Skip to main content

Advertisement

SpringerLink
Log in

Doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) as an HIV/neuroAIDS model

  • Review
  • Published:
Journal of NeuroVirology Aims and scope Submit manuscript

Abstract

HIV-1 Tat is known to be neurotoxic and important for HIV/neuroAIDS pathogenesis. However, the overwhelming majority of the studies involved use of recombinant Tat protein. To understand the contributions of Tat protein to HIV/neuroAIDS and the underlying molecular mechanisms of HIV-1 Tat neurotoxicity in the context of a whole organism and independently of HIV-1 infection, a doxycycline-inducible astrocyte-specific HIV-1 Tat transgenic mouse (iTat) was created. Tat expression in the brains of iTat mice was determined to be in the range of 1–5 ng/ml and led to astrocytosis, loss of neuronal dendrites, and neuroinflammation. iTat mice have allowed us to define the direct effects of Tat on astrocytes and the molecular mechanisms of Tat-induced GFAP expression/astrocytosis, astrocyte-mediated Tat neurotoxicity, Tat-impaired neurogenesis, Tat-induced loss of neuronal integrity, and exosome-associated Tat release and uptake. In this review, we will provide an overview about the creation and characterization of this model and its utilities for our understanding of Tat neurotoxicity and the underlying molecular mechanisms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Adle-Biassette H, Chretien F, Wingertsmann L, Hery C, Ereau T, Scaravilli F, Tardieu M, Gray F (1999) Neuronal apoptosis does not correlate with dementia in HIV infection but is related to microglial activation and axonal damage. Neuropathol Appl Neurobiol 25:123–133

    Article  CAS  PubMed  Google Scholar 

  • Aksamit AJ, Sever JL, Major EO (1986) Progressive multifocal leukoencephalopathy: JC virus detection by in situ hybridization compared with immunohistochemistry. Neurology 36:499–504

    Article  CAS  PubMed  Google Scholar 

  • Albini A, Ferrini S, Benelli R, Sforzini S, Giunciuglio D, Aluigi MG, Proudfoot AE, Alouani S, Wells TN, Mariani G, Rabin RL, Farber JM, Noonan DM (1998) HIV-1 Tat protein mimicry of chemokines. Proc Natl Acad Sci USA 95:13153–13158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aubert C, Chamorro M, Brahic M (1987) Identification of Theiler’s virus infected cells in the central nervous system of the mouse during demyelinating disease. Microb Pathog 3:319–326

    Article  CAS  PubMed  Google Scholar 

  • Barres BA (1991) New roles for glia. J Neurosci 11:3685–3694

    Article  CAS  PubMed  Google Scholar 

  • Bell JE, Anthony IC, Simmonds P (2006a) Impact of HIV on regional & cellular organisation of the brain. Curr HIV Res 4:249–257

    Article  CAS  PubMed  Google Scholar 

  • Bell JE, Arango JC, Anthony IC (2006b) Neurobiology of multiple insults: HIV-1-associated brain disorders in those who use illicit drugs. J NeuroImmune Pharmacol 1:182–191

    Article  PubMed  Google Scholar 

  • Belmadani A, Tran PB, Ren D, Assimacopoulos S, Grove EA, Miller RJ (2005) The chemokine stromal cell-derived factor-1 regulates the migration of sensory neuron progenitors. J Neurosci 25:3995–4003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Belmadani A, Tran PB, Ren D, Miller RJ (2006) Chemokines regulate the migration of neural progenitors to sites of neuroinflammation. J Neurosci 26:3182–3191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Benos DJ, Hahn BH, Shaw GM, Bubien JK, Benveniste EN (1994) gp120-mediated alterations in astrocyte ion transport. Adv Neuroimmunol 4:175–179

    Article  CAS  PubMed  Google Scholar 

  • Bonifaci N, Sitia R, Rubartelli A (1995) Nuclear translocation of an exogenous fusion protein containing HIV Tat requires unfolding. AIDS 9:995–1000

    Article  CAS  PubMed  Google Scholar 

  • Brenner M, Kisseberth WC, Su Y, Besnard F, Messing A (1994) GFAP promoter directs astrocyte-specific expression in transgenic mice. J Neurosci 14:1030–1037

    Article  CAS  PubMed  Google Scholar 

  • Campbell IL (1998) Transgenic mice and cytokine actions in the brain: bridging the gap between structural and functional neuropathology. Brain Res Brain Res Rev 26:327–336

    Article  CAS  PubMed  Google Scholar 

  • Campbell IL, Abraham CR, Masliah E, Kemper P, Inglis JD, Oldstone MB, Mucke L (1993) Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc Natl Acad Sci USA 90:10061–10065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Campbell IL, Stalder AK, Akwa Y, Pagenstecher A, Asensio VC (1998) Transgenic models to study the actions of cytokines in the central nervous system. Neuroimmunomodulation 5:126–135

    Article  CAS  PubMed  Google Scholar 

  • Canani RB, Cirillo P, Mallardo G, Buccigrossi V, Secondo A, Annunziato L, Bruzzese E, Albano F, Selvaggi F, Guarino A (2003) Effects of HIV-1 Tat protein on ion secretion and on cell proliferation in human intestinal epithelial cells. Gastroenterology 124:368–376

    Article  CAS  PubMed  Google Scholar 

  • Carbone KM, Moench TR, Lipkin WI (1991) Borna disease virus replicates in astrocytes, Schwann cells and ependymal cells in persistently infected rats: location of viral genomic and messenger RNAs by in situ hybridization. J Neuropathol Exp Neurol 50:205–214

    Article  CAS  PubMed  Google Scholar 

  • Carey AN, Sypek EI, Singh HD, Kaufman MJ, McLaughlin JP (2012) Expression of HIV-Tat protein is associated with learning and memory deficits in the mouse. Behav Brain Res 229:48–56

    Article  CAS  PubMed  Google Scholar 

  • Carey AN, Liu X, Mintzopoulos D, Paris JJ, Muschamp JW, McLaughlin JP, Kaufman MJ (2013) Conditional Tat protein expression in the GT-tg bigenic mouse brain induces gray matter density reductions. Prog Neuro-Psychopharmacol Biol Psychiatry 43:49–54

    Article  CAS  Google Scholar 

  • Carey AN, Liu X, Mintzopoulos D, Paris JJ, McLaughlin JP, Kaufman MJ (2015) Conditional Tat protein brain expression in the GT-tg bigenic mouse induces cerebral fractional anisotropy abnormalities. Curr HIV Res 13:3–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carr DJ, Veress LA, Noisakran S, Campbell IL (1998) Astrocyte-targeted expression of IFN-alpha1 protects mice from acute ocular herpes simplex virus type 1 infection. J Immunol 161:4859–4865

    CAS  PubMed  Google Scholar 

  • Chang HC, Samaniego F, Nair BC, Buonaguro L, Ensoli B (1997) HIV-1 Tat protein exits from cells via a leaderless secretory pathway and binds to extracellular matrix-associated heparan sulfate proteoglycans through its basic region. AIDS 11:1421–1431

    Article  CAS  PubMed  Google Scholar 

  • Chen P, Mayne M, Power C, Nath A (1997) The Tat protein of HIV-1 induces tumor necrosis factor-alpha production. Implications for HIV-1-associated neurological diseases. J Biol Chem 272:22385–22388

    Article  CAS  PubMed  Google Scholar 

  • Chen J, Kelz MB, Zeng G, Sakai N, Steffen C, Shockett PE, Picciotto MR, Duman RS, Nestler EJ (1998) Transgenic animals with inducible, targeted gene expression in brain. Mol Pharmacol 54:495–503

    Article  CAS  PubMed  Google Scholar 

  • Cheng J, Nath A, Knudsen B, Hochman S, Geiger JD, Ma M, Magnuson DS (1998) Neuronal excitatory properties of human immunodeficiency virus type 1 Tat protein. Neuroscience 82:97–106

    Article  CAS  PubMed  Google Scholar 

  • Choi J, Liu RM, Kundu RK, Sangiorgi F, Wu W, Maxson R, Forman HJ (2000) Molecular mechanism of decreased glutathione content in human immunodeficiency virus type 1 Tat-transgenic mice. J Biol Chem 275:3693–3698

    Article  CAS  PubMed  Google Scholar 

  • Churchill MJ, Wesselingh SL, Cowley D, Pardo CA, McArthur JC, Brew BJ, Gorry PR (2009) Extensive astrocyte infection is prominent in human immunodeficiency virus-associated dementia. Ann Neurol 66:253–258

    Article  PubMed  Google Scholar 

  • 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 USA 95:3117–3121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Curtis K, Rollins M, Carryl H, Bradshaw K, Van Rompay KK, Abel K, Burke MW (2014) Reduction of pyramidal and immature hippocampal neurons in pediatric simian immunodeficiency virus infection. Neuroreport 25:973–978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dube B, Benton T, Cruess DG, Evans DL (2005) Neuropsychiatric manifestations of HIV infection and AIDS. J Psychiatry Neurosci 30:237–246

    PubMed  PubMed Central  Google Scholar 

  • Eddleston M, Mucke L (1993) Molecular profile of reactive astrocytes—implications for their role in neurologic disease. Neuroscience 54:15–36

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Ensoli B, Barillari G, Salahuddin SZ, Gallo RC, Wong-Staal F (1990) Tat protein of HIV-1 stimulates growth of cells derived from Kaposi’s sarcoma lesions of AIDS patients. Nature 345:84–86

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Fan Y, He JJ (2016a) HIV-1 Tat induces unfolded protein response and endoplasmic reticulum stress in astrocytes and causes neurotoxicity through glial Fibrillary acidic protein (GFAP) activation and aggregation. J Biol Chem 291:22819–22829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fan Y, He JJ (2016b) HIV-1 Tat promotes Lysosomal exocytosis in astrocytes and contributes to astrocyte-mediated Tat neurotoxicity. J Biol Chem 291:22830–22840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fan Y, Zou W, Green LA, Kim BO, He JJ (2011) Activation of Egr-1 expression in astrocytes by HIV-1 Tat: new insights into astrocyte-mediated Tat neurotoxicity. J NeuroImmune Pharmacol 6:121–129

