Analysis of the patterns of stromal cell-derived factor 1alpha (SDF-1alpha) expression in the brains from HIV-positive patients suggests that in neuronal cells, SDF-1alpha might play a role in neuroprotection and neurite extension in response to HIV infection. In all cases analyzed, SDF-1alpha immunoreactivity was primarily present in astroglial cells. Patients with HIV encephalitis (HIVE) showed intense somato-dendritic neuronal SDF-1alpha immunoreactivity, while HIVE negative patients with neurodegeneration had a significant decrease in neuronal SDF-1alpha immunoreactivity. Neuronal cells treated with SDF-1alpha displayed increased neurite outgrowth. Similarly, neurons treated with HIV-Tat, which induced SDF-1alpha expression, also showed neurite outgrowth. Tat-mediated neurite outgrowth was blocked by anti-SDF-1alpha antibody. These results suggest that SDF-1alpha may play a role in the neuronal response to HIV in the brains of AIDS patients.