TNF-related apoptosis-inducing ligand (TRAIL) induces neuronal apoptosis in HIV-encephalopathy

Neuronal loss is frequently found in brains ofpatients with human immunodeficiency virus(HIV)-encephalopathy. Extensive apoptosis ofneurons is probably involved in the development ofHIV-encephalopathy. The present study wasdesigned to investigate the mechanism of neuronalapoptosis. For this purpose, we examined autopsybrains of two patients with HIV-encephalopathy.Terminal deoxynucleotidyl transferase-mediateddUTP nick-end labeling (TUNEL)-positive cellsand active forms of caspase-3- and -8-positivecells, including neurons, were found in theperivascular regions of the brains. In theseregions, TNF-related apoptosis-inducing ligand(TRAIL)+ macrophages were also observed. Wealso examined brains of HIV-1-infected mousemodel inoculated with human cells. In thesebrains, TUNEL+ neurons were also found in theperivascular region, the site where infiltrated HIV-1-infected and TRAIL-expressing macrophageswere observed. Using an in vitro-culture system,we also demonstrated that the HIV-1-infectedmonocyte-derived macrophages preferentiallyexpressed TRAIL and that the addition of HIV-1-infected macrophages or human TRAIL-overexpressingmouse cells to cultured mouse primaryneurons/glia resulted in neuronal apoptosis. Ourresults suggest the involvement of TRAILexpressed on HIV-1-infected macrophages in theinduction of neuronal apoptosis in infected brain.