Skip to main content

Advertisement

Log in

Protective effect of glutathione in HIV-1 lytic peptide 1-induced cell death in human neuronal cells

  • Published:
Journal of NeuroVirology Aims and scope Submit manuscript

Abstract

To elucidate the pathogenic mechanisms involved in neurodegeneration in AIDS patients with cognitive deficits, we have examined the toxic effect of the lentivirus lytic peptide 1 (LLP-1) corresponding to the carboxyl terminus of HIV-1 transmembrane glycoprotein gp41 on human neuronal and glial cell lines. LLP-1 induced a significant lactate dehydrogenase (LDH, a marker of cell death) release from these cells in a concentration- and time-dependent manner, while the noncytolytic LLP-1 analog 2 had little effect. Application of LLP-1 to SH-SY5Y, a well-characterizedhuman neuronal cell line, causedthe decline of intracellular glutathione (GSH) content that appeared to occur before a significant LDH release. Furthermore, LLP-1 elicited a significant loss of mitochondrial function as measured by mitochondrial transmembrane potential (MTP). Among the reducing agents and antioxidants tested, GSH and a GSH prodrug N-acetylcysteine (NAC) provided protection against LLP-1-induced neuronal cell death, evidently by restoring the intracellular GSH levels and blocking the disruption of mitochondrial integrity. Thus, gp41-derived LLP-1 may be a potential neurotoxic agent capable of causing the intracellular GSH depletion and disturbing the mitochondrial function, possibly contributing to the neurodegenerative cascade as seen in HIV-1-associated dementia. Our data indicate that restoring both GSH concentration and mitochondrial function may hold promise as possible therapeutic strategies for slowing disease progression of dementia in AIDS patients.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Adamson DC, McArthur JC, Dawson TM, Dawson VL (1999). Rate and severity of HIV-associated dementia (HAD): Correlations with Gp41 and iNOS. Mol Med 5: 98–109.

    CAS  PubMed  Google Scholar 

  • Adamson DC, Wildemann B, Sasak MI, Glass JD, Mcarthur JC, Christov VI, Dawson TM, Dawson VL (1996). Immunologic NO synthase: Elevation in severe AIDS dementia and induction by HIV-1gp41. Science 274: 1917–1921.

    Article  CAS  PubMed  Google Scholar 

  • Ankarcrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton SA, Nicotera P (1995). Glutamate-induced neuronal death: A succession of necrosis or apoptosis depending on mitochondrial function. Neuron 15: 961–973.

    Article  CAS  PubMed  Google Scholar 

  • Bains JS, Shaw CA (1997). Neurodegenerative disorders in humans: The role of glutathione in oxidative stress-mediated neuronal death. Brain Res Rev 25: 335–358.

    Article  CAS  PubMed  Google Scholar 

  • Beary TP, Tencza SB, Mietzner TA, Montelaro RC (1998). Interruption of T-cell signal transduction by lentivirus lytic peptides from HIV-1 transmembrane protein. J Peptide Res 51: 75–79.

    Article  CAS  Google Scholar 

  • Castagna A, Le Grazie C, Accordini A, Giulidori P, Cavalli G, Bottiglieri T, Lazzarin A (1995). Cerebrospinal fluid S-adenosylmethionine (SAMe) and glutathione concentrations in HIV infection: Effect of parenteral treatment with SAMe. Neurology 45: 1678–1683.

    CAS  PubMed  Google Scholar 

  • Chernomordik L, Chanturiya A, Suss-Toby E, Nora E, Zimmerburg J (1994). An amphipathic peptide from the C-terminal region of the human immunodeficiency virus envelope glycoprotein causes pore formation in membranes. J Virol 68: 7115–7123.

    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 

  • Chong YH, Lee MJ (2000). Expression of complement inhibitor protein CD59 in human neuronal and glial cell lines treated with HIV-1 gp41 peptides. J Neuro Virol 6: 51–60.

    CAS  Google Scholar 

  • Comardelle AM, Norris CH, Plymale DR, Gatti PJ, Choi B, Fermin CD, Haislip AM, Tencza SB, Mietzner TA, Montelaro RC, Garry RF (1997). A synthetic peptide corresponding to the carboxy terminus of human immunodeficiency virus type 1 transmembrane glycoprotein induces alterations in the ionic permeability of Xenopus laevis oocytes. AIDS Res Hum Retro 13: 1525–1532.

