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HIV-1 infected immune competent mononuclear phagocytes influence the pathways to neuronal demise

J Zheng1, M R Thylin, Y Persidsky

  • 1The Center for Neurovirology and Neurodegenerative Disorders, Department of Pathology and Microbiology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5215, USA. jzheng@unmc.edu

Neurotoxicity Research
|January 13, 2004
PubMed

Insights

Secretory products from immune-activated, HIV-1-infected macrophages cause neuronal damage. This neurotoxicity, involving apoptosis and NMDA receptor pathways, contributes to neuronal demise in HIV-associated neurodegeneration.

Area of Science:

  • Neuroscience
  • Immunology
  • Virology

Background:

  • Secretory products from HIV-1-infected mononuclear phagocytes (MP) can damage neurons.
  • The precise mechanisms of HIV-1-induced neurotoxicity and its species/strain dependency require further elucidation.

Purpose of the Study:

  • To investigate if HIV-1-infected and lipopolysaccharide (LPS)-activated human monocyte-derived macrophages (MDM) cause neuronal injury in primary human neurons.
  • To compare this neuronal damage with that observed in rat neurons.
  • To understand the role of immune activation in MP-mediated neurotoxicity.

Main Methods:

  • Primary human neurons were exposed to culture supernatants from HIV-1-infected and LPS-activated human MDM.
  • Different HIV-1 strains were used to infect human MDM.
  • Neuronal damage, apoptosis, glutamate signaling, and calcium influx were assessed.
  • The effect of the NMDA receptor antagonist MK-801 was evaluated.

Main Results:

  • Productive viral replication in MDM was necessary but not sufficient for neuronal injury.
  • Virion-free supernatants from HIV-1-infected and immune-activated MDM induced neuronal demise.
  • Maximal alterations in glutamate-mediated neuronal signaling were observed.
  • Apoptosis was the primary mechanism of neuronal cell death.
  • Neuronal injury and calcium influx were partially blocked by MK-801.

Conclusions:

  • Immune activation plays a crucial role in the neurotoxic activities of mononuclear phagocytes (MP) in the context of HIV-1 infection.
  • HIV-1-infected and immune-activated MDM upregulate NMDA receptor-sensitive soluble factors and induce neuronal apoptosis.
  • These findings offer insights into the link between MP immune responses, soluble factors, and neuronal death in HIV-associated dementia (HAD).

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