    Article  PubMed  Google Scholar 

  • Fan Y, Timani KA, He JJ (2015) STAT3 and its phosphorylation are involved in HIV-1 Tat-induced transactivation of glial fibrillary acidic protein. Curr HIV Res 13:55–63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fan Y, Gao X, Chen J, Liu Y, He JJ (2016) HIV Tat impairs neurogenesis through functioning as a notch ligand and activation of notch signaling pathway. J Neurosci 36:11362–11373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fawell S, Seery J, Daikh Y, Moore C, Chen LL, Pepinsky B, Barsoum J (1994) Tat-mediated delivery of heterologous proteins into cells. Proc Natl Acad Sci USA 91:664–668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fields J, Dumaop W, Eleuteri S, Campos S, Serger E, Trejo M, Kosberg K, Adame A, Spencer B, Rockenstein E, He JJ, Masliah E (2015a) HIV-1 Tat alters neuronal autophagy by modulating autophagosome fusion to the lysosome: implications for HIV-associated neurocognitive disorders. J Neurosci 35:1921–1938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fields JA, Dumaop W, Crews L, Adame A, Spencer B, Metcalf J, He J, Rockenstein E, Masliah E (2015b) Mechanisms of HIV-1 Tat neurotoxicity via CDK5 translocation and hyper-activation: role in HIV-associated neurocognitive disorders. Curr HIV Res 13:43–54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fitting S, Xu R, Bull C, Buch SK, El-Hage N, Nath A, Knapp PE, Hauser KF (2010) Interactive comorbidity between opioid drug abuse and HIV-1 Tat: chronic exposure augments spine loss and sublethal dendritic pathology in striatal neurons. Am J Pathol 177:1397–1410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fitting S, Scoggins KL, Xu R, Dever SM, Knapp PE, Dewey WL, Hauser KF (2012) Morphine efficacy is altered in conditional HIV-1 Tat transgenic mice. Eur J Pharmacol 689:96–103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fitting S, Ignatowska-Jankowska BM, Bull C, Skoff RP, Lichtman AH, Wise LE, Fox MA, Su J, Medina AE, Krahe TE, Knapp PE, Guido W, Hauser KF (2013) Synaptic dysfunction in the hippocampus accompanies learning and memory deficits in human immunodeficiency virus type-1 Tat transgenic mice. Biol Psychiatry 73:443–453

    Article  CAS  PubMed  Google Scholar 

  • Frankel AD, Pabo CO (1988) Cellular uptake of the tat protein from human immunodeficiency virus. Cell 55:1189–1193

    Article  CAS  PubMed  Google Scholar 

  • Fuchs E, Gould E (2000) Mini-review: in vivo neurogenesis in the adult brain: regulation and functional implications. Eur J Neurosci 12:2211–2214

    Article  CAS  PubMed  Google Scholar 

  • Furth PA, St Onge L, Boger H, Gruss P, Gossen M, Kistner A, Bujard H, Hennighausen L (1994) Temporal control of gene expression in transgenic mice by a tetracycline-responsive promoter. Proc Natl Acad Sci USA 91:9302–9306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garza HH Jr, Prakash O, Carr DJ (1996) Aberrant regulation of cytokines in HIV-1 TAT72-transgenic mice. J Immunol 156:3631–3637

    CAS  PubMed  Google Scholar 

  • Gelman BB (2015) Neuropathology of HAND with suppressive antiretroviral therapy: encephalitis and neurodegeneration reconsidered. Curr HIV/AIDS Rep 12:272–279

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 Neuro ATC (2012) The national NeuroAIDS tissue consortium brain gene array: two types of HIV-associated neurocognitive impairment. PLoS One 7:e46178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • Genis P, Jett M, Bernton EW, Boyle T, Gelbard HA, Dzenko K, Keane RW, Resnick L, Mizrachi Y, Volsky DJ et al (1992) Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)-infected macrophage-astroglia interactions: implications for the neuropathogenesis of HIV disease. J Exp Med 176:1703–1718

    Article  CAS  PubMed  Google Scholar 

  • Ghafouri M, Amini S, Khalili K, Sawaya BE (2006) HIV-1 associated dementia: symptoms and causes. Retrovirology 3:28

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gibellini D, Caputo A, Celeghini C, Bassini A, La Placa M, Capitani S, Zauli G (1995) Tat-expressing Jurkat cells show an increased resistance to different apoptotic stimuli, including acute human immunodeficiency virus-type 1 (HIV-1) infection. Br J Haematol 89:24–33

    Article  CAS  PubMed  Google Scholar 

  • Gomi H, Yokoyama T, Fujimoto K, Ikeda T, Katoh A, Itoh T, Itohara S (1995) Mice devoid of the glial fibrillary acidic protein develop normally and are susceptible to scrapie prions. Neuron 14:29–41

    Article  CAS  PubMed  Google Scholar 

  • Gossen M, Bujard H (1992) Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci USA 89:5547–5551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Green M, Ishino M, Loewenstein PM (1989) Mutational analysis of HIV-1 Tat minimal domain peptides: identification of trans-dominant mutants that suppress HIV-LTR-driven gene expression. Cell 58:215–223

    Article  CAS  PubMed  Google Scholar 

  • Hahn YK, Masvekar RR, Xu R, Hauser KF, Knapp PE (2015a) Chronic HIV-1 Tat and HIV reduce Rbfox3/NeuN: evidence for sex-related effects. Curr HIV Res 13:10–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hahn YK, Podhaizer EM, Farris SP, Miles MF, Hauser KF, Knapp PE (2015b) Effects of chronic HIV-1 Tat exposure in the CNS: heightened vulnerability of males versus females to changes in cell numbers, synaptic integrity, and behavior. Brain Struct Funct 220:605–623

    Article  PubMed  Google Scholar 

  • Hahn YK, Paris JJ, Lichtman AH, Hauser KF, Sim-Selley LJ, Selley DE, Knapp PE (2016) Central HIV-1 Tat exposure elevates anxiety and fear conditioned responses of male mice concurrent with altered mu-opioid receptor-mediated G-protein activation and beta-arrestin 2 activity in the forebrain. Neurobiol Dis 92:124–136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hauser KF, Hahn YK, Adjan VV, Zou S, Buch SK, Nath A, Bruce-Keller AJ, Knapp PE (2009) HIV-1 Tat and morphine have interactive effects on oligodendrocyte survival and morphology. Glia 57:194–206

    Article  PubMed  PubMed Central  Google Scholar 

  • He J, Choe S, Walker R, Di Marzio P, Morgan DO, Landau NR (1995) Human immunodeficiency virus type 1 viral protein R (Vpr) arrests cells in the G2 phase of the cell cycle by inhibiting p34cdc2 activity. J Virol 69:6705–6711

    CAS  PubMed  PubMed Central  Google Scholar 

  • Heaton RK, Clifford DB, Franklin DR Jr, Woods SP, Ake C, Vaida F, Ellis RJ, Letendre SL, Marcotte TD, Atkinson JH, Rivera-Mindt M, Vigil OR, Taylor MJ, Collier AC, Marra CM, Gelman BB, McArthur JC, Morgello S, Simpson DM, McCutchan JA, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I, Group C (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER study. Neurology 75:2087–2096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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, Group C, Group H (2011) HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neuro-Oncol 17:3–16

    CAS  Google Scholar 

  • Helland DE, Welles JL, Caputo A, Haseltine WA (1991) Transcellular transactivation by the human immunodeficiency virus type 1 tat protein. J Virol 65:4547–4549

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hofman FM, Chen P, Incardona F, Zidovetzki R, Hinton DR (1999) HIV-1 tat protein induces the production of interleukin-8 by human brain-derived endothelial cells. J Neuroimmunol 94:28–39

    Article  CAS  PubMed  Google Scholar 

  • Hudson L, Liu J, Nath A, Jones M, Raghavan R, Narayan O, Male D, Everall I (2000) Detection of the human immunodeficiency virus regulatory protein tat in CNS tissues. J Neuro-Oncol 6:145–155

    CAS  Google Scholar 

  • Hult B, Chana G, Masliah E, Everall I (2008) Neurobiology of HIV. Int Rev Psychiatry 20:3–13

    Article  PubMed  Google Scholar 

  • Itoyama Y, Sekizawa T, Openshaw H, Kogure K, Goto I (1991) Early loss of astrocytes in herpes simplex virus-induced central nervous system demyelination. Ann Neurol 29:285–292

    Article  CAS  PubMed  Google Scholar 

  • Jaeger LB, Nath A (2012) Modeling HIV-associated neurocognitive disorders in mice: new approaches in the changing face of HIV neuropathogenesis. Dis Model Mech 5:313–322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson JO, Mandrioli J, Benatar M, Abramzon Y, Van Deerlin VM, Trojanowski JQ, Gibbs JR, Brunetti M, Gronka S, Wuu J, Ding J, McCluskey L, Martinez-Lage M, Falcone D, Hernandez DG, Arepalli S, Chong S, Schymick JC, Rothstein J, Landi F, Wang YD, Calvo A, Mora G, Sabatelli M, Monsurro MR, Battistini S, Salvi F, Spataro R, Sola P, Borghero G, Consortium I, Galassi G, Scholz SW, Taylor JP, Restagno G, Chio A, Traynor BJ (2010) Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68:857–864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson TP, Patel K, Johnson KR, Maric D, Calabresi PA, Hasbun R, Nath A (2013) Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein. Proc Natl Acad Sci USA 110:13588–13593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones M, Olafson K, Del Bigio MR, Peeling J, Nath A (1998) Intraventricular injection of human immunodeficiency virus type 1 (HIV-1) tat protein causes inflammation, gliosis, apoptosis, and ventricular enlargement. J Neuropathol Exp Neurol 57:563–570

    Article  CAS  PubMed  Google Scholar 

  • Kadri F, Pacifici M, Wilk A, Parker-Struckhoff A, Del Valle L, Hauser KF, Knapp PE, Parsons C, Jeansonne D, Lassak A, Peruzzi F (2015) HIV-1-Tat protein inhibits SC35-mediated tau exon 10 inclusion through up-regulation of DYRK1A kinase. J Biol Chem 290:30931–30946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kiebala M, Polesskaya O, Yao Z, Perry SW, Maggirwar SB (2010) Nuclear factor-kappa B family member RelB inhibits human immunodeficiency virus-1 Tat-induced tumor necrosis factor-alpha production. PLoS One 5:e11875

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kim BO, Liu Y, Ruan Y, ZC X, Schantz L, He JJ (2003) Neuropathologies in transgenic mice expressing human immunodeficiency virus type 1 Tat protein under the regulation of the astrocyte-specific glial fibrillary acidic protein promoter and doxycycline. Am J Pathol 162:1693–1707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim BO, Liu Y, Zhou BY, He JJ (2004) Induction of C chemokine XCL1 (lymphotactin/single C motif-1 alpha/activation-induced, T cell-derived and chemokine-related cytokine) expression by HIV-1 Tat protein. J Immunol 172:1888–1895

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Krathwohl MD, Kaiser JL (2004a) Chemokines promote quiescence and survival of human neural progenitor cells. Stem Cells 22:109–118

    Article  CAS  PubMed  Google Scholar 

  • Krathwohl MD, Kaiser JL (2004b) HIV-1 promotes quiescence in human neural progenitor cells. J Infect Dis 190:216–226

    Article  CAS  PubMed  Google Scholar 

  • Kruman II, Nath A, Mattson MP (1998) HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress. Exp Neurol 154:276–288

    Article  CAS  PubMed  Google Scholar 

  • Kundu M, Sharma S, De Luca A, Giordano A, Rappaport J, Khalili K, Amini S (1998) HIV-1 Tat elongates the G1 phase and indirectly promotes HIV-1 gene expression in cells of glial origin. J Biol Chem 273:8130–8136

    Article  CAS  PubMed  Google Scholar 

  • Kundu RK, Sangiorgi F, LY W, Pattengale PK, Hinton DR, Gill PS, Maxson R (1999) Expression of the human immunodeficiency virus-Tat gene in lymphoid tissues of transgenic mice is associated with B-cell lymphoma. Blood 94:275–282

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leuner B, Gould E, Shors TJ (2006) Is there a link between adult neurogenesis and learning? Hippocampus 16:216–224

    Article  PubMed  Google Scholar 

  • Levi G, Patrizio M, Bernardo A, Petrucci TC, Agresti C (1993) Human immunodeficiency virus coat protein gp120 inhibits the beta-adrenergic regulation of astroglial and microglial functions. Proc Natl Acad Sci USA 90:1541–1545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liedtke W, Edelmann W, Bieri PL, Chiu FC, Cowan NJ, Kucherlapati R, Raine CS (1996) GFAP is necessary for the integrity of CNS white matter architecture and long-term maintenance of myelination. Neuron 17:607–615

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Jones M, Hingtgen CM, Bu G, Laribee N, Tanzi RE, Moir RD, Nath A, He JJ (2000) Uptake of HIV-1 tat protein mediated by low-density lipoprotein receptor-related protein disrupts the neuronal metabolic balance of the receptor ligands. Nat Med 6:1380–1387

    Article  CAS  PubMed  Google Scholar 

  • Mann DA, Frankel AD (1991) Endocytosis and targeting of exogenous HIV-1 Tat protein. EMBO J 10:1733–1739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mansuy IM, Winder DG, Moallem TM, Osman M, Mayford M, Hawkins RD, Kandel ER (1998) Inducible and reversible gene expression with the rtTA system for the study of memory. Neuron 21:257–265

    Article  CAS  PubMed  Google Scholar 

  • Marcuzzi A, Lowy I, Weinberger OK (1992) Transcellular activation of the human immunodeficiency virus type 1 long terminal repeat in T lymphocytes requires CD4-gp120 binding. J Virol 66:4536–4539

    CAS  PubMed  PubMed Central  Google Scholar 

  • Masliah E, Achim CL, Ge N, DeTeresa R, Terry RD, Wiley CA (1992) Spectrum of human immunodeficiency virus-associated neocortical damage. Ann Neurol 32:321–329

    Article  CAS  PubMed  Google Scholar 

  • 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. HNRC group. The HIV neurobehavioral research center. Ann Neurol 42:963–972

    Article  CAS  PubMed  Google Scholar 

  • Mediouni S, Jablonski J, Paris JJ, Clementz MA, Thenin-Houssier S, McLaughlin JP, Valente ST (2015) Didehydro-cortistatin A inhibits HIV-1 Tat mediated neuroinflammation and prevents potentiation of cocaine reward in Tat transgenic mice. Curr HIV Res 13:64–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Messing A, Head MW, Galles K, Galbreath EJ, Goldman JE, Brenner M (1998) Fatal encephalopathy with astrocyte inclusions in GFAP transgenic mice. Am J Pathol 152:391–398

    CAS  PubMed  PubMed Central  Google Scholar 

  • Milani D, Zauli G, Neri LM, Marchisio M, Previati M, Capitani S (1993) Influence of the human immunodeficiency virus type 1 Tat protein on the proliferation and differentiation of PC12 rat pheochromocytoma cells. J Gen Virol 74(Pt 12):2587–2594

    Article  CAS  PubMed  Google Scholar 

  • Ming GL, Song H (2005) Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 28:223–250

    Article  CAS  PubMed  Google Scholar 

  • Mishra M, Taneja M, Malik S, Khalique H, Seth P (2010) Human immunodeficiency virus type 1 Tat modulates proliferation and differentiation of human neural precursor cells: implication in NeuroAIDS. J Neuro-Oncol 16:355–367

    CAS  Google Scholar 

  • Moore DJ, Masliah E, Rippeth JD, Gonzalez R, Carey CL, Cherner M, Ellis RJ, Achim CL, Marcotte TD, Heaton RK, Grant I, Group H (2006) Cortical and subcortical neurodegeneration is associated with HIV neurocognitive impairment. AIDS 20:879–887