    Article  CAS  Google Scholar 

  • Cooper JJL (1997). Glutathione in the brain: Disorders of glutathione metabolism. In: The molecular and genetic basis of neurological disease. Barchi RL, Kunk LM (eds). Butterworth-Heinemann: Boston, pp 1195–1230.

    Google Scholar 

  • Cossarizza A, Mussini C, Mongiardo N, Borghi V, Sabbatini A, De Rienzo B, Franceschi C (1996). Mitochondrial alterations and a dramatic tendency to undergo apoptosis in peripheral blood lymphocytes during acute HIV syndrome. AIDS 11: 19–26.

    Article  Google Scholar 

  • Coyle JT, Puttfarcken P (1993). Oxidative stress, glutamate, and neurodegenerative disorders. Science 262: 689–695.

    Article  CAS  PubMed  Google Scholar 

  • Droge W (1993). Cysteine and glutathione deficiency in AIDS patients: A rationale for the treatment with N-acetylcysteine. Pharmacology 46: 61–65.

    Article  CAS  PubMed  Google Scholar 

  • Fermin CD, Garry RF (1992). Membrane alterations linked to early interactions of HIV with the cell surface. Virology 191: 941–946.

    Article  CAS  PubMed  Google Scholar 

  • Fernandez-Checa JC, Kaplowitz N (1990). The use of monochlorobimane to determine hepatic GSH levels and synthesis. Anal Biochem 190: 212–219.

    Article  CAS  PubMed  Google Scholar 

  • Genini D, Sheeter D, Rought S, Zaunders JJ, Susin SA, Kroemer G, Richman DD, Carson DA, Corbeil J, Leoni LM (2001). HIV induces lymphocyte apoptosis by a p53-initiated, mitochondrial-mediated mechanism. FASER J 15: 5–6.

    CAS  Google Scholar 

  • Glass JD, Fedor H, Wesselingh SL, McArthur JC (1995). Immunocytochemical quantitation of human immunodeficiency virus in the brain: Correlations with dementia. Ann Neurol 38: 755–762.

    Article  CAS  PubMed  Google Scholar 

  • Glass JD, Johnson RT (1996). Human immunodeficiency virus and the brain. Annu Rev Neurosci 19: 1–26.

    Article  CAS  PubMed  Google Scholar 

  • Haraguchi S, Good RA, Day NK (1995). Immunosuppressive retroviral peptides: cAMP and cytokine patterns. Immunol Today 16: 595–603.

    Article  CAS  PubMed  Google Scholar 

  • Helbling B, von Overbeck J, Lauterburg BH (1996). Decreased release of glutathione into the systemic circulation of patients with HIV infection. Eur J Clin Invest 26: 38–44.

    Article  CAS  PubMed  Google Scholar 

  • Herzenberg LA, De Rosa SC, Dubs JG, Roederer M, Anderson MT, Ela SW, Deresinski SC, Herzenberg LA (1997). Glutathione deficiency is associated with impaired survival in HIV disease. Proc Natl Acad Sci USA 94: 1967–1972.

    Article  CAS  PubMed  Google Scholar 

  • Hoyt KR, Gallagher AJ, Hastings TG, Reynolds IJ (1997). Characterization of hydrogen peroxide toxicity in cultured rat forebrain neurons. Neurochem Res 22: 333–340.

    Article  CAS  PubMed  Google Scholar 

  • Jain A, Martensson J, Stole E, Auld PA, Meister A (1991). Glutathione deficiency leads to mitochondrial damage in brain. Proc Natl Acad Sci USA 88: 1913–1917.

    Article  CAS  PubMed  Google Scholar 

  • Ju C, Yoon KN, Oh YK, Kim HC, Shin CY, Ryu JR, Ko KH, Kim WK (2000). Synergistic depletion of astrocytic glutathione by glucose deprivation and peroxynitrite: Correlation with mitochondrial dysfunction and subsequent cell death. J Neurochem 74: 1989–1998.

