HIV-1 gp120 upregulates matrix metalloproteinases and their inhibitors in a rat model of HIV encephalopathy

Eur J Neurosci. 2011 Dec;34(12):2015-23. doi: 10.1111/j.1460-9568.2011.07908.x. Epub 2011 Nov 17.


Matrix metalloproteinases (MMPs) are implicated in diverse processes, such as neuroinflammation, leakiness of the blood-brain barrier (BBB) and direct cellular damage in neurodegenerative and other CNS diseases. Tissue destruction by MMPs is regulated by their endogenous tissue inhibitors (TIMPs). TIMPs prevent excessive MMP-related degradation of extracellular matrix components. In a rat model of human immunodeficiency virus (HIV)-related encephalopathy, we described MMP-2 and MMP-9 upregulation by HIV-1 envelope gp120, probably via gp120-induced reactive oxygen species. Antioxidant gene delivery blunted gp120-induced MMP production. We also studied the effect of gp120 on TIMP-1 and TIMP-2 production. TIMP-1 and TIMP-2 levels increased 6 h after gp120 injection into rat caudate-putamen (CP). TIMP-1 and TIMP-2 colocalized mainly with neurons (92 and 95%, respectively). By 24 h, expression of these protease inhibitors diverged, as TIMP-1 levels remained high but TIMP-2 subsided. Gene delivery of the antioxidant enzymes Cu/Zn superoxide dismutase or glutathione peroxidase into the CP before injecting gp120 there reduced levels of gp120-induced TIMP-1 and TIMP-2, recapitulating the effect of antioxidant enzymes on gp120-induced MMP-2 and MMP-9. A significant correlation was observed between MMP/TIMP upregulation and BBB leakiness. Thus, HIV-1 gp120 upregulated TIMP-1 and TIMP-2 in the CP. Prior antioxidant enzyme treatment mitigated production of these TIMPs, probably by reducing MMP expression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AIDS Dementia Complex / pathology
  • AIDS Dementia Complex / physiopathology*
  • Animals
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / pathology
  • Blood-Brain Barrier / physiology
  • Caudate Nucleus / cytology
  • Caudate Nucleus / drug effects*
  • Caudate Nucleus / physiology
  • Disease Models, Animal
  • Female
  • Glutathione Peroxidase / genetics
  • Glutathione Peroxidase / metabolism
  • HIV Envelope Protein gp120 / genetics
  • HIV Envelope Protein gp120 / pharmacology*
  • Humans
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinase 9 / metabolism*
  • Putamen / cytology
  • Putamen / drug effects*
  • Putamen / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism*
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism*
  • Up-Regulation


  • HIV Envelope Protein gp120
  • Reactive Oxygen Species
  • Tissue Inhibitor of Metalloproteinase-1
  • Tissue Inhibitor of Metalloproteinase-2
  • Glutathione Peroxidase
  • Superoxide Dismutase
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9