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Nat Neurosci. 2003 Oct;6(10):1064-71. Epub 2003 Sep 21.

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

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

Abstract

The mechanisms of neurodegeneration that result in human immunodeficiency virus (HIV) type 1 dementia have not yet been identified. Here, we report that HIV-infected macrophages secrete the zymogen matrix metalloproteinase-2 (MMP-2), which is activated by exposure to MT1-MMP on neurons. Stromal cell-derived factor 1 alpha (SDF-1), a chemokine overexpressed by astrocytes during HIV infection, was converted to a highly neurotoxic protein after precise proteolytic processing by active MMP-2, which removed the N-terminal tetrapeptide. Implantation of cleaved SDF-1(5-67) into the basal ganglia of mice resulted in neuronal death and inflammation with ensuing neurobehavioral deficits that were abrogated by neutralizing antibodies to SDF-1 and an MMP inhibitor drug. Hence, this study identifies a new in vivo neurotoxic pathway in which cleavage of a chemokine by an induced metalloproteinase results in neuronal apoptosis that leads to neurodegeneration.

PMID:
14502291
DOI:
10.1038/nn1127
[Indexed for MEDLINE]
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