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

Kunyan Zhang; G Angus McQuibban; Claudia Silva; Georgina S Butler; James B Johnston; Janet Holden; Ian Clark-Lewis; Christopher M Overall; Christopher Power

doi:10.1038/nn1127

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

Nat Neurosci. 2003 Oct;6(10):1064-71. doi: 10.1038/nn1127. Epub 2003 Sep 21.

Authors

Kunyan Zhang¹, G Angus McQuibban, Claudia Silva, Georgina S Butler, James B Johnston, Janet Holden, Ian Clark-Lewis, Christopher M Overall, Christopher Power

Affiliation

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

PMID: 14502291
DOI: 10.1038/nn1127

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AIDS Dementia Complex / enzymology*
AIDS Dementia Complex / etiology
AIDS Dementia Complex / physiopathology
Animals
Antibodies / pharmacology
Astrocytes / metabolism
Cell Line
Chemokine CXCL12
Chemokines, CXC / antagonists & inhibitors
Chemokines, CXC / metabolism
Chemokines, CXC / toxicity*
Disease Models, Animal
Encephalitis / chemically induced
Encephalitis / enzymology
Encephalitis / physiopathology
Enzyme Inhibitors / pharmacology
HIV-1 / metabolism
HIV-1 / pathogenicity
Humans
Macrophages / enzymology
Macrophages / metabolism
Matrix Metalloproteinase 2 / metabolism*
Matrix Metalloproteinase Inhibitors
Mice
Neostriatum / drug effects
Neostriatum / pathology
Neostriatum / physiopathology
Nerve Degeneration / chemically induced
Nerve Degeneration / enzymology*
Nerve Degeneration / virology
Neurotoxins / metabolism
Neurotoxins / toxicity*
Peptide Fragments / metabolism
Peptide Fragments / toxicity

Substances

Antibodies
CXCL12 protein, human
Chemokine CXCL12
Chemokines, CXC
Cxcl12 protein, mouse
Enzyme Inhibitors
Matrix Metalloproteinase Inhibitors
Neurotoxins
Peptide Fragments
Matrix Metalloproteinase 2