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HIV-1 transcriptional regulation in the central nervous system and implications for HIV cure research

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Abstract

Human immunodeficiency virus type-1 (HIV-1) invades the central nervous system (CNS) during acute infection which can result in HIV-associated neurocognitive disorders in up to 50 % of patients, even in the presence of combination antiretroviral therapy (cART). Within the CNS, productive HIV-1 infection occurs in the perivascular macrophages and microglia. Astrocytes also become infected, although their infection is restricted and does not give rise to new viral particles. The major barrier to the elimination of HIV-1 is the establishment of viral reservoirs in different anatomical sites throughout the body and viral persistence during long-term treatment with cART. While the predominant viral reservoir is believed to be resting CD4+ T cells in the blood, other anatomical compartments including the CNS, gut-associated lymphoid tissue, bone marrow, and genital tract can also harbour persistently infected cellular reservoirs of HIV-1. Viral latency is predominantly responsible for HIV-1 persistence and is most likely governed at the transcriptional level. Current clinical trials are testing transcriptional activators, in the background of cART, in an attempt to purge these viral reservoirs and reverse viral latency. These strategies aim to activate viral transcription in cells constituting the viral reservoir, so they can be recognised and cleared by the immune system, while new rounds of infection are blocked by co-administration of cART. The CNS has several unique characteristics that may result in differences in viral transcription and in the way latency is established. These include CNS-specific cell types, different transcription factors, altered immune surveillance, and reduced antiretroviral drug bioavailability. A comprehensive understanding of viral transcription and latency in the CNS is required in order to determine treatment outcomes when using transcriptional activators within the CNS.

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References

  • Ait-Khaled M, McLaughlin JE, Johnson MA, Emery VC (1995) Distinct HIV-1 long terminal repeat quasispecies present in nervous tissues compared to that in lung, blood and lymphoid tissues of an AIDS patient. AIDS 9:675–683

    Article  CAS  PubMed  Google Scholar 

  • Ananworanich J, Gayet-Ageron A, Le Braz M, Prasithsirikul W, Chetchotisakd P, Kiertiburanakul S, Munsakul W, Raksakulkarn P, Tansuphasawasdikul S, Sirivichayakul S, Cavassini M, Karrer U, Genne D, Nuesch R, Vernazza P, Bernasconi E, Leduc D, Satchell C, Yerly S, Perrin L, Hill A, Perneger T, Phanuphak P, Furrer H, Cooper D, Ruxrungtham K, Hirschel B, Staccato Study G, Swiss HIVCS (2006) CD4-guided scheduled treatment interruptions compared with continuous therapy for patients infected with HIV-1: results of the Staccato randomised trial. Lancet 368:459–465

    Article  CAS  PubMed  Google Scholar 

  • Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, Parker DC, Anderson EM, Kearney MF, Strain MC, Richman DD, Hudgens MG, Bosch RJ, Coffin JM, Eron JJ, Hazuda DJ, Margolis DM (2012) Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature 487:482–485

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ashburner BP, Westerheide SD, Baldwin AS Jr (2001) The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression. Mol Cell Biol 21:7065–7077

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Asin S, Bren GD, Carmona EM, Solan NJ, Paya CV (2001) NF-kappaB cis-acting motifs of the human immunodeficiency virus (HIV) long terminal repeat regulate HIV transcription in human macrophages. J Virol 75:11408–11416

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Baeuerle PA, Baltimore D (1988) I kappa B: a specific inhibitor of the NF-kappa B transcription factor. Science 242:540–546

    Article  CAS  PubMed  Google Scholar 

  • Barber SA, Gama L, Dudaronek JM, Voelker T, Tarwater PM, Clements JE (2006) Mechanism for the establishment of transcriptional HIV latency in the brain in a simian immunodeficiency virus-macaque model. J Infect Dis 193:963–970

    Article  CAS  PubMed  Google Scholar 

  • Barboric M, Nissen RM, Kanazawa S, Jabrane-Ferrat N, Peterlin BM (2001) NF-kappaB binds P-TEFb to stimulate transcriptional elongation by RNA polymerase II. Mol Cell 8:327–337