    Article  PubMed  Google Scholar 

  • Morgavi P, Bonifaci N, Pagani M, Costigliolo S, Sitia R, Rubartelli A (1997) The association of HIV-1 Tat with nuclei is regulated by Ca2+ ions and cytosolic factors. J Biol Chem 272:11256–11260

    Article  CAS  PubMed  Google Scholar 

  • Mucke L, Abraham CR, Ruppe MD, Rockenstein EM, Toggas SM, Mallory M, Alford M, Masliah E (1995) Protection against HIV-1 gp120-induced brain damage by neuronal expression of human amyloid precursor protein. J Exp Med 181:1551–1556

    Article  CAS  PubMed  Google Scholar 

  • Nath A (2002) Human immunodeficiency virus (HIV) proteins in neuropathogenesis of HIV dementia. J Infect Dis 186(Suppl 2):S193–S198

    Article  CAS  PubMed  Google Scholar 

  • Nerenberg M, Hinrichs SH, Reynolds RK, Khoury G, Jay G (1987) The tat gene of human T-lymphotropic virus type 1 induces mesenchymal tumors in transgenic mice. Science 237:1324–1329

    Article  CAS  PubMed  Google Scholar 

  • New DR, Maggirwar SB, Epstein LG, Dewhurst S, Gelbard HA (1998) HIV-1 Tat induces neuronal death via tumor necrosis factor-alpha and activation of non-N-methyl-D-aspartate receptors by a NFkappaB-independent mechanism. J Biol Chem 273:17852–17858

    Article  CAS  PubMed  Google Scholar 

  • Ngwainmbi J, De DD, Smith TH, El-Hage N, Fitting S, Kang M, Dewey WL, Hauser KF, Akbarali HI (2014) Effects of HIV-1 Tat on enteric neuropathogenesis. J Neurosci 34:14243–14251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okamoto S, Kang YJ, Brechtel CW, Siviglia E, Russo R, Clemente A, Harrop A, McKercher S, Kaul M, Lipton SA (2007) HIV/gp120 decreases adult neural progenitor cell proliferation via checkpoint kinase-mediated cell-cycle withdrawal and G1 arrest. Cell Stem Cell 1:230–236

    Article  CAS  PubMed  Google Scholar 

  • Paris JJ, Carey AN, Shay CF, Gomes SM, He JJ, McLaughlin JP (2014a) Effects of conditional central expression of HIV-1 tat protein to potentiate cocaine-mediated psychostimulation and reward among male mice. Neuropsychopharmacology 39:380–388

    Article  CAS  PubMed  Google Scholar 

  • Paris JJ, Fenwick J, McLaughlin JP (2014b) Progesterone protects normative anxiety-like responding among ovariectomized female mice that conditionally express the HIV-1 regulatory protein, Tat, in the CNS. Horm Behav 65:445–453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paris JJ, Singh HD, Ganno ML, Jackson P, McLaughlin JP (2014c) Anxiety-like behavior of mice produced by conditional central expression of the HIV-1 regulatory protein, Tat. Psychopharmacology 231:2349–2360

    Article  CAS  PubMed  Google Scholar 

  • Paris JJ, Singh HD, Carey AN, McLaughlin JP (2015) Exposure to HIV-1 Tat in brain impairs sensorimotor gating and activates microglia in limbic and extralimbic brain regions of male mice. Behav Brain Res 291:209–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Passman RS, Fishman GI (1994) Regulated expression of foreign genes in vivo after germline transfer. J Clin Invest 94:2421–2425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pekny M, Eliasson C, Chien CL, Kindblom LG, Liem R, Hamberger A, Betsholtz C (1998) GFAP-deficient astrocytes are capable of stellation in vitro when cocultured with neurons and exhibit a reduced amount of intermediate filaments and an increased cell saturation density. Exp Cell Res 239:332–343

    Article  CAS  PubMed  Google Scholar 

  • Perry SW, Barbieri J, Tong N, Polesskaya O, Pudasaini S, Stout A, Lu R, Kiebala M, Maggirwar SB, Gelbard HA (2010) Human immunodeficiency virus-1 Tat activates calpain proteases via the ryanodine receptor to enhance surface dopamine transporter levels and increase transporter-specific uptake and Vmax. J Neurosci 30:14153–14164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Poluektova L, Meyer V, Walters L, Paez X, Gendelman HE (2005) Macrophage-induced inflammation affects hippocampal plasticity and neuronal development in a murine model of HIV-1 encephalitis. Glia 52:344–353

    Article  PubMed  Google Scholar 

  • Price RW (1996) Neurological complications of HIV infection. Lancet 348:445–452

    Article  CAS  PubMed  Google Scholar 

  • Raber J, O'Shea RD, Bloom FE, Campbell IL (1997) Modulation of hypothalamic-pituitary-adrenal function by transgenic expression of interleukin-6 in the CNS of mice. J Neurosci 17:9473–9480

    Article  CAS  PubMed  Google Scholar 

  • Rahimian P, He JJ (2016a) Exosome-associated release, uptake, and neurotoxicity of HIV-1 Tat protein. J Neuro-Oncol 22:774–788

