Apoptotic death of striatal neurons induced by human immunodeficiency virus-1 Tat and gp120: Differential involvement of caspase-3 and endonuclease G

J Neurovirol. 2004 Jun;10(3):141-51. doi: 10.1080/13550280490441103.

Abstract

Human immunodeficiency virus-1 (HIV-1) infection affects the striatum, resulting in gliosis and neuronal losses. To determine whether HIV-1 proteins induce striatal neurotoxicity through an apoptotic mechanism, mouse striatal neurons isolated on embryonic day 15 and the effects of HIV-1 Tat(1-72) and gp120 on survival were assessed in vitro. Mitochondrial release of cytochrome c, caspase-3 activation, and neuron survival, as well as an alternative apoptotic pathway involving endonuclease G (endo G), were assessed at 4 h, 24 h, 48 h, and/or 72 h using enzyme assays and immunoblotting. Both HIV-1 Tat and gp120 significantly increased caspase-3 activation in a concentration-dependent manner in striatal neurons at 4 h following continuous exposure in vitro. Tat(1-72) and gp120 caused significant neuronal losses at 48 h and/or 72 h. Tat(1-72) increased cytochrome c release, and caspase-3 and endo G activation at 4 h, 24 h, and/or 72 h. By contrast, gp120 increased caspase-3 activation, but failed to increase cytochrome c or endo G levels in the cytoplasm at 4 h, 24 h, and/or 72 h. The cell permeant caspase inhibitor Z-DEVD-FMK significantly attenuated gp120-induced, but not Tat(1-72)-induced, neuronal death, suggesting that gp120 acts in large part through the activation of caspase(s), whereas Tat(1-72)-induced neurotoxicity was accompanied by activating an alternative pathway involving endo G. Thus, although Tat(1-72) and gp120 induced significant neurotoxicity, the nature of the apoptotic events preceding death differed. Collectively, our findings suggest that HIV-1 proteins are intrinsically toxic to striatal neurons and the pathogenesis is mediated through separate actions involving both caspase-3 and endo G.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Caspase 3
  • Caspases / metabolism*
  • Cells, Cultured
  • Corpus Striatum / drug effects
  • Corpus Striatum / virology
  • Cytochromes c / drug effects
  • Cytochromes c / metabolism
  • Dose-Response Relationship, Drug
  • Electrophoresis, Polyacrylamide Gel
  • Endodeoxyribonucleases / metabolism*
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • Gene Products, tat / pharmacology*
  • Gene Products, tat / physiology
  • HIV Envelope Protein gp120 / pharmacology*
  • HIV Envelope Protein gp120 / physiology
  • HIV-1 / physiology
  • Immunoblotting
  • Mice
  • Mice, Inbred ICR
  • Nerve Degeneration / enzymology
  • Nerve Degeneration / virology
  • Neurons / drug effects*
  • Neurons / virology
  • tat Gene Products, Human Immunodeficiency Virus

Substances

  • Enzyme Inhibitors
  • Gene Products, tat
  • HIV Envelope Protein gp120
  • tat Gene Products, Human Immunodeficiency Virus
  • Cytochromes c
  • Endodeoxyribonucleases
  • endonuclease G
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases