Skip to main content

Advertisement

SpringerLink
Log in

PTEN gene silencing prevents HIV-1 gp120IIIB-induced degeneration of striatal neurons

  • Published:
Journal of NeuroVirology Aims and scope Submit manuscript

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstract

To assess the role of the phosphatase and tensin homologue on chromosome 10 (PTEN) in mediating envelope glycoprotein 120 (gp120)-induced neurotoxicity in the striatum, PTEN was silenced using short interfering RNA (siRNA) vectors. PTEN activity directs multiple downstream pathways implicated in gp120-induced neuronal injury and death. PTEN is a negative regulator of Akt (protein kinase B) phosphorylation, but has also been shown to directly activate extrasynaptic NMDA receptors and dephosphorylate focal adhesion kinase. Rodent striatal neurons were nucleofected with green fluorescent protein (GFP)-expressing siRNA constructs to silence PTEN (PTENsi-GFP) or with negative-control (NCsi-GFP) vectors, and exposed to HIV-1 gp120IIIB using rigorously controlled, cell culture conditions including computerized time-lapse microscopy to track the fate of individual neurons following gp120 exposure. Immunofluorescence labeling showed that subpopulations of striatal neurons possess CXCR4 and CCR5 co-receptor immunoreactivity and that gp120IIIB was intrinsically neurotoxic to isolated striatal neurons. Importantly, PTENsi-GFP, but not control NCsi-GFP, constructs markedly decreased PTEN mRNA and protein levels and significantly attenuated gp120-induced death. These findings implicate PTEN as a critical factor in mediating the direct neurotoxic effects of HIV-1 gp120, and suggest that effectors downstream of PTEN such as Akt or other targets are potentially affected. The selective abatement of PTEN activity in neurons may represent a potential therapeutic strategy for the CNS complications of HIV-1.

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

Access this article

Log in via an institution

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Bachis A, Major EO, Mocchetti I (2003) Brain-derived neurotrophic factor inhibits human immunodeficiency virus-1/gp120-mediated cerebellar granule cell death by preventing gp120 internalization. J Neurosci 23:5715–5722

    CAS  PubMed  Google Scholar 

  • Bachis A, Biggio F, Major EO, Mocchetti I (2009) M- and T-tropic HIVs promote apoptosis in rat neurons. J Neuroimmune Pharmacol 4:150–160

    Article  PubMed  Google Scholar 

  • Bakalkin G, Watanabe H, Jezierska J, Depoorter C, Verschuuren-Bemelmans C, Bazov I, Artemenko KA, Yakovleva T, Dooijes D, Van de Warrenburg BPC, Zubarev RA, Kremer B, Knapp PE, Hauser KF, Wijmenga C, Nyberg F, Sinke RJ, Verbeek DS (2010) Prodynorphin mutations cause the neurodegenerative disorder spinocerebellar ataxia type 23. Am J Hum Genet 87:593–603

    Article  CAS  PubMed  Google Scholar 

  • Barry FA, Gibbins JM (2002) Protein kinase B is regulated in platelets by the collagen receptor glycoprotein VI. J Biol Chem 277:12874–12878

    Article  CAS  PubMed  Google Scholar 

  • Benos DJ, Hahn BH, Bubien JK, Ghosh SK, Mashburn NA, Chaikin MA, Shaw GM, Benveniste EN (1994) Envelope glycoprotein gp120 of human immunodeficiency virus type 1 alters ion transport in astrocytes: implications for AIDS dementia complex. Proc Natl Acad Sci USA 91:494–498

    Article  CAS  PubMed  Google Scholar 

  • Berger EA, Murphy PM, Farber JM (1999) Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol 17(657–700):657–700

    Article  CAS  PubMed  Google Scholar 

  • Bhattacharya J, Peters PJ, Clapham PR (2003) CD4-independent infection of HIV and SIV: implications for envelope conformation and cell tropism in vivo. AIDS 17(Suppl 4):S35–S43

    Article  PubMed  Google Scholar 

  • Degtyarev M, De MA, Orr C, Lin J, Lee BB, Tien JY, Prior WW, van Dijk S, Wu H, Gray DC, Davis DP, Stern HM, Murray LJ, Hoeflich KP, Klumperman J, Friedman LS, Lin K (2008) Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents. J Cell Biol 183:101–116

