APOPTOSIS INDUCED BY HIV-1 INFECTION OF THE CENTRAL-NERVOUS-SYSTEM

Apoptosis plays a role in AIDS pathogenesis in the immune system, but its role in HIV-l-induced neurological disease is unknown. In this stu dy, we examine apoptosis induced by HIV-1 infection of the central ner vous system (CNS) in an in vitro model and in brain tissue from AIDS p atients. HIV-I infection of primary brain cultures induced apoptosis i n neurons and astrocytes in vitro as determined by terminal deoxynucle otidyl transferase-mediated dUTP nick end labeling (TUNEL) and propidi um iodide staining and by electron microscopy. Apoptosis was not signi ficantly induced until 1-2 wk after the time of peak virus production, suggesting induction by soluble factors rather than by direct viral i nfection, Apoptosis of neurons and astrocytes was also detected in bra in tissue from 10/11 AIDS patients, including 5/5 patients with HIV-1 dementia and 4/5 nondemented patients. In addition, endothelial cell a poptosis was frequently detected in the brain of AIDS patients and was confirmed by electron microscopy, Most of the apoptotic cells were no t localized adjacent to HIV-l-infected cells, providing further eviden ce for induction by soluble factors, In six non-AIDS control patients with normal brain, apoptotic cells were absent or limited to rare astr ocytes. However, TUNEL-positive neurons and astrocytes were frequently detected in seven patients with Alzheimer's disease or abundant senil e plaques. These studies suggest that apoptosis is a mechanism of CNS injury in AIDS which is likely to be induced by soluble factors. The a poptosis of endothelial cells in the CNS raises the possibility that s ome of these factors may be blood-derived.