    Article  CAS  PubMed  Google Scholar 

  • Kalebic T, Masiero L, Onisto M, Garbisa S (1994). HIV-1 modulates the expression of gelatinase A and B in monocyic cells. Riochem Riophy Res Commun 205: 1243–1249.

    Article  CAS  Google Scholar 

  • Kort JJ (1998). Impairment of excitatory amino acid transport in astroglial cells infected with the human immunodeficiency virus type 1. AIDS Res Hum Retro 14: 1329–1339.

    Article  CAS  Google Scholar 

  • Kroemer G, Dallaporta B, Resche-Rigion M (1998). The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol 60: 619–642.

    Article  CAS  PubMed  Google Scholar 

  • Kroemer G, Reed JC (2000). Mitochondrial control of cell death. Nat Med 6: 513–519.

    Article  CAS  PubMed  Google Scholar 

  • Macho A, Castedo M, Marchetti P, Aguilar JJ, Decaudin D, Zamzami N, Girard PM, Uriel J, Kroemer G (1995). Mitochondrial dysfunctions in circulating T lymphocytes from human immunodeficiency virus-1 carriers. Rlood 86: 2481–2487.

    CAS  Google Scholar 

  • Marschang P, Kruger U, Ochsenbauer C, Gurtler L, Hittmair A, Bosch V, Patsch JR, Dierich MP (1997). Complement activation by HIV-1 infected cells: The role of transmembrane glycoprotein gp41. J AIDS Hum Retrovirol 14: 102–109.

    CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Mattson MP, Culmsee C, Yu Z, Camandola S (2000). Roles of nuclear factor κB in neuronal survival and plasticity. J Neurochem 74: 443–456.

    Article  CAS  PubMed  Google Scholar 

  • Miller MA, Cloyd MW, Liebmann J, Rinaldo C, Islam KR Jr, Wang SZ, Mietzner TA, Montelaro RC (1993a). Alterations in cell membrane permeability by the lentivirus lytic peptide (LLP-1) of HIV-1 transmembrane protein. Virology 196: 89–100.

    Article  CAS  PubMed  Google Scholar 

  • Miller MA, Garry RF, Jaynes JM, Montelaro RC (1991). A structural correlation between lentivirus transmembrane proteins and natural cytolytic peptides. AIDS Res Hum Retro 7: 511–519.

    Article  CAS  Google Scholar 

  • Miller MA, Mietzner TA, Cloyd MW, Robey WG, Montelaro RC (1993b). Identification of a calmodulin-binding and inhibitory peptide domain in the HIV-1 transmembrane glycoprotein. AIDS Res Hum Retro 9: 1057–1066.

    Article  CAS  Google Scholar 

  • Millis KK, Lesko SA, Gamcsik MP (1997). Formation, intracellular distribution and efflux of glutathione-bimane conjugates in drug-sensitive and -resistant MCF-7 cells. Cancer Chemother Pharmacol 40: 101–111.

    Article  CAS  PubMed  Google Scholar 

  • Nuydens R, Novalbos J, Dispersyn G, Weber C, Borgers M, Geerts H (1999). A rapid method for the evaluation of compounds with mitochondria-protective properties. J Neurosci Methods 92: 153–159.

    Article  CAS  PubMed  Google Scholar 

  • Plymale DR, Comardelle AM, Fermin CD, Martin DS, Costin JM, Norris CH, Tencza SB, Mietzner TA, Montelaro RC, Garry RF (1999a). Concentration-dependent differential induction of necrosis or apoptosis by HIV-1 lytic peptide 1. Peptides 20: 1275–1283.

    Article  CAS  PubMed  Google Scholar 

  • Plymale DR, Ng Tang DS, Comardelle AM, Fermin CD, Martin DS, Lewis DE, Garry RF (1999b). Both necrosis and apoptosis contribute to HIV-1-induced killing of CD4 cells. AIDS 13: 1827–1839.

    Article  CAS  PubMed  Google Scholar 

  • Reers M, Smith TW, Chen LB (1991). J-aggregate formation of a carbocyanine as a quantitative fluorescent indicator of membrane potential. Biochemistry 30: 4480–4486.

