 78: 3255–3264.
Ji JF, He BP, Dheen ST, Tay SSW (2004). Expression of chemokine receptors CXCR4, CCR2, CCR5, and CX3CR1 in neural progenitor cells isolated from the subventricular zone of the adult rat brain. Neurosci Lett 355: 236–240.
Krathwohl MD, Kaiser JL (2004a). Chemokines promote quiescence and survival of human neural progenitor cells. Stem Cells 22: 109–118.
Krathwohl MD, Kaiser JL (2004b). HIV-1 promotes quiescence in human neural progenitor cells. J Infect Dis 190: 216–226.
Kumar RB, Maher DM, Herzberg MC, Southern PJ (2006). Expression of HIV receptors, alternate receptors and coreceptors on tonsillar epithelium: implications for HIV binding and primary oral infection. Virol J 3: www.virologyj.com/content/3/1/25 (open access): 25–37.
Kure K, Llena JF, Lyman WD, Soeiro R, Weidenheim KM, Hirano A, Dickson DW (1991). Human immunodeficiency virus-1 infection of the central nervous system: an autopsy study of 268 adult, pediatric and fetal brains. Hum Pathol 22: 700–710.
Lawrence DM, Durham LC, Schwartz L, Seth P, Maric D, Major EO (2004). Human immunodeficiency virus type 1 infection of human brain-derived progenitor cells. J Virol 78: 7319–7328.
Lawrence DM, Major EO (2002). HIV-1 and the brain: connections between HIV-1 associated dementia, neuropathology and Neuroimmunology. Microb Infect 4: 301–308.
Lendahl U, Zimmerman LB, McKay RD (1990). CNS stem cells express a new class of intermediate filament protein. Cell 60: 585–595.
Li XL, Moudgil T, Vinters HV, Ho DD (1990). CD4-independent, productive infection of a neuronal cell line by human immunodeficiency virus type 1. J Virol 64: 1383–1387.
Liu Y, Liu H, Kim BO, Gattone VH, Li J, Nath A, Blum J, He JJ (2004). CD-4 independent infection of astrocytes by human immunodeficiency virus type 1: requirement for the human mannose receptor. J Virol 78: 4120–4133.
Lyman WD, Kress Y, Kure K, Rashbaum WK, Rubinstein A, Soeiro R (1990). Detection of HIV in fetal central nervous system tissue. AIDS 4: 917–920.
Messam CA, Hou J, Berman JW, Major EO (2002). Analysis of the temporal expression of nestin in human fetal brain-derived neuronal and glial progenitor cells. Dev Brain Res 134: 87–92.
Messam CA, Hou J, Major EO (2000). Coexpression of nestin in neural and glial cells in the developing human CNS defined by a human-specific anti-nestin antibody. Exp Neurol 161: 585–596.
Mintz M (1994). Clinical comparison of adult and pediatric neuroAIDS. Adv Neuroimmunol 4: 207–221.
Nakatomi H, Kuriu T, Okabe S, Yamamoto S-i, Hatano O, Kawahara N, Tamura A, Kirino T, Nakafuku M (2002). Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 110: 429–441.
Neil SJD, Aasa-Chapman MMI, Clapham PR, Nibbs RJ, McKnight A, Weiss RA (2005). The promiscuous CC chemokine receptor D6 is a functional coreceptor for primary isolates of human immunodeficiency virus type 1 (HIV-1) and HIV-2 on astrocytes. J Virol 79: 9618–9624.
Ni HT, Hu S, Sheng WS, Olson JM, Cheeran MC-J, Chan ASH, Lokensgard JR, Peterson PK (2004). High-level expression of functional chemokine receptor CXCR4 on human neural precursor cells. Dev Brain Res 152: 159–169.
Nunes MC, Roy NS, Keyoung HM, Goodman RR, McKhann G 2nd, Jiang L, Nedergaard M, Goldman SA (2003). Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain. Nat Med 9: 439–447.
Ranki A, Nyberg M, Ovod V, Haltia M, Elovaara I, Raininko R, Haapasalo H, Krohn K (1995). Abundant expression of HIV nef and rev proteins in brain astrocytes in vivo is associated with dementia. AIDS 9: 1001–1008.
Rollison DEM, Utaipat U, Ryschkewitsch C, Hou J, Goldthwaite P, Daniel R, Helzlsouer KJ, Burger PC, Shah KV, Major EO (2005). Investigation of human brain tumors for the presence of polyomavirus genome sequences by two independent laboratories. Int J Cancer 113: 769–774.
Sabri F, Tresoldi E, Di Stefano M, Polo S, Monaco MC, Verani A, Fiore JR, Lusso P, Major E, Chiodi F, Scarlatti G (1999). Nonproductive human immunodeficiency virus type 1 infection of human fetal astrocytes: independence from CD4 and major chemokine receptors. Virology 264: 370–384.
Saito Y, Sharer LR, Epstein LG, Michaels J, Mintz M, Louder M, Golding BA, Cvetkovich TA, Blumberg BM (1994). Overexpression of nef as a marker for restricted HIV-1 infection as astrocytes in postmortem pediatric central nervous tissues. Neurology 44: 474–481.
Schwartz L, Major EO (2006). Neural progenitors and HIV-1 associated central nervous system disease in adults and children. Curr HIV Res 4: 319–327.
Strappe PM, Wang TH, McKenzie CA, Lowrie S, Simmonds P, Bell JE (1997). Enhancement of immunohistochemical detection of HIV-1 p24 antigen in brain by tyramide signal amplification. J Virol Methods 67: 103–112.
Tamula MA, Wolters PL, Walsek C, Zeichner S, Civitello L (2003). Cognitive decline with immunologic and virologic stability in four children with human immunodeficiency virus disease. Pediatrics 112: 679–684.
Tohyama T, Lee VM, Rorke LB, Marvin M, McKay RDG, Trojanowski JQ (1992). Nestin expression in embryonic human neuroepithelium and in human neuroepithelial tumor cells. Lab Invest 66: 303–313.
Tornatore C, Chandra R, Berger JR, Major EO (1994). HIV-1 infection of subcortical astrocytes in the pediatric central nervous system. Neurology 44: 481–487.
Tornatore C, Nath A, Amemiya K, Major EO (1991). Persistent human immunodeficiency virus type 1 infection in human fetal glial cells reactivated by T-cell factor(s) or by the cytokines tumor necrosis factor alpha and interleukin-1 beta. J Virol 65: 6094–6100.
Torres-Munoz J, Stockton P, Tacoronte N, Roberts B, Maronpot RR, Petito CK (2001). Detection of HIV-1 gene sequences in hippocampal neurons isolated from postmortem AIDS brains by laser capture microdissection. J Neuropathol Exp Neurol 60: 885–892.
Tran PB, Banisadr G, Ren D, Chenn A, Miller RJ (2007). Chemokine receptor expression by neural progenitor cells in neurogenic regions of mouse brain. J Comp Neurol 500: 1007–1033.
Tran PB, Ren D, Veldhouse TJ, Miller RJ (2004). Chemokine receptors are expressed widely by embryonic and adult neural progenitor cells. J Neurosci Res 76: 20–34.
Trillo-Pazos G, Diamanturos A, Rislove L, Menza T, Chao W, Belem P, Sadiq S, Morgello S, Sharer L, Volsky DJ (2003). Detection of HIV-1 DNA in microglia/macrophages, astrocytes and neurons isolated from brain tissue with HIV-1 encephalitis by laser capture microdissection. Brain Pathol 13: 144–154.
Vallat A-V, Girolami UD, He J, Mhashilkar A, Marasco W, Shi B, Grey F, Bell J, Keohane C, Smith TW, Gabuzda D (1998). Localization of HIV-1 co-receptors CCR5 and CXCR4 in the brain of children with AIDS. Am J Pathol 152: 167–178.
van der Meer P, Ulrich AM, Gonzalez-Scarano F, Lavi E (2000). Immunohistochemical analysis of CCR2, CCR3, CCR5, and CXCR4 in the human brain: potential mechanisms for HIV dementia. Exp Mol Pathol 69: 192–201.
van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH. (2002). Functional neurogenesis in the adult hippocampus. Nature 415: 1030–1034.
Wang G, Achim CL, Hamilton RL, Wiley CA, Soontornniyomkij V (1999). Tyramide signal amplification method in multiple-label immunofluorescence confocal microscopy. Methods 18: 459–464.
Wang Z, Trillo-Pazos G, Kim S-Y, Canki M, Morgello S, Sharer LR, Sharer LR, Gelbard HA, Su Z-z, Kang D-c, Brooks AI, Fisher PB, Volsky DJ (2004). Effects of human immunodeficiency virus type 1 on astrocyte gene expression and function; potential role in neuropathogenesis. J NeuroVirol 10(Suppl): 25–32.
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.
Yachnis AT, Rorke LB, Lee VM-Y, Trojanowski JQ (1993). Expression of neuronal and glial polypeptides during histogenesis of the human cerebellar cortex including observations on the dentate gyrus. J Comp Neurol 334: 356–369.
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This work was supported through the Intramural Research Program, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
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Schwartz, L., Civitello, L., Dunn-Pirio, A. et al. Evidence of human immunodeficiency virus type 1 infection of nestin-positive neural progenitors in archival pediatric brain tissue. Journal of NeuroVirology 13, 274–283 (2007). https://doi.org/10.1080/13550280701344975
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DOI: https://doi.org/10.1080/13550280701344975