    Article  CAS  PubMed  Google Scholar 

  • Dreyer EB, Kaiser PK, Offermann JT, Lipton SA (1990) HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists. Science 248:364–367

    Article  CAS  PubMed  Google Scholar 

  • Endo H, Nito C, Kamada H, Nishi T, Chan PH (2006) Activation of the Akt/GSK3beta signaling pathway mediates survival of vulnerable hippocampal neurons after transient global cerebral ischemia in rats. J Cereb Blood Flow Metab 26:1479–1489

    Article  CAS  PubMed  Google Scholar 

  • Everall IP, Bell C, Mallory M, Langford D, Adame A, Rockestein E, Masliah E (2002) Lithium ameliorates HIV-gp120-mediated neurotoxicity. Mol Cell Neurosci 21:493–501

    Article  CAS  PubMed  Google Scholar 

  • Francois F, Klotman ME (2003) Phosphatidylinositol 3-kinase regulates human immunodeficiency virus type 1 replication following viral entry in primary CD4+ T lymphocytes and macrophages. J Virol 77:2539–2549

    Article  CAS  PubMed  Google Scholar 

  • Freeman DJ, Li AG, Wei G, Li HH, Kertesz N, Lesche R, Whale AD, Martinez-Diaz H, Rozengurt N, Cardiff RD, Liu X, Wu H (2003) PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell 3:117–130

    Article  CAS  PubMed  Google Scholar 

  • Gabuzda D, Wang J (2000) Chemokine receptors and mechanisms of cell death in HIV neuropathogenesis. J Neurovirol 6(Suppl 1):S24–S32

    CAS  PubMed  Google Scholar 

  • Gao T, Furnari F, Newton AC (2005) PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell 18:13–24

    Article  CAS  PubMed  Google Scholar 

  • Garden GA, Budd SL, Tsai E, Hanson L, Kaul M, D'Emilia DM, Friedlander RM, Yuan J, Masliah E, Lipton SA (2002) Caspase cascades in human immunodeficiency virus-associated neurodegeneration. J Neurosci 22:4015–4024

    CAS  PubMed  Google Scholar 

  • Garden GA, Guo W, Jayadev S, Tun C, Balcaitis S, Choi J, Montine TJ, Moller T, Morrison RS (2004) HIV associated neurodegeneration requires p53 in neurons and microglia. FASEB J 18:1141–1143

    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 

  • Hesselgesser J, Halks-Miller M, DelVecchio V, Peiper SC, Hoxie J, Kolson DL, Taub D, Horuk R (1997) CD4-independent association between HIV-1 gp120 and CXCR4: functional chemokine receptors are expressed in human neurons. Curr Biol 7:112–121

    Article  CAS  PubMed  Google Scholar 

  • Hesselgesser J, Taub D, Baskar P, Greenberg M, Hoxie J, Kolson DL, Horuk R (1998) Neuronal apoptosis induced by HIV-1 gp120 and the chemokine SDF-1 alpha is mediated by the chemokine receptor CXCR4. Curr Biol 8:595–598

    Article  CAS  PubMed  Google Scholar 

  • Holden CP, Nath A, Haughey NJ, Geiger JD (1999) Involvement of Na+/H+ exchangers, Ca2+ channels, and excitatory amino acid receptors in intracellular Ca2+ responses to HIV-1 gp120 in cultured human fetal brain cells. Neuroscience 91:1369–1378

    Article  CAS  PubMed  Google Scholar 

  • Hu S, Sheng WS, Lokensgard JR, Peterson PK (2005) Morphine potentiates HIV-1 gp120-induced neuronal apoptosis. J Infect Dis 191:886–889

    Article  CAS  PubMed  Google Scholar 

  • Huang MB, Bond VC (2000) Involvement of protein kinase C in HIV-1 gp120-induced apoptosis in primary endothelium. J Acquir Immune Defic Syndr 25:375–389

    Article  CAS  PubMed  Google Scholar 

  • Huang MB, Hunter M, Bond VC (1999) Effect of extracellular human immunodeficiency virus type 1 glycoprotein 120 on primary human vascular endothelial cell cultures. AIDS Res Hum Retroviruses 15:1265–1277

    Article  CAS  PubMed  Google Scholar 

  • Jordan CA, Watkins BA, Kufta C, Dubois-Dalcq M (1991) Infection of brain microglial cells by human immunodeficiency virus type 1 is CD4 dependent. J Virol 65:736–742

