Abstract
The blood-brain barrier (BBB) is compromised in many systemic and CNS diseases, including HIV-1 infection of the brain. We studied BBB disruption caused by HIV-1 envelope glycoprotein 120 (gp120) as a model. Exposure to gp120, whether acute [by direct intra-caudate-putamen (CP) injection] or chronic [using SV(gp120), an experimental model of ongoing production of gp120] disrupted the BBB, and led to leakage of vascular contents. Gp120 was directly toxic to brain endothelial cells. Abnormalities of the BBB reflect the activity of matrix metalloproteinases (MMPs). These target laminin and attack the tight junctions between endothelial cells and BBB basal laminae. MMP-2 and MMP-9 were upregulated following gp120-injection. Gp120 reduced laminin and tight junction proteins. Reactive oxygen species (ROS) activate MMPs. Injecting gp120 induced lipid peroxidation. Gene transfer of antioxidant enzymes protected against gp120-induced BBB abnormalities. NMDA upregulates the proform of MMP-9. Using the NMDA receptor (NMDAR-1) inhibitor, memantine, we observed partial protection from gp120-induced BBB injury. Thus, (1) HIV-envelope gp120 disrupts the BBB; (2) this occurs via lesions in brain microvessels, MMP activation and degradation of vascular basement membrane and vascular tight junctions; (3) NMDAR-1 activation plays a role in this BBB injury; and (4) antioxidant gene delivery as well as NMDAR-1 antagonists may protect the BBB.
Highlights
The blood-brain barrier (BBB) protects the brain by limiting the ability of molecules and cells from the blood to enter the CNS
This is in part the reason why we developed experimental models of chronic human immunodeficiency virus-1 (HIV-1) neurotoxicity based on recombinant SV40 vector-modified expression of gp120 [19] or Tat, in the brain
Induced matrix metalloproteinases (MMPs)-9 promoter activity, indicating a close relationship among HIV-1-induced cerebrovascular toxicity, redox-regulated mechanisms, and functional caveolae. Such a link was further confirmed in MMP-9-deficient mice exposed to PPARα or PPARγ agonist and injected with the HIV-1 protein Tat into cerebral vasculature. These results indicate that ERK1/2, Akt, and cav-1 are involved in the regulatory mechanisms of peroxisome proliferator-activated receptor (PPAR)-mediated protection against HIV-1-induced MMP-9 expression in brain endothelial cells
Summary
The blood-brain barrier (BBB) protects the brain by limiting the ability of molecules and cells from the blood to enter the CNS. Animal models have been used to study brain injury due to HIV-1 infection [16,17,18,19]. HIV-1 infection of the brain is a chronic process, and its study would benefit from a model system allowing longer-term exposure to HIV-1 gene product. This is in part the reason why we developed experimental models of chronic HIV-1 neurotoxicity based on recombinant SV40 (rSV40) vector-modified expression of gp120 [19] or Tat, in the brain. The effects of HIV-1 gp120 exposure, either acute or protracted, on BBB and their consequences are examined in the present review
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