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Uptake of HIV-1 Tat protein mediated by low-density lipoprotein receptor-related protein disrupts the neuronal metabolic balance of the receptor ligands

Nature Medicine volume 6, pages 1380–1387 (2000)Cite this article

Abstract

Neurological disorders develop in most people infected with human immunodeficiency virus type 1 (HIV-1). However, the underlying mechanisms remain largely unknown. Here we report that binding of HIV-1 transactivator (Tat) protein to low-density lipoprotein receptor-related protein (LRP) promoted efficient uptake of Tat into neurons. LRP-mediated uptake of Tat was followed by translocation to the neuronal nucleus. Furthermore, the binding of Tat to LRP resulted in substantial inhibition of neuronal binding, uptake and degradation of physiological ligands for LRP, including α2-macroglobulin, apolipoprotein E4, amyloid precursor protein and amyloid β-protein. In a model of macaques infected with a chimeric strain of simian–human immunodeficiency virus, increased staining of amyloid precursor protein was associated with Tat expression in the brains of simian–human immunodeficiency virus-infected macaques with encephalitis. These results indicate that HIV-1 Tat may mediate HIV-1-induced neuropathology through a pathway involving disruption of the metabolic balance of LRP ligands and direct activation of neuronal genes.

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Figure 1: Interaction of Tat with neurons.
Figure 2: Specific interaction of Tat and LRP.
Figure 3: Neuronal uptake of Tat mediated by LRP.
Figure 4: Competitive inhibition of interaction between LRP and LRP ligands by Tat.
Figure 5: Immunostaining for APP and Tat in the brains of SHIV-infected macaques.

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References

  1. Price, R.W. et al. The brain in AIDS: central nervous system HIV-1 infection and AIDS dementia complex. Science 239, 586–592 (1988).

    Article  CAS  Google Scholar 

  2. Lee, S.C. et al. Productive infection of human fetal microglia by HIV-1. Am. J. Pathol. 143, 1032–1039 (1993).

    CAS  PubMed  Google Scholar 

  3. He, J., deCastro, C.M., Vandenbark, G.R., Busciglio, J. & Gabuzda, D. Astrocyte apoptosis induced by HIV-1 transactivation of the c-kit protooncogene. Proc. Natl. Acad. Sci. USA 94, 3954–3959 (1997).

    Article  CAS  Google Scholar 

  4. Gendelman, H.E., Lipton, S.A., Tardieu, M., Bukrinsky, M.I. & Nottet, H.S. The neuropathogenesis of HIV-1 infection. J. Leukoc. Biol. 56, 389–398 (1994).

    Article  CAS  Google Scholar 

  5. Sabatier, J.M. et al. Evidence for neurotoxic activity of tat from human immunodeficiency virus type 1. J. Virol. 65, 961–967 (1991).

    CAS  PubMed  Google Scholar 

  6. Kruman, II, Nath, A. & Mattson, M.P. 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 (1998).

    Article  CAS  Google Scholar 

  7. Chang, H.C., Samaniego, F., Nair, B.C., Buonaguro, L. & Ensoli, B. 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 (1997).

    Article  CAS  Google Scholar 

  8. Ensoli, B. et al. Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. J. Virol. 67, 277–287 (1993).

    CAS  PubMed  Google Scholar 

  9. New, D.R., Maggirwar, S.B., Epstein, L.G., Dewhurst, S. & Gelbard, H.A. 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 (1998).

    Article  CAS  Google Scholar 

  10. Jones, M., Olafson, K., Del Bigio, M.R., Peeling, J. & Nath, A. 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 (1998).

    Article  CAS  Google Scholar 

  11. Rappaport, J. et al. Molecular pathway involved in HIV-1-induced CNS pathology: role of viral regulatory protein, Tat. J. Leukoc. Biol. 65, 458–465 (1999).

    Article  CAS  Google Scholar 

  12. Marcuzzi, A., Weinberger, J. & Weinberger, O.K. Transcellular activation of the human immunodeficiency virus type 1 long terminal repeat in cocultured lymphocytes. J. Virol. 66, 4228–4232 (1992).

    CAS  PubMed  Google Scholar 

  13. Milani, D. et al. Influence of the human immunodeficiency virus type 1 Tat protein on the proliferation and differentiation of PC12 rat pheochromocytoma cells. J. Gen. Virol. 74, 2587–2594 (1993).

    Article  CAS  Google Scholar 

  14. Kolson, D.L. et al. HIV-1 Tat alters normal organization of neurons and astrocytes in primary rodent brain cell cultures: RGD sequence dependence. AIDS Res. Hum. Retroviruses 9, 677–685 (1993).