    CAS  PubMed  Google Scholar 

  • Kapasi AA, Fan S, Singhal PC (2001) Role of 14-3-3epsilon, c-Myc/Max, and Akt phosphorylation in HIV-1 gp 120-induced mesangial cell proliferation. Am J Physiol Renal Physiol 280:F333–F342

    CAS  PubMed  Google Scholar 

  • Kaul M, Lipton SA (1999) Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis. Proc Natl Acad Sci USA 96:8212–8216

    Article  CAS  PubMed  Google Scholar 

  • Kaul M, Garden GA, Lipton SA (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410:988–994

    Article  CAS  PubMed  Google Scholar 

  • Kaul M, Ma Q, Medders KE, Desai MK, Lipton SA (2007) HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection. Cell Death Differ 14:296–305

    Article  CAS  PubMed  Google Scholar 

  • Khan MZ, Brandimarti R, Patel JP, Huynh N, Wang J, Huang Z, Fatatis A, Meucci O (2004) Apoptotic and antiapoptotic effects of CXCR4: is it a matter of intrinsic efficacy? Implications for HIV neuropathogenesis. AIDS Res Hum Retrovir 20:1063–1071

    Article  CAS  PubMed  Google Scholar 

  • Kolson DL (2002) Neuropathogenesis of central nervous system HIV-1 infection. Clin Lab Med 22:703–717

    Article  PubMed  Google Scholar 

  • Kurose K, Zhou XP, Araki T, Cannistra SA, Maher ER, Eng C (2001) Frequent loss of PTEN expression is linked to elevated phosphorylated Akt levels, but not associated with p27 and cyclin D1 expression, in primary epithelial ovarian carcinomas. Am J Pathol 158:2097–2106

    Article  CAS  PubMed  Google Scholar 

  • Kurose K, Gilley K, Matsumoto S, Watson PH, Zhou XP, Eng C (2002) Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat Genet 32:355–357

    Article  CAS  PubMed  Google Scholar 

  • Langford D, Hurford R, Hashimoto M, Digicaylioglu M, Masliah E (2005) Signalling crosstalk in FGF2-mediated protection of endothelial cells from HIV-gp120. BMC Neurosci 6(8):8

    Article  PubMed  Google Scholar 

  • Lannuzel A, Lledo PM, Lamghitnia HO, Vincent JD, Tardieu M (1995) HIV-1 envelope proteins gp120 and gp160 potentiate NMDA-induced [Ca2+]i increase, alter [Ca2+]i homeostasis and induce neurotoxicity in human embryonic neurons. Eur J Neurosci 7:2285–2293

    Article  CAS  PubMed  Google Scholar 

  • Lannuzel A, Barnier JV, Hery C, Huynh VT, Guibert B, Gray F, Vincent JD, Tardieu M (1997) Human immunodeficiency virus type 1 and its coat protein gp120 induce apoptosis and activate JNK and ERK mitogen-activated protein kinases in human neurons. Ann Neurol 42:847–856

    Article  CAS  PubMed  Google Scholar 

  • Lipton SA (1992) Memantine prevents HIV coat protein-induced neuronal injury in vitro. Neurology 42:1403–1405

    CAS  PubMed  Google Scholar 

  • Lipton SA (1994) HIV-related neuronal injury. Potential therapeutic intervention with calcium channel antagonists and NMDA antagonists. Mol Neurobiol 8:181–196

    Article  CAS  PubMed  Google Scholar 

  • Lipton SA (1996) Similarity of neuronal cell injury and death in AIDS dementia and focal cerebral ischemia: potential treatment with NMDA open-channel blockers and nitric oxide-related species. Brain Pathol 6:507–517

    Article  CAS  PubMed  Google Scholar 

  • Lipton SA, Sucher NJ, Kaiser PK, Dreyer EB (1991) Synergistic effects of HIV coat protein and NMDA receptor-mediated neurotoxicity. Neuron 7:111–118

    Article  CAS  PubMed  Google Scholar 

  • Madani N, Kozak SL, Kavanaugh MP, Kabat D (1998) gp120 envelope glycoproteins of human immunodeficiency viruses competitively antagonize signaling by coreceptors CXCR4 and CCR5. Proc Natl Acad Sci USA 95:8005–8010

    Article  CAS  PubMed  Google Scholar 

  • Medders KE, Sejbuk NE, Maung R, Desai MK, Kaul M (2010) Activation of p38 MAPK is required in monocytic and neuronal cells for HIV glycoprotein 120-induced neurotoxicity. J Immunol 185:4883–4895

