HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration.
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.
D015526:AIDS Dementia Complex / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism; D002460:Cell Line; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000378:metabolism / Q000472:pathogenicity; D006801:Humans; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D017072:Neostriatum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology* / Q000821:virology; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity*; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity
D000906:Antibodies; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D009498:Neurotoxins; D010446:Peptide Fragments; D020778:Matrix Metalloproteinase 2