    Article  CAS  Google Scholar 

  15. Barillari, G., Gendelman, R., Gallo, R.C. & Ensoli, B. The Tat protein of human immunodeficiency virus type 1, a growth factor for AIDS Kaposi sarcoma and cytokine-activated vascular cells, induces adhesion of the same cell types by using integrin receptors recognizing the RGD amino acid sequence. Proc. Natl. Acad. Sci. USA 90, 7941–7945 (1993).

    Article  CAS  Google Scholar 

  16. Strickland, D.K., Kounnas, M.Z. & Argraves, W.S. LDL receptor-related protein: a multiligand receptor for lipoprotein and proteinase catabolism. FASEB J. 9, 890–898 (1995).

    Article  CAS  Google Scholar 

  17. Krieger, M. & Herz, J. Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). Annu. Rev. Biochem. 63, 601–637 (1994).

    Article  CAS  Google Scholar 

  18. Rhim, H., Echetebu, C.O., Herrmann, C.H. & Rice, A.P. Wild-type and mutant HIV-1 and HIV-2 Tat proteins expressed in Escherichia coli as fusions with glutathione S-transferase. J. Acquir. Immune Defic. Syndr. 7, 1116–1121 (1994).

    CAS  PubMed  Google Scholar 

  19. Bu, G. & Rennke, S. Receptor-associated protein is a folding chaperone for low density lipoprotein receptor-related protein. J. Biol. Chem. 271, 22218–22224 (1996).

    Article  CAS  Google Scholar 

  20. Mann, D.A. & Frankel, A.D. Endocytosis and targeting of exogenous HIV-1 Tat protein. EMBO J. 10, 1733–1739 (1991).

    Article  CAS  Google Scholar 

  21. Rusnati, M. et al. Interaction of HIV-1 Tat protein with heparin. Role of the backbone structure, sulfation, and size. J. Biol. Chem. 272, 11313–11320 (1997).

    Article  CAS  Google Scholar 

  22. FitzGerald, D.J. et al. Pseudomonas exotoxin-mediated selection yields cells with altered expression of low-density lipoprotein receptor-related protein. J. Cell Biol. 129, 1533–1541 (1995); erratum 130, 1015 (1995).

    Article  CAS  Google Scholar 

  23. Esko, J.D., Rostand, K.S. & Weinke, J.L. Tumor formation dependent on proteoglycan biosynthesis. Science 241, 1092–1096 (1988).

    Article  CAS  Google Scholar 

  24. Westendorp, M.O. et al. Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature 375, 497–500 (1995).

    Article  CAS  Google Scholar 

  25. Howard, G.C., Misra, U.K., DeCamp, D.L. & Pizzo, S.V. Altered interaction of Cis-dichlorodiammineplatinum(II)—modified α2-macroglobulin (α2M) with the low density lipoprotein receptor-related protein/α2M receptor but not the α2M signaling receptor. J. Clin. Invest. 97, 1193–1203 (1996).

    Article  CAS  Google Scholar 

  26. Narita, M., Holtzman, D.M., Schwartz, A.L. & Bu, G. Alpha2-macroglobulin complexes with and mediates the endocytosis of β-amyloid peptide via cell surface low-density lipoprotein receptor- related protein. J. Neurochem. 69, 1904–1911 (1997).

    Article  CAS  Google Scholar 

  27. Raghavan, R. et al. Neuropathogenesis of chimeric simian/human immunodeficiency virus infection in pig-tailed and rhesus macaques. Brain Pathol. 7, 851–861 (1997).

    Article  CAS  Google Scholar 

  28. Kruman, I.I. et al. Evidence that Par-4 participates in the pathogenesis of HIV encephalitis. Am. J. Pathol. 155, 39–46 (1999).

    Article  CAS  Google Scholar 

  29. Hudson, L. et al. Detection of the human immunodeficiency virus regulatory protein tat in CNS tissues. J. Neurovirol. 6, 145–155 (2000).

    Article  CAS  Google Scholar 

  30. Liu, Z.Q. et al. Derivation and biological characterization of a molecular clone of SHIV(KU-2) that causes AIDS, neurological disease, and renal disease in rhesus macaques. Virology 260, 295–307 (1999).

    Article  CAS  Google Scholar 

  31. Kang, J. et al. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733–736 (1987).

    Article  CAS  Google Scholar 

  32. Masters, C.L. et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl. Acad. Sci. USA 82, 4245–4249 (1985).

    Article  CAS  Google Scholar 

  33. Bu, G., Maksymovitch, E.A., Nerbonne, J.M. & Schwartz, A.L. Expression and function of the low density lipoprotein receptor-related protein (LRP) in mammalian central neurons. J. Biol. Chem. 269, 18521–18528 (1994).