    Article  CAS  PubMed  Google Scholar 

  • Beg AA, Finco TS, Nantermet PV, Baldwin AS Jr (1993) Tumor necrosis factor and interleukin-1 lead to phosphorylation and loss of I kappa B alpha: a mechanism for NF-kappa B activation. Mol Cell Biol 13:3301–3310

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bernhard W, Barreto K, Saunders A, Dahabieh MS, Johnson P, Sadowski I (2011) The Suv39H1 methyltransferase inhibitor chaetocin causes induction of integrated HIV-1 without producing a T cell response. FEBS Lett 585:3549–3554

    Article  CAS  PubMed  Google Scholar 

  • Brew BJ, Chan P (2014) Update on HIV dementia and HIV-associated neurocognitive Disorders. Curr Neurol Neurosci Rep 14:468

    Article  PubMed  Google Scholar 

  • Brew BJ, Gray L, Lewin S, Churchill M (2013) Is specific HIV eradication from the brain possible or needed? Expert Opin Biol Ther 13:403–409

    Article  PubMed  Google Scholar 

  • Burdo TH, Gartner S, Mauger D, Wigdahl B (2004a) Region-specific distribution of human immunodeficiency virus type 1 long terminal repeats containing specific configurations of CCAAT/enhancer-binding protein site II in brains derived from demented and nondemented patients. J Neurovirol 10(Suppl 1):7–14

    Article  CAS  PubMed  Google Scholar 

  • Burdo TH, Nonnemacher M, Irish BP, Choi CH, Krebs FC, Gartner S, Wigdahl B (2004b) High-affinity interaction between HIV-1 Vpr and specific sequences that span the C/EBP and adjacent NF-kappaB sites within the HIV-1 LTR correlate with HIV-1-associated dementia. DNA Cell Biol 23:261–269

    Article  CAS  PubMed  Google Scholar 

  • Carson MJ, Doose JM, Melchior B, Schmid CD, Ploix CC (2006) CNS immune privilege: hiding in plain sight. Immunol Rev 213:48–65

    Article  PubMed Central  PubMed  Google Scholar 

  • Chiang CM, Roeder RG (1995) Cloning of an intrinsic human TFIID subunit that interacts with multiple transcriptional activators. Science 267:531–536

    Article  CAS  PubMed  Google Scholar 

  • Chun TW, Engel D, Mizell SB, Ehler LA, Fauci AS (1998) Induction of HIV-1 replication in latently infected CD4+ T cells using a combination of cytokines. J Exp Med 188:83–91

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Churchill M, Nath A (2013) Where does HIV hide? A focus on the central nervous system. Curr Opin HIV AIDS 8:165–169

    Article  CAS  PubMed  Google Scholar 

  • Churchill MJ, Gorry PR, Cowley D, Lal L, Sonza S, Purcell DF, 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

    Article  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 

  • Cosenza MA, Zhao ML, Si Q, Lee SC (2002) Human brain parenchymal microglia express CD14 and CD45 and are productively infected by HIV-1 in HIV-1 encephalitis. Brain Pathol 12:442–455

    Article  CAS  PubMed  Google Scholar 

  • Deeks SG (2012) HIV: Shock and kill. Nature 487:439–440

    Article  CAS  PubMed  Google Scholar 

  • Deeks SG, Autran B, Berkhout B, Benkirane M, Cairns S, Chomont N, Chun TW, Churchill M, Di Mascio M, Katlama C, Lafeuillade A, Landay A, Lederman M, Lewin SR, Maldarelli F, Margolis D, Markowitz M, Martinez-Picado J, Mullins JI, Mellors J, Moreno S, O'Doherty U, Palmer S, Penicaud MC, Peterlin M, Poli G, Routy JP, Rouzioux C, Silvestri G, Stevenson M, Telenti A, Van Lint C, Verdin E, Woolfrey A, Zaia J, Barre-Sinoussi F (2012) Towards an HIV cure: a global scientific strategy. Nat Rev Immunol 12:607–614

    Article  CAS  PubMed  Google Scholar 

  • Desplats P, Dumaop W, Smith D, Adame A, Everall I, Letendre S, Ellis R, Cherner M, Grant I, Masliah E (2013) Molecular and pathologic insights from latent HIV-1 infection in the human brain. Neurology 80:1415–1423