    Article  CAS  PubMed  Google Scholar 

  • Meucci O, Miller RJ (1996) gp120-induced neurotoxicity in hippocampal pyramidal neuron cultures: protective action of TGF-beta1. J Neurosci 16:4080–4088

    CAS  PubMed  Google Scholar 

  • Meucci O, Fatatis A, Simen AA, Bushell TJ, Gray PW, Miller RJ (1998) Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity. Proc Natl Acad Sci USA 95:14500–14505

    Article  CAS  PubMed  Google Scholar 

  • Meucci O, Fatatis A, Simen AA, Miller RJ (2000) Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival. Proc Natl Acad Sci USA 97:8075–8080

    Article  CAS  PubMed  Google Scholar 

  • Miyawaki T, Ofengeim D, Noh KM, Latuszek-Barrantes A, Hemmings BA, Follenzi A, Zukin RS (2009) The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death. Nat Neurosci 12:618–626

    Article  CAS  PubMed  Google Scholar 

  • Ning K, Pei L, Liao M, Liu B, Zhang Y, Jiang W, Mielke JG, Li L, Chen Y, El-Hayek YH, Fehlings MG, Zhang X, Liu F, Eubanks J, Wan Q (2004) Dual neuroprotective signaling mediated by downregulating two distinct phosphatase activities of PTEN. J Neurosci 24:4052–4060

    Article  CAS  PubMed  Google Scholar 

  • Ohagen A, Ghosh S, He J, Huang K, Chen Y, Yuan M, Osathanondh R, Gartner S, Shi B, Shaw G, Gabuzda D (1999) Apoptosis induced by infection of primary brain cultures with diverse human immunodeficiency virus type 1 isolates: evidence for a role of the envelope. J Virol 73:897–906

    CAS  PubMed  Google Scholar 

  • Peng F, Dhillon N, Callen S, Yao H, Bokhari S, Zhu X, Baydoun HH, Buch S (2008a) Platelet-derived growth factor protects neurons against gp120-mediated toxicity. J Neurovirol 14:62–72

    Article  CAS  PubMed  Google Scholar 

  • Peng F, Dhillon NK, Yao H, Zhu X, Williams R, Buch S (2008b) Mechanisms of platelet-derived growth factor-mediated neuroprotection—implications in HIV dementia. Eur J Neurosci 28:1255–1264

    Article  PubMed  Google Scholar 

  • Pulliam L, West D, Haigwood N, Swanson RA (1993) HIV-1 envelope gp120 alters astrocytes in human brain cultures. AIDS Res Hum Retroviruses 9:439–444

    Article  CAS  PubMed  Google Scholar 

  • Robinson B, Li Z, Nath A (2007) Nucleoside reverse transcriptase inhibitors and human immunodeficiency virus proteins cause axonal injury in human dorsal root ganglia cultures. J Neurovirol 13:160–167

    Article  CAS  PubMed  Google Scholar 

  • Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor–mTOR complex. Science 307:1098–1101

    Article  CAS  PubMed  Google Scholar 

  • Sato S, Fujita N, Tsuruo T (2002) Regulation of kinase activity of 3-phosphoinositide-dependent protein kinase-1 by binding to 14-3-3. J Biol Chem 277:39360–39367

    Article  CAS  PubMed  Google Scholar 

  • Singh IN, Goody RJ, Dean C, Ahmad NM, Lutz SE, Knapp PE, Nath A, Hauser KF (2004) Apoptotic death of striatal neurons induced by HIV-1 Tat and gp120: differential involvement of caspase-3 and endonuclease G. J Neurovirol 10:141–151

    Article  CAS  PubMed  Google Scholar 

  • Singh IN, El-Hage N, Campbell ME, Lutz SE, Knapp PE, Nath A, Hauser KF (2005) Differential involvement of p38 and JNK MAP kinases in HIV-1 Tat and gp120-induced apoptosis and neurite degeneration in striatal neurons. Neuroscience 135:781–790

    Article  CAS  PubMed  Google Scholar 

  • Stambolic V, MacPherson D, Sas D, Lin Y, Snow B, Jang Y, Benchimol S, Mak TW (2001) Regulation of PTEN transcription by p53. Mol Cell 8:317–325