    CAS  PubMed  Google Scholar 

  34. Higuchi, M. et al. Expression of the α2-macroglobulin-encoding gene in rat brain and cultured astrocytes. Gene 141, 155–162 (1994).

    Article  CAS  Google Scholar 

  35. Mouchel, Y., Lefrancois, T., Fages, C. & Tardy, M. Apolipoprotein E gene expression in astrocytes: developmental pattern and regulation. Neuroreport 7, 205–208 (1995).

    CAS  PubMed  Google Scholar 

  36. Banati, R.B. et al. Early and rapid de novo synthesis of Alzheimer β A4-amyloid precursor protein (APP) in activated microglia. Glia 9, 199–210 (1993).

    Article  CAS  Google Scholar 

  37. Higgins, L.S., Rodems, J.M., Catalano, R., Quon, D. & Cordell, B. Early Alzheimer disease-like histopathology increases in frequency with age in mice transgenic for beta-APP751. Proc. Natl. Acad. Sci. USA 92, 4402–4406 (1995).

    Article  CAS  Google Scholar 

  38. Sturchler-Pierrat, C. et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Natl. Acad. Sci. USA 994, 13287–13292 (1997).

    Article  Google Scholar 

  39. Giometto, B. et al. Accumulation of β-amyloid precursor protein in HIV encephalitis: relationship with neuropsychological abnormalities. Ann. Neurol. 42, 34–40 (1997).

    Article  CAS  Google Scholar 

  40. An, S.F. et al. Axonal damage revealed by accumulation of β-APP in HIV-positive individuals without AIDS. J. Neuropathol. Exp. Neurol. 56, 1262–1268 (1997).

    Article  CAS  Google Scholar 

  41. Raja, F., Sherriff, F.E., Morris, C.S., Bridges, L.R. & Esiri, M.M. Cerebral white matter damage in HIV infection demonstrated using beta- amyloid precursor protein immunoreactivity. Acta Neuropathol. (Berl) 93, 184–189 (1997).

    Article  CAS  Google Scholar 

  42. Kounnas, M.Z. et al. LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted β-amyloid precursor protein and mediates its degradation. Cell 82, 331–340 (1995).

    Article  CAS  Google Scholar 

  43. Magnuson, D.S., Knudsen, B.E., Geiger, J.D., Brownstone, R.M. & Nath, A. Human immunodeficiency virus type 1 tat activates non-N-methyl-D- aspartate excitatory amino acid receptors and causes neurotoxicity. Ann. Neurol. 37, 373–380 (1995).

    Article  CAS  Google Scholar 

  44. Fields, S. & Sternglanz, R. The two-hybrid system: an assay for protein-protein interactions. Trends Genet. 10, 286–292 (1994).

    Article  CAS  Google Scholar 

  45. Sodroski, J. et al. Trans-acting transcriptional regulation of human T-cell leukemia virus type III long terminal repeat. Science 227, 171–173 (1985).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank C. Herrmann for advice on the GST–Tat protein purification, and H. Broxmeyer, S. Spinola, J. Blum, Y.-C. Yang, A. Srivastava and G. Alkhatib for critical reading of the manuscript. This work was supported by grants from Indiana University School of Medicine and the Ralph W. and Grace M. Showalter Trust Foundation, and funds from Department of Microbiology and Immunology and Walther Oncology Center at Indiana University School of Medicine, and the grant NS39253 (to AN).

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, 46202, Indiana, USA

    Ying Liu, Cynthia M. Hingtgen, Nick Laribee & Johnny J. He

  2. Walther Oncology Center, Indiana University School of Medicine, Indianapolis, 46202, Indiana, USA

    Ying Liu & Johnny J. He

  3. Departments of Neurology, Microbiology and Immunology, University of Kentucky, Lexington, 40536, Kentucky, USA

    Melina Jones & Avindra Nath

  4. Department of Neurology, Indiana University School of Medicine, Indianapolis, 46202, Indiana, USA

    Cynthia M. Hingtgen

  5. Departments of Pediatrics, and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Guojun Bu

  6. Department of Neurology, Massachusetts General Hospital, Boston, 02129, Massachusetts, USA

    Rudolph E. Tanzi & Robert D. Moir

  7. Walther Cancer Institute, Indianapolis, 46206, Indiana, USA

    Johnny J. He

  8. Department of Medicine, Indiana University School of Medicine, Indianapolis, 46202, Indiana, USA

    Johnny J. He

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Liu, Y., Jones, M., Hingtgen, C. et al. 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 (2000). https://doi.org/10.1038/82199

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