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Discher DJ, Bishopric NH, Wu X, Peterson CA, Webster KA (1998) Hypoxia regulates beta-enolase and pyruvate kinase-M promoters by modulating Sp1/Sp3 binding to a conserved GC element. J Biol Chem 273:26087–26093

    Article  CAS  PubMed  Google Scholar 

  • Doetzlhofer A, Rotheneder H, Lagger G, Koranda M, Kurtev V, Brosch G, Wintersberger E, Seiser C (1999) Histone deacetylase 1 can repress transcription by binding to Sp1. Mol Cell Biol 19:5504–5511

    PubMed Central  CAS  PubMed  Google Scholar 

  • du Chene I, Basyuk E, Lin YL, Triboulet R, Knezevich A, Chable-Bessia C, Mettling C, Baillat V, Reynes J, Corbeau P, Bertrand E, Marcello A, Emiliani S, Kiernan R, Benkirane M (2007) Suv39H1 and HP1gamma are responsible for chromatin-mediated HIV-1 transcriptional silencing and post-integration latency. EMBO J 26:424–435

    Article  PubMed Central  PubMed  Google Scholar 

  • Eisele E, Siliciano RF (2012) Redefining the viral reservoirs that prevent HIV-1 eradication. Immunity 37:377–388

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Emili A, Greenblatt J, Ingles CJ (1994) Species-specific interaction of the glutamine-rich activation domains of Sp1 with the TATA box-binding protein. Mol Cell Biol 14:1582–1593

    PubMed Central  CAS  PubMed  Google Scholar 

  • Felzien LK, Woffendin C, Hottiger MO, Subbramanian RA, Cohen EA, Nabel GJ (1998) HIV transcriptional activation by the accessory protein, VPR, is mediated by the p300 co-activator. Proc Natl Acad Sci U S A 95:5281–5286

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gehrmann J, Matsumoto Y, Kreutzberg GW (1995) Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev 20:269–287

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Gorry PR, Howard JL, Churchill MJ, Anderson JL, Cunningham A, Adrian D, McPhee DA, Purcell DF (1999) Diminished production of human immunodeficiency virus type 1 in astrocytes results from inefficient translation of gag, env, and nef mRNAs despite efficient expression of Tat and Rev. J Virol 73:352–361

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gorry PR, Ong C, Thorpe J, Bannwarth S, Thompson KA, Gatignol A, Vesselingh SL, Purcell DF (2003) Astrocyte infection by HIV-1: mechanisms of restricted virus replication, and role in the pathogenesis of HIV-1-associated dementia. Curr HIV Res 1:463–473

    Article  CAS  PubMed  Google Scholar 

  • Gray LR, Cowley D, Crespan E, Welsh C, Mackenzie C, Wesselingh SL, Gorry PR, Churchill MJ (2013a) Reduced basal transcriptional activity of central nervous system-derived HIV type 1 long terminal repeats. AIDS Res Hum Retroviruses 29:365–370

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gray LR, Tachedjian G, Ellett AM, Roche MJ, Cheng WJ, Guillemin GJ, Brew BJ, Turville SG, Wesselingh SL, Gorry PR, Churchill MJ (2013b) The NRTIs lamivudine, stavudine and zidovudine have reduced HIV-1 inhibitory activity in astrocytes. PLoS ONE 8:e62196

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gray LR, Turville SG, Hitchen TL, Cheng WJ, Ellett AM, Salimi H, Roche MJ, Wesselingh SL, Gorry PR, Churchill MJ (2014) HIV-1 entry and trans-infection of astrocytes involves CD81 vesicles. PLoS ONE 9:e90620

    Article  PubMed Central  PubMed  Google Scholar 

  • Griffin GE, Leung K, Folks TM, Kunkel S, Nabel GJ (1989) Activation of HIV gene expression during monocyte differentiation by induction of NF-kappa B. Nature 339:70–73

    Article  CAS  PubMed  Google Scholar 

  • Guillemin GJ, Brew BJ (2004) Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification. J Leukoc Biol 75:388–397