    Article  CAS  PubMed  Google Scholar 

  • Tamura M, Gu J, Danen EH, Takino T, Miyamoto S, Yamada KM (1999) PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway. J Biol Chem 274:20693–20703

    Article  CAS  PubMed  Google Scholar 

  • Trushin SA, Algeciras-Schimnich A, Vlahakis SR, Bren GD, Warren S, Schnepple DJ, Badley AD (2007) Glycoprotein 120 binding to CXCR4 causes p38-dependent primary T cell death that is facilitated by, but does not require cell-associated CD4. J Immunol 178:4846–4853

    CAS  PubMed  Google Scholar 

  • Wan Q, Douglas SD, Wang X, Kolson DL, O'Donnell LA, Ho WZ (2006) Morphine upregulates functional expression of neurokinin-1 receptor in neurons. J Neurosci Res 84:1588–1596

    Article  CAS  PubMed  Google Scholar 

  • Wang SI, Puc J, Li J, Bruce JN, Cairns P, Sidransky D, Parsons R (1997) Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res 57:4183–4186

    CAS  PubMed  Google Scholar 

  • Wang Z, Pekarskaya O, Bencheikh M, Chao W, Gelbard HA, Ghorpade A, Rothstein JD, Volsky DJ (2003) Reduced expression of glutamate transporter EAAT2 and impaired glutamate transport in human primary astrocytes exposed to HIV-1 or gp120. Virology 312:60–73

    Article  CAS  PubMed  Google Scholar 

  • Yi Y, Lee C, Liu QH, Freedman BD, Collman RG (2004) Chemokine receptor utilization and macrophage signaling by human immunodeficiency virus type 1 gp120: implications for neuropathogenesis. J Neurovirol 10:91–96, Suppl 1

    CAS  PubMed  Google Scholar 

  • Yoo LI, Liu DW, Le VS, Bronson RT, Wu H, Yuan J (2006) Pten deficiency activates distinct downstream signaling pathways in a tissue-specific manner. Cancer Res 66:1929–1939

    Article  CAS  PubMed  Google Scholar 

  • Zhang K, Rana F, Silva C, Ethier J, Wehrly K, Chesebro B, Power C (2003) Human immunodeficiency virus type 1 envelope-mediated neuronal death: uncoupling of viral replication and neurotoxicity. J Virol 77:6899–6912

    Article  CAS  PubMed  Google Scholar 

  • Zhao TY, Zou SP, Alimova YV, Wang G, Hauser KF, Ghandour MS, Knapp PE (2006) Short interfering RNA-induced gene silencing is transmitted between cells from the mammalian central nervous system. J Neurochem 98:1541–1550

    Article  CAS  PubMed  Google Scholar 

  • Zhao T, Adams MH, Zou SP, El-Hage N, Hauser KF, Knapp PE (2007) Silencing the PTEN gene is protective against neuronal death induced by human immunodeficiency virus type 1 Tat. J Neurovirol 13:97–106

    Article  CAS  PubMed  Google Scholar 

  • Zheng J, Thylin MR, Ghorpade A, Xiong H, Persidsky Y, Cotter R, Niemann D, Che M, Zeng YC, Gelbard HA, Shepard RB, Swartz JM, Gendelman HE (1999) Intracellular CXCR4 signaling, neuronal apoptosis and neuropathogenic mechanisms of HIV-1-associated dementia. J Neuroimmunol 98:185–200

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The support of NIDA grants R01 DA018633, P01 DA019398, T32 DA007027, and K02 DA027374 is gratefully acknowledged.

Author information

Authors and Affiliations

  1. Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA

    Shiping Zou & Pamela E. Knapp

  2. Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, 1217 East Marshall Street, Richmond, VA, 23298-0613, USA

    Nazira El-Hage, Elizabeth M. Podhaizer, Pamela E. Knapp & Kurt F. Hauser

  3. Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Pamela E. Knapp & Kurt F. Hauser

Authors
  1. Shiping Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nazira El-Hage
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elizabeth M. Podhaizer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pamela E. Knapp
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kurt F. Hauser
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kurt F. Hauser.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zou, S., El-Hage, N., Podhaizer, E.M. et al. PTEN gene silencing prevents HIV-1 gp120IIIB-induced degeneration of striatal neurons. J. Neurovirol. 17, 41–49 (2011). https://doi.org/10.1007/s13365-010-0016-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13365-010-0016-z

Keywords

Search

Navigation