Neuroprotective effects of IGF-I against TNFalpha-induced neuronal damage in HIV-associated dementia

Virology. 2003 Jan 5;305(1):66-76. doi: 10.1006/viro.2002.1690.


Human immunodeficiency virus type 1 (HIV-1) infection often results in disorders of the central nervous system, including HIV-associated dementia (HAD). It is suspected that tumor necrosis factor-alpha (TNFalpha) released by activated and/or infected macrophages/microglia plays a role in the process of neuronal damage seen in AIDS patients. In light of earlier studies showing that the activation of the insulin-like growth factor I receptor (IGF-IR) exerts a strong neuroprotective effect, we investigated the ability of IGF-I to protect neuronal cells from HIV-infected macrophages. Our results demonstrate that the conditioned medium from HIV-1-infected macrophages, HIV/CM, causes loss of neuronal processes in differentiated PC12 and P19 neurons and that these neurodegenerative effects are associated with the presence of TNFalpha. Furthermore, we demonstrate that IGF-I rescues differentiated neurons from both HIV/CM and TNFalpha-induced damage and that IGF-I-mediated neuroprotection is strongly enhanced by overexpression of the wt IGF-IR cDNA and attenuated by the antisense IGF-IR cDNA. Finally, IGF-I-mediated antiapoptotic pathways are continuously functional in differentiated neurons exposed to HIV/CM and are likely supported by TNFalpha-mediated phosphorylation of I(kappa)B. All together these results suggest that the balance between TNFalpha and IGF-IR signaling pathways may control the extent of neuronal injury in this HIV-related experimental setting.

Publication types

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

MeSH terms

  • AIDS Dementia Complex / pathology*
  • Animals
  • Cell Line
  • Culture Media, Conditioned / toxicity
  • Humans
  • Insulin-Like Growth Factor I / physiology*
  • Macrophages / physiology
  • Macrophages / virology
  • Mice
  • Neurons / drug effects
  • Neurons / pathology*
  • Neuroprotective Agents*
  • Rats
  • Receptor, IGF Type 1 / physiology
  • Tumor Necrosis Factor-alpha / toxicity*


  • Culture Media, Conditioned
  • Neuroprotective Agents
  • Tumor Necrosis Factor-alpha
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1