    Article  CAS  PubMed  Google Scholar 

  • Hagen G, Dennig J, Preiss A, Beato M, Suske G (1995) Functional analyses of the transcription factor Sp4 reveal properties distinct from Sp1 and Sp3. J Biol Chem 270:24989–24994

    Article  CAS  PubMed  Google Scholar 

  • Hagen G, Muller S, Beato M, Suske G (1992) Cloning by recognition site screening of two novel GT box binding proteins: a family of Sp1 related genes. Nucleic Acids Res 20:5519–5525

    Article  PubMed Central  CAS  PubMed  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  PubMed Central  CAS  PubMed  Google Scholar 

  • Henderson AJ, Zou X, Calame KL (1995) C/EBP proteins activate transcription from the human immunodeficiency virus type 1 long terminal repeat in macrophages/monocytes. J Virol 69:5337–5344

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hogan TH, Stauff DL, Krebs FC, Gartner S, Quiterio SJ, Wigdahl B (2003) Structural and functional evolution of human immunodeficiency virus type 1 long terminal repeat CCAAT/enhancer binding protein sites and their use as molecular markers for central nervous system disease progression. J Neurovirol 9:55–68

    Article  CAS  PubMed  Google Scholar 

  • Imai K, Togami H, Okamoto T (2010) Involvement of histone H3 lysine 9 (H3K9) methyltransferase G9a in the maintenance of HIV-1 latency and its reactivation by BIX01294. J Biol Chem 285:16538–16545

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jones KA, Kadonaga JT, Luciw PA, Tjian R (1986) Activation of the AIDS retrovirus promoter by the cellular transcription factor, Sp1. Science 232:755–759

    Article  CAS  PubMed  Google Scholar 

  • Kadonaga JT, Carner KR, Masiarz FR, Tjian R (1987) Isolation of cDNA encoding transcription factor Sp1 and functional analysis of the DNA binding domain. Cell 51:1079–1090

    Article  CAS  PubMed  Google Scholar 

  • Kauder SE, Bosque A, Lindqvist A, Planelles V, Verdin E (2009) Epigenetic regulation of HIV-1 latency by cytosine methylation. PLoS Pathog 5:e1000495

    Article  PubMed Central  PubMed  Google Scholar 

  • Kent SJ, Reece JC, Petravic J, Martyushev A, Kramski M, De Rose R, Cooper DA, Kelleher AD, Emery S, Cameron PU, Lewin SR, Davenport MP (2013) The search for an HIV cure: tackling latent infection. Lancet Infect Dis 13:614–621

    Article  PubMed  Google Scholar 

  • Kimelberg HK, Norenberg MD (1989) Astrocytes. Sci Am 260:66–72, 74, 76

    Article  CAS  PubMed  Google Scholar 

  • Kleinschmidt A, Neumann M, Moller C, Erfle V, Brack-Werner R (1994) Restricted expression of HIV1 in human astrocytes: molecular basis for viral persistence in the CNS. Res Virol 145:147–153

    Article  CAS  PubMed  Google Scholar 

  • Kowenz-Leutz E, Leutz A (1999) A C/EBP beta isoform recruits the SWI/SNF complex to activate myeloid genes. Mol Cell 4:735–743

    Article  CAS  PubMed  Google Scholar 

  • Kulkosky J, Culnan DM, Roman J, Dornadula G, Schnell M, Boyd MR, Pomerantz RJ (2001) Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART. Blood 98:3006–3015

    Article  CAS  PubMed  Google Scholar 

  • Letendre S, Ellis R, Deutsch R, Clifford D, Marra C, McCutchan A, Morgello S, Simpson D, Heaton R, Grant I, Group atC (2010) Correlates of time-to-loss-of-viral-response in CSF and plasma in the CHARTER Cohort. In: 17th Conference on Retroviruses and Opportunistic Infections (CROI): San Francisco, CA, USA

  • Letendre S, Marquie-Beck J, Capparelli E, Best B, Clifford D, Collier AC, Gelman BB, McArthur JC, McCutchan JA, Morgello S, Simpson D, Grant I, Ellis RJ, Group C (2008) Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol 65:65–70

    Article  PubMed Central  PubMed  Google Scholar 

  • Levy DN, Refaeli Y, MacGregor RR, Weiner DB (1994) Serum Vpr regulates productive infection and latency of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A 91:10873–10877

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Levy DN, Refaeli Y, Weiner DB (1995) Extracellular Vpr protein increases cellular permissiveness to human immunodeficiency virus replication and reactivates virus from latency. J Virol 69:1243–1252

    PubMed Central  CAS  PubMed  Google Scholar 

  • Li L, Aiamkitsumrit B, Pirrone V, Nonnemacher MR, Wojno A, Passic S, Flaig K, Kilareski E, Blakey B, Ku J, Parikh N, Shah R, Martin-Garcia J, Moldover B, Servance L, Downie D, Lewis S, Jacobson JM, Kolson D, Wigdahl B (2011) Development of co-selected single nucleotide polymorphisms in the viral promoter precedes the onset of human immunodeficiency virus type 1-associated neurocognitive impairment. J Neurovirol 17:92–109

    Article  PubMed Central  PubMed  Google Scholar 

  • Liu Y, Nonnemacher MR, Wigdahl B (2009) CCAAT/enhancer-binding proteins and the pathogenesis of retrovirus infection. Future Microbiol 4:299–321

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Majello B, De Luca P, Hagen G, Suske G, Lania L (1994) Different members of the Sp1 multigene family exert opposite transcriptional regulation of the long terminal repeat of HIV-1. Nucleic Acids Res 22:4914–4921

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • McManus H, Li PC, Nolan D, Bloch M, Kiertiburanakul S, Choi JY, Mulhall B, Petoumenos K, Zhou J, Law M, Brew BJ, Wright E (2011) Does use of antiretroviral therapy regimens with high central nervous system penetration improve survival in HIV-infected adults? HIV Med 12:610–619

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mingyan Y, Xinyong L, De Clercq E (2009) NF-kappaB: the inducible factors of HIV-1 transcription and their inhibitors. Mini Rev Med Chem 9:60–69

    Article  PubMed  Google Scholar 

  • Mink S, Haenig B, Klempnauer KH (1997) Interaction and functional collaboration of p300 and C/EBPbeta. Mol Cell Biol 17:6609–6617

    PubMed Central  CAS  PubMed  Google Scholar 

  • Mondal D, Alam J, Prakash O (1994) NF-kappa B site-mediated negative regulation of the HIV-1 promoter by CCAAT/enhancer binding proteins in brain-derived cells. J Mol Neurosci 5:241–258

    Article  CAS  PubMed  Google Scholar 

  • Nabel G, Baltimore D (1987) An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature 326:711–713

    Article  CAS  PubMed  Google Scholar 

  • Nonnemacher MR, Irish BP, Liu Y, Mauger D, Wigdahl B (2004) Specific sequence configurations of HIV-1 LTR G/C box array result in altered recruitment of Sp isoforms and correlate with disease progression. J Neuroimmunol 157:39–47

    Article  CAS  PubMed  Google Scholar 

  • Obel N, Omland LH, Kronborg G, Larsen CS, Pedersen C, Pedersen G, Sorensen HT, Gerstoft J (2011) Impact of non-HIV and HIV risk factors on survival in HIV-infected patients on HAART: a population-based nationwide cohort study. PLoS ONE 6:e22698

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ohagen A, Devitt A, Kunstman KJ, Gorry PR, Rose PP, Korber B, Taylor J, Levy R, Murphy RL, Wolinsky SM, Gabuzda D (2003) 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 77:12336–12345

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ong CL, Thorpe JC, Gorry PR, Bannwarth S, Jaworowski A, Howard JL, Chung S, Campbell S, Christensen HS, Clerzius G, Mouland AJ, Gatignol A, Purcell DF (2005) Low TRBP levels support an innate human immunodeficiency virus type 1 resistance in astrocytes by enhancing the PKR antiviral response. J Virol 79:12763–12772

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ousman SS, Kubes P (2012) Immune surveillance in the central nervous system. Nat Neurosci 15:1096–1101

    Article  CAS  PubMed  Google Scholar 

  • Perkins ND, Edwards NL, Duckett CS, Agranoff AB, Schmid RM, Nabel GJ (1993) A cooperative interaction between NF-kappa B and Sp1 is required for HIV-1 enhancer activation. EMBO J 12:3551–3558

