HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 AND ITS COAT PROTEIN GP120 INDUCEAPOPTOSIS AND ACTIVATE JNK AND ERK MITOGEN-ACTIVATED PROTEIN-KINASES IN HUMAN NEURONS

Detection of apoptotic neurons and microglial cells in the brains of h uman immunodeficiency virus type 1 (HIV-1)-infected patients has sugge sted that programmed cell death may be implicated in the physiopatholo gy of HIV-1 encephalopathy. To analyze in vitro the intracellular sign als induced by HIV-1 in human neurons and the associated neuronal deat h, we tested cultured human central nervous system (CNS) cells for apo ptosis induced by HIV-1 and gp120 and for signaling pathways activated by gp120. HIV-1 and gp120 induced apoptosis of neurons and microglial cells but not of astrocytes or transformed microglial cells. Gp120 ac tivated c-Jun N-terminal kinase (JNK) and p42 extracellular-regulated kinase (ERK) in primary CNS cells, with an early peak of activation at 2 to 5 minutes that was not present when pure microglial or astrocyte cultures were tested, followed by a late and sustained activation (10 and 60 minