Intracellular CXCR4 signaling, neuronal apoptosis and neuropathogenic mechanisms of HIV-1-associated dementia

The mechanism(s) by which HIV-1 affects neural injury in HIV-l-associated d ementia (HAD) remains unknown. To ascertain the role that cellular and vira l macrophage products play in HAD neurotoxicity, we explored one potential route for neuronal demise, CXCR4. CXCR4, expressed on lymphocytes and neuro ns, is bath a pare of neural development and a co-receptor for HIV-1. Its l igand, stromal cell-derived factor-1 alpha (SDF-1 alpha), affects neuronal viability. GTP binding protein (G-prorein) linked signaling after neuronal exposure to SDF-1 alpha, virus-infected monocyte-derived macrophage (MDM) s ecretory products, and virus was determined. In both human and rat neurons, CXCR4 was expressed at high levels. SDF-1 alpha/beta was detected predomin antly in astrocytes and at low levels in MDM. SDF-1 alpha/beta was expresse d in HAD brain tissue and upregulated in astrocytes exposed to virus infect ed and/or immune activated MDM conditioned media (fluids). HIV-1-infected M DM secretions, virus and SDF-1 alpha induced a G inhibitory (Gi) protein-li nked decrease in cyclic AMP (cAMP) and increase inositol 1,4,5-trisphosphat e (IP3) and intracellular calcium. Such effects were partially blocked by a ntibodies to CXCR4 or removal of virus from MDM fluids. Changes in G-protei n-coupled signaling correlated, but were not directly linked, to increased neuronal synaptic transmission, Caspase 3 activation and apoptosis. These d ata, taken together, suggest that CXCR4-mediated signal transduction may be a potential mechanism for neuronal dysfunction during HAD. (C) 1999 Elsevi er Science B.V. All rights reserved.