    CAS  Google Scholar 

  • Rahimian P, He JJ (2016b) HIV-1 Tat-shortened neurite outgrowth through regulation of microRNA-132 and its target gene expression. J Neuroinflammation 13:247

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rao JS, Kim HW, Kellom M, Greenstein D, Chen M, Kraft AD, Harry GJ, Rapoport SI, Basselin M (2011) Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in brain of HIV-1 transgenic rats. J Neuroinflammation 8:101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rao JS, Kellom M, Kim HW, Rapoport SI, Reese EA (2012) Neuroinflammation and synaptic loss. Neurochem Res 37:903–910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rappaport J, Joseph J, Croul S, Alexander G, Del Valle L, Amini S, Khalili K (1999) Molecular pathway involved in HIV-1-induced CNS pathology: role of viral regulatory protein, tat. J Leukoc Biol 65:458–465

    Article  CAS  PubMed  Google Scholar 

  • Rinaman L, Card JP, Enquist LW (1993) Spatiotemporal responses of astrocytes, ramified microglia, and brain macrophages to central neuronal infection with pseudorabies virus. J Neurosci 13:685–702

    Article  CAS  PubMed  Google Scholar 

  • Sabatier JM, Vives E, Mabrouk K, Benjouad A, Rochat H, Duval A, Hue B, Bahraoui E (1991) Evidence for neurotoxic activity of tat from human immunodeficiency virus type 1. J Virol 65:961–967

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Saylor D, Dickens AM, Sacktor N, Haughey N, Slusher B, Pletnikov M, Mankowski JL, Brown A, Volsky DJ, McArthur JC (2016) HIV-associated neurocognitive disorder—pathogenesis and prospects for treatment. Nat Rev Neurol 12:234–248

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Schwarze SR, Ho A, Vocero-Akbani A, Dowdy SF (1999) In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285:1569–1572

    Article  CAS  PubMed  Google Scholar 

  • Shi B, Raina J, Lorenzo A, Busciglio J, Gabuzda D (1998) Neuronal apoptosis induced by HIV-1 Tat protein and TNF-alpha: potentiation of neurotoxicity mediated by oxidative stress and implications for HIV-1 dementia. J Neuro-Oncol 4:281–290

    CAS  Google Scholar 

  • Silva JN, Polesskaya O, Wei HS, Rasheed IY, Chamberlain JM, Nishimura C, Feng C, Dewhurst S (2014) Chronic central nervous system expression of HIV-1 Tat leads to accelerated rarefaction of neocortical capillaries and loss of red blood cell velocity heterogeneity. Microcirculation 21:664–676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith JD, Sikes J, Levin JA (1998) Human apolipoprotein E allele-specific brain expressing transgenic mice. Neurobiol Aging 19:407–413

    Article  CAS  PubMed  Google Scholar 

  • Stowring L, Haase AT, Petursson G, Georgsson G, Palsson P, Lutley R, Roos R, Szuchet S (1985) Detection of visna virus antigens and RNA in glial cells in foci of demyelination. Virology 141:311–318

    Article  CAS  PubMed  Google Scholar 

  • Sun Y, Wu S, Bu G, Onifade MK, Patel SN, LaDu MJ, Fagan AM, Holtzman DM (1998) Glial fibrillary acidic protein-apolipoprotein E (apoE) transgenic mice: astrocyte-specific expression and differing biological effects of astrocyte-secreted apoE3 and apoE4 lipoproteins. J Neurosci 18:3261–3272

    Article  CAS  PubMed  Google Scholar 

  • Toggas SM, Masliah E, Rockenstein EM, Rall GF, Abraham CR, Mucke L (1994) Central nervous system damage produced by expression of the HIV-1 coat protein gp120 in transgenic mice. Nature 367:188–193

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tran PB, Ren D, Miller RJ (2005) The HIV-1 coat protein gp120 regulates CXCR4-mediated signaling in neural progenitor cells. J Neuroimmunol 160:68–76

    Article  CAS  PubMed  Google Scholar 

  • Valcour VG, Shikuma CM, Watters MR, Sacktor NC (2004) Cognitive impairment in older HIV-1-seropositive individuals: prevalence and potential mechanisms. AIDS 18(Suppl 1):S79–S86

    Article  PubMed  PubMed Central  Google Scholar 

  • Vellutini C, Horschowski N, Philippon V, Gambarelli D, Nave KA, Filippi P (1995) Development of lymphoid hyperplasia in transgenic mice expressing the HIV tat gene. AIDS Res Hum Retrovir 11:21–29

    Article  CAS  PubMed  Google Scholar 

  • Viscidi RP, Mayur K, Lederman HM, Frankel AD (1989) Inhibition of antigen-induced lymphocyte proliferation by Tat protein from HIV-1. Science 246:1606–1608

    Article  CAS  PubMed  Google Scholar 

  • Vives E, Brodin P, Lebleu B (1997) A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J Biol Chem 272:16010–16017

    Article  CAS  PubMed  Google Scholar 

  • Vogel J, Hinrichs SH, Reynolds RK, Luciw PA, Jay G (1988) The HIV tat gene induces dermal lesions resembling Kaposi’s sarcoma in transgenic mice. Nature 335:606–611

    Article  CAS  PubMed  Google Scholar 

  • Westendorp MO, Frank R, Ochsenbauer C, Stricker K, Dhein J, Walczak H, Debatin KM, Krammer PH (1995) Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature 375:497–500

    Article  CAS  PubMed  Google Scholar 

  • Wheeler D, Bandaru VV, Calabresi PA, Nath A, Haughey NJ (2008) A defect of sphingolipid metabolism modifies the properties of normal appearing white matter in multiple sclerosis. Brain 131:3092–3102

    Article  PubMed  PubMed Central  Google Scholar 

  • Whitney NP, Eidem TM, Peng H, Huang Y, Zheng JC (2009) Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders. J Neurochem 108:1343–1359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wolf K, Tsakiris DA, Weber R, Erb P, Battegay M, Swiss HIVCS (2002) Antiretroviral therapy reduces markers of endothelial and coagulation activation in patients infected with human immunodeficiency virus type 1. J Infect Dis 185:456–462

    Article  CAS  PubMed  Google Scholar 

  • Xiao H, Neuveut C, Tiffany HL, Benkirane M, Rich EA, Murphy PM, Jeang KT (2000) Selective CXCR4 antagonism by Tat: implications for in vivo expansion of coreceptor use by HIV-1. Proc Natl Acad Sci USA 97:11466–11471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yao H, Duan M, Yang L, Buch S (2012) Platelet-derived growth factor-BB restores human immunodeficiency virus Tat-cocaine-mediated impairment of neurogenesis: role of TRPC1 channels. J Neurosci 32:9835–9847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zauli G, Gibellini D, Milani D, Mazzoni M, Borgatti P, La Placa M, Capitani S (1993) Human immunodeficiency virus type 1 Tat protein protects lymphoid, epithelial, and neuronal cell lines from death by apoptosis. Cancer Res 53:4481–4485

    CAS  PubMed  Google Scholar 

  • Zauli G, La Placa M, Vignoli M, Re MC, Gibellini D, Furlini G, Milani D, Marchisio M, Mazzoni M, Capitani S (1995) An autocrine loop of HIV type-1 Tat protein responsible for the improved survival/proliferation capacity of permanently Tat-transfected cells and required for optimal HIV-1 LTR transactivating activity. J Acquir Immune Defic Syndr Hum Retrovirol 10:306–316

    Article  CAS  PubMed  Google Scholar 

  • Zhou BY, He JJ (2004) Proliferation inhibition of astrocytes, neurons, and non-glial cells by intracellularly expressed human immunodeficiency virus type 1 (HIV-1) Tat protein. Neurosci Lett 359:155–158

    Article  CAS  PubMed  Google Scholar 

  • Zhou BY, Liu Y, Kim B, Xiao Y, He JJ (2004) Astrocyte activation and dysfunction and neuron death by HIV-1 Tat expression in astrocytes. Mol Cell Neurosci 27:296–305

    Article  CAS  PubMed  Google Scholar 

  • Zidovetzki R, Wang JL, Chen P, Jeyaseelan R, Hofman F (1998) Human immunodeficiency virus Tat protein induces interleukin 6 mRNA expression in human brain endothelial cells via protein kinase C- and cAMP-dependent protein kinase pathways. AIDS Res Hum Retrovir 14:825–833

    Article  CAS  PubMed  Google Scholar 

  • Zou W, Kim BO, Zhou BY, Liu Y, Messing A, He JJ (2007) Protection against human immunodeficiency virus type 1 Tat neurotoxicity by Ginkgo biloba extract EGb 761 involving glial fibrillary acidic protein. Am J Pathol 171:1923–1935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zou W, Wang Z, Liu Y, Fan Y, Zhou BY, Yang XF, He JJ (2010) Involvement of p300 in constitutive and HIV-1 Tat-activated expression of glial fibrillary acidic protein in astrocytes. Glia 58:1640–1648

    PubMed  PubMed Central  Google Scholar 

  • Zou S, Fitting S, Hahn YK, Welch SP, El-Hage N, Hauser KF, Knapp PE (2011) Morphine potentiates neurodegenerative effects of HIV-1 Tat through actions at mu-opioid receptor-expressing glia. Brain 134:3616–3631

    Article  PubMed  Google Scholar 

Download references

Funding

This work was supported in part by the grants NIH/NINDS R01NS090960 and NIH/NIDA R01DA043162 (to JJH), and NIH/NIMH R01MH107340 and NIH/NIDA P01DA037830 (to DL and KK).

Author information

Authors and Affiliations

  1. Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA

    Dianne Langford

  2. School of Food Science & Biotechnology and College of Agriculture & Life Sciences, Kyungpook National University, Daegu, 702-701, South Korea

    Byung oh Kim

  3. The 1st Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China

    Wei Zou

  4. Graduate School of Biomedical Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, 76107, USA

    Yan Fan, Pejman Rahimain, Ying Liu & Johnny J. He

Authors
  1. Dianne Langford
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Byung oh Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yan Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pejman Rahimain
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ying Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Johnny J. He
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Johnny J. He.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Langford, D., oh Kim, B., Zou, W. et al. Doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) as an HIV/neuroAIDS model. J. Neurovirol. 24, 168–179 (2018). https://doi.org/10.1007/s13365-017-0598-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13365-017-0598-9

Keywords

Search

Navigation