    Article  CAS  PubMed  Google Scholar 

  • Rostasy K, Monti L, Yiannoutsos C, Kneissl M, Bell J, Kemper TL, Hedreen JC, Navia BA (1999). Human immunodeficiency virus infection, inducible nitric oxide synthase expression, and microglial activation: Pathogenetic relationship to the acquired immunodeficiency syndrome dementia complex. Ann Neurol 46: 207–216.

    Article  CAS  PubMed  Google Scholar 

  • Ruegg CL, Strand MA (1991). Synthetic peptide with sequence identity to the transmembrane protein Gp41 of HIV-1 inhibits distinct lymphocytes activation pathways dependent on protein kinase C and intracellular calcium influx. Cell Immunol 137: 1–13.

    Article  CAS  PubMed  Google Scholar 

  • Salvioli S, Ardizzoni A, Franceschi C, Cossarizza A (1997). JC-1, but not DiOC6(3) or rhodamine 123, is areliable fluorescent probe to assess delta psi changes in intact cells: Implications for studies on mitochondrial functionality during apoptosis. FEBS Lett 411: 77–82.

    Article  CAS  PubMed  Google Scholar 

  • Schuchmann S, Heinemann U (2000). Diminished glutathione levels cause spontaneous and mitochondria-mediated cell death in neurons from trisomy 16 mice: A model of Down’s syndrome. J Neurochem 74: 1205–1214.

    Article  CAS  PubMed  Google Scholar 

  • Srinivas S, Srinivas R, Anantharamaiah G, Segrest J, Compans R, Segrest J (1993). Cytosolic domain of the HIV envelope glycoprotein binds to calmodulin and inhibits calmodulin-regulated proteins. J Biol Chem 268: 22895–22899.

    CAS  PubMed  Google Scholar 

  • Staal FJ, Ela SW, Roeder M, Anderson MT, Herzenberg LA, Herzenberg LA (1992). Glutathione deficiency and human immunodeficiency virus infection. Lancet 339: 909–912.

    Article  CAS  PubMed  Google Scholar 

  • Taub DD, Anver M, Oppenheim JJ, Longo DL, Murphy WJ (1996). T lymphocyte recruitment by interleukin-8 (IL-8). IL-8-induced degranulation of neutrophils releases potent chemoattractants for human T lymphocytes both in vitro and in vivo. J Clin Invest 97: 931–1941.

    Article  Google Scholar 

  • Tencza S, Miller M, Islam K, Mietzner T, Montelaro RC (1995). Effect of amino acid substitutions on calcodulin binding and cytolytic properties of the LLP-1 peptide segment of HIV-1 transmembrane protein. J Virol 69: 5199–5202.

    CAS  PubMed  Google Scholar 

  • van der Ven AJ, Blom HJ, Peters W, Jacobs LE, Verver TJ, Koopmans PP, Demacker P, van der Meer JW (1998). Glutathione homeostasis is disturbed in CD4-positive lymphocytes of HIV-seropositive individuals. Eur J Clinic Invest 28: 187–193.

    Article  Google Scholar 

  • Westendorp MO, Shatrov VA, Schulze-Osthoff K, Frank R, Kraft M, Los M, Krammer PH, Droge W, Lehmann V (1995). HIV-1 Tat potentiates TNF-induced NF-kappa B activation and cytotoxicity by altering the cellular redox state. EMBO J 14: 546–554.

    CAS  PubMed  Google Scholar 

  • Zamzami N, Hirsch T, Dallaporta B, Petit PX, Kroemer G (1997). Mitochondrial implication in accidental and programmed cell death: Apoptosis and necrosis. J Bioenerg Biomembr 29: 185–193.

    Article  CAS  PubMed  Google Scholar 

  • Zasloff M, Martin B, Chen HC (1988). Antimicrobial activity of synthetic magainin peptides and several analogues. Proc Natl Acad Sci USA 85: 910–913.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Young Hae Chong.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sung, J.H., Shin, S.A., Park, H.K. et al. Protective effect of glutathione in HIV-1 lytic peptide 1-induced cell death in human neuronal cells. Journal of NeuroVirology 7, 454–465 (2001). https://doi.org/10.1080/135502801753170318

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1080/135502801753170318

Keywords

Navigation