Evidence that Par-4 participates in the pathogenesis of HIV encephalitis

Progressive neuronal degeneration in brain regions involved in learning and memory processes is a common occurrence in patients infected with human im munodeficiency virus type 1 (HIV-1). We now report that levels of Par-4, a protein recently linked to neuronal apoptosis in Alzheimer's disease, are i ncreased in neurons in hippocampus of human patients with HIV encephalitis and in monkeys infected with a chimeric strain of HIV-1 and simian immunode ficiency virus. Par-4 levels Increased rapidly in cultured hippocampal neur ons following exposure to the neurotoxic HIV-1 protein Tat, and treatment o f the cultures with a Par-4 antisense oligonucleotide protected the neurons against Tat-induced apoptosis, Additional findings show that Par-4 partici pates at an early stage of Tat-induced neuronal apoptosis before caspase ac tivation, oxidative stress, and mitochondrial dysfunction. Our data suggest that Par-4 may be a mediator of neuronal apoptosis in HIV encephalitis and that therapeutic approaches targeting the Par-4 apoptotic cascade may prov e beneficial in preventing neuronal degeneration and associated dementia in patients infected with HIV-1.