    PubMed Central  CAS  PubMed  Google Scholar 

  • Pierson T, McArthur J, Siliciano RF (2000) Reservoirs for HIV-1: mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy. Annu Rev Immunol 18:665–708

    Article  CAS  PubMed  Google Scholar 

  • Rasmussen TA, Schmeltz Sogaard O, Brinkmann C, Wightman F, Lewin SR, Melchjorsen J, Dinarello C, Ostergaard L, Tolstrup M (2013) Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation. Hum Vaccin Immunother 9:993–1001

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Redel L, Le Douce V, Cherrier T, Marban C, Janossy A, Aunis D, Van Lint C, Rohr O, Schwartz C (2010) HIV-1 regulation of latency in the monocyte-macrophage lineage and in CD4+ T lymphocytes. J Leukoc Biol 87:575–588

    Article  CAS  PubMed  Google Scholar 

  • Rong L, Perelson AS (2009) Modeling HIV persistence, the latent reservoir, and viral blips. J Theor Biol 260:308–331

    Article  PubMed Central  PubMed  Google Scholar 

  • Ross HL, Gartner S, McArthur JC, Corboy JR, McAllister JJ, Millhouse S, Wigdahl B (2001) HIV-1 LTR C/EBP binding site sequence configurations preferentially encountered in brain lead to enhanced C/EBP factor binding and increased LTR-specific activity. J Neurovirol 7:235–249

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Schwartz C, Catez P, Rohr O, Lecestre D, Aunis D, Schaeffer E (2000) Functional interactions between C/EBP, Sp1, and COUP-TF regulate human immunodeficiency virus type 1 gene transcription in human brain cells. J Virol 74:65–73

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K, Margolick JB, Kovacs C, Gange SJ, Siliciano RF (2003) Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med 9:727–728

    Article  CAS  PubMed  Google Scholar 

  • Suske G (1999) The Sp-family of transcription factors. Gene 238:291–300

    Article  CAS  PubMed  Google Scholar 

  • Thomas ER, Dunfee RL, Stanton J, Bogdan D, Kunstman K, Wolinsky SM, Gabuzda D (2007) High frequency of defective vpu compared with tat and rev genes in brain from patients with HIV type 1-associated dementia. AIDS Res Hum Retroviruses 23:575–580

    Article  CAS  PubMed  Google Scholar 

  • Thompson KA, Churchill MJ, Gorry PR, Sterjovski J, Oelrichs RB, Wesselingh SL, McLean CA (2004) Astrocyte specific viral strains in HIV dementia. Ann Neurol 56:873–877

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Trono D, Van Lint C, Rouzioux C, Verdin E, Barre-Sinoussi F, Chun TW, Chomont N (2010) HIV persistence and the prospect of long-term drug-free remissions for HIV-infected individuals. Science 329:174–180

    Article  CAS  PubMed  Google Scholar 

  • Van Lint C, Emiliani S, Ott M, Verdin E (1996) Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation. EMBO J 15:1112–1120

    PubMed Central  PubMed  Google Scholar 

  • Wang FX, Xu Y, Sullivan J, Souder E, Argyris EG, Acheampong EA, Fisher J, Sierra M, Thomson MM, Najera R, Frank I, Kulkosky J, Pomerantz RJ, Nunnari G (2005) IL-7 is a potent and proviral strain-specific inducer of latent HIV-1 cellular reservoirs of infected individuals on virally suppressive HAART. J Clin Invest 115:128–137

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang L, Mukherjee S, Jia F, Narayan O, Zhao LJ (1995) Interaction of virion protein Vpr of human immunodeficiency virus type 1 with cellular transcription factor Sp1 and trans-activation of viral long terminal repeat. J Biol Chem 270:25564–25569

    Article  CAS  PubMed  Google Scholar 

  • Watkins BA, Dorn HH, Kelly WB, Armstrong RC, Potts BJ, Michaels F, Kufta CV, Dubois-Dalcq M (1990) Specific tropism of HIV-1 for microglial cells in primary human brain cultures. Science 249:549–553

    Article  CAS  PubMed  Google Scholar 

  • Wesselingh SL, Glass JD (2000) Localization of HIV-1 DNA and tumor necrosis factor-alpha mRNA in human brain using polymerase chain reaction in situ hybridization and immunocytochemistry. Methods Mol Biol 123:323–337

    CAS  PubMed  Google Scholar 

  • WHO (2013). Global update on HIV treatment 2013: results, impact and opportunities. WHO report in partnership with UNICEF and UNAIDS World Health Organisation 2013

  • Widlak P, Gaynor RB, Garrard WT (1997) In vitro chromatin assembly of the HIV-1 promoter. ATP-dependent polar repositioning of nucleosomes by Sp1 and NFkappaB. J Biol Chem 272:17654–17661

    Article  CAS  PubMed  Google Scholar 

  • Wightman F, Lu HK, Solomon AE, Saleh S, Harman AN, Cunningham AL, Gray L, Churchill M, Cameron PU, Dear AE, Lewin SR (2013) Entinostat is a histone deacetylase inhibitor selective for class 1 histone deacetylases and activates HIV production from latently infected primary T cells. AIDS

  • Wiley CA, Schrier RD, Nelson JA, Lampert PW, Oldstone MB (1986) Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc Natl Acad Sci U S A 83:7089–7093

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Xing S, Bullen CK, Shroff NS, Shan L, Yang HC, Manucci JL, Bhat S, Zhang H, Margolick JB, Quinn TC, Margolis DM, Siliciano JD, Siliciano RF (2011) Disulfiram reactivates latent HIV-1 in a Bcl-2-transduced primary CD4+ T cell model without inducing global T cell activation. J Virol 85:6060–6064

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yedavalli VS, Benkirane M, Jeang KT (2003) Tat and trans-activation-responsive (TAR) RNA-independent induction of HIV-1 long terminal repeat by human and murine cyclin T1 requires Sp1. J Biol Chem 278:6404–6410

    Article  CAS  PubMed  Google Scholar 

  • Yilmaz A, Verhofstede C, D'Avolio A, Watson V, Hagberg L, Fuchs D, Svennerholm B, Gisslen M (2010) Treatment intensification has no effect on the HIV-1 central nervous system infection in patients on suppressive antiretroviral therapy. J Acquir Immune Defic Syndr 55:590–596

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported, in part, from project grants from the Australian National Health and Medical Research Council (NHMRC) (APP1051093) and from the National Institutes of Health (NIH) (R21 MH100594) to MJC and PRG. LRG was supported by a NHMRC Early Career Fellowship (GNT0606967). PRG is the recipient of an Australian Research Council Future Fellowship (FT120100389). The authors gratefully acknowledge the contribution to this work of the Victorian Operational Infrastructure Support Program received by the Burnet Institute.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Center for Biomedical Research, Burnet Institute, 85 Commercial Rd, Melbourne, 3004, Victoria, Australia

    Melissa J. Churchill, Steve L. Wesselingh, Paul R. Gorry & Lachlan R. Gray

  2. Department of Microbiology, Monash University, Clayton, Victoria, Australia

    Melissa J. Churchill

  3. Department of Medicine, Monash University, Melbourne, Victoria, Australia

    Melissa J. Churchill

  4. Murdoch Childrens Research Institute, Melbourne, Victoria, Australia

    Daniel J. Cowley

  5. South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia

    Steve L. Wesselingh

  6. Department of Infectious Diseases, Monash University, Melbourne, Victoria, Australia

    Paul R. Gorry & Lachlan R. Gray

  7. Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria, Australia

    Paul R. Gorry

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  1. Melissa J. Churchill
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  2. Daniel J. Cowley
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  3. Steve L. Wesselingh
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  4. Paul R. Gorry
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  5. Lachlan R. Gray
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Correspondence to Melissa J. Churchill.

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Churchill, M.J., Cowley, D.J., Wesselingh, S.L. et al. HIV-1 transcriptional regulation in the central nervous system and implications for HIV cure research. J. Neurovirol. 21, 290–300 (2015). https://doi.org/10.1007/s13365-014-0271-5

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  • DOI: https://doi.org/10.1007/s13365-014-0271-5

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