Understanding HIV dementia

HIV can infect brain macrophages and microglia, causing neuroinflammation and neuronal death. This damage results in the neurodegenerative syndrome HIV dementia, but the molecular mechanisms that mediate the neurodegeneration have been unclear. In the September 21 Nature Neuroscience, Kunyan Zhang and colleagues at the University of Calgary show that HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor 1 (SDF-1) causes neurodegeneration (Nature Neuroscience, DOI:10.1038/nn1127, September 21, 2003).

Zhang et al. infected primary human macrophages from HIV-seronegative donors with a pseudotyped virus containing a luciferase-expressing transgene and the env-encoded envelope protein derived from a patient with HIV dementia. They observed that HIV-infected macrophages secreted the zymogen matrix metalloproteinase 2 (MMP-2), which is activated by exposure to MT1-MMP on neurons. 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. In addition, the authors showed that implantation of cleaved ...