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HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration

Kunyan Zhang1, G Angus McQuibban, Claudia Silva

  • 1Department of Clinical Neurosciences, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.

Nature Neuroscience
|September 23, 2003
PubMed

Insights

HIV-infected macrophages release matrix metalloproteinase-2 (MMP-2), which activates and cleaves a chemokine, causing neurotoxicity and neurodegeneration in HIV dementia. This pathway involves MMP-2, stromal cell-derived factor 1 alpha (SDF-1), and neuronal apoptosis.

Area of Science:

  • Neuroscience
  • Immunology
  • Biochemistry

Background:

  • Mechanisms underlying HIV-1 dementia remain unclear.
  • HIV-1 infection impacts macrophage and astrocyte function.

Purpose of the Study:

  • To elucidate the molecular mechanisms of neurodegeneration in HIV-1 dementia.
  • To identify specific proteins and pathways involved in HIV-1-associated neurotoxicity.

Main Methods:

  • Investigated the role of matrix metalloproteinase-2 (MMP-2) secreted by HIV-infected macrophages.
  • Examined the activation of MMP-2 by neuronal MT1-MMP.
  • Analyzed the processing of stromal cell-derived factor 1 alpha (SDF-1) by active MMP-2.
  • Utilized in vivo mouse models with basal ganglia implantation of cleaved SDF-1(5-67).
  • Assessed neurobehavioral deficits and inflammation in mice.
  • Employed neutralizing antibodies to SDF-1 and MMP inhibitors for therapeutic assessment.

Main Results:

  • HIV-infected macrophages secrete latent MMP-2, activated by neuronal MT1-MMP.
  • Active MMP-2 cleaves SDF-1, generating a neurotoxic fragment (SDF-1(5-67)).
  • Intracranial implantation of SDF-1(5-67) induced neuronal death, inflammation, and neurobehavioral deficits in mice.
  • These deficits were reversed by SDF-1 antibodies and MMP inhibitors.

Conclusions:

  • Identified a novel in vivo neurotoxic pathway in HIV-1 dementia.
  • This pathway involves MMP-2-mediated cleavage of SDF-1, leading to neuronal apoptosis.
  • Targeting MMP-2 or SDF-1 may offer therapeutic strategies for HIV-1-associated neurodegeneration.

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