ABSTRACT
Tat, the HIV transactivating protein, and matrix metalloproteinases (MMPs), a family of extracellular matrix (ECM) endopeptidases, have been implicated in the pathogenesis of HIV-associated dementia. However, the possibility that MMPs interact with viral proteins has remained unexplored. We therefore treated mixed human fetal neuronal cultures with recombinant Tat and select MMPs. Neurotoxicity was determined by measuring mitochondrial membrane potential and neuronal cell death. Previous studies have shown that Tat and MMP independently cause neurotoxicity. Surprisingly, we found the combination of Tat and MMP produced significant attenuation of neurotoxicity. To determine whether there was a physical interaction between Tat and MMP, we used protein electrophoresis and Western blot techniques, and found that MMP-1 can degrade Tat. This effect was blocked by MMP inhibitors. Furthermore, MMP-1 decreased Tat-mediated transactivation of the HIV long terminal repeat region, and this functionality was restored when MMP-1 activity was inhibited. These results suggest that the decrease in Tat-induced neurotoxicity and HIV transactivation is due to Tat's enzymatic cleavage by MMP-1. The direct interaction of human MMPs with viral proteins has now been demonstrated, with resultant modulation of Tat-mediated neurotoxicity and transactivation. This study elucidates a unique viral-host interaction that may serve as an innate host defense mechanism.
Subject(s)
Gene Products, tat/metabolism , Matrix Metalloproteinase 1/metabolism , Neurons/virology , Cells, Cultured , Dementia/etiology , Fetus/cytology , Gene Products, tat/toxicity , HIV Infections/complications , HIV Infections/immunology , HIV Long Terminal Repeat , Humans , Immunity , Matrix Metalloproteinase 1/toxicity , Membrane Potentials/drug effects , Mitochondrial Membranes/drug effects , Neurons/pathology , Protein Binding , Transcriptional Activation/drug effects , tat Gene Products, Human Immunodeficiency VirusABSTRACT
Soluble Fas (sFas) and soluble Fas ligand (sFasL) are associated with cellular dysfunction and death and are elevated in CSF from patients with HIV dementia (HIV-D). The authors investigated whether these markers correlated with dementia severity and course. sFas and sFasL were measured in 15 highly active antiretroviral therapy (HAART)-naïve HIV-D subjects, 30 HAART-naïve HIV+ controls, and 17 HIV-controls. HIV-D subjects had higher CSF sFas levels than controls. Subjects with moderate/severe dementia had higher CSF sFas levels than those with mild dementia. CSF sFas trended lower in those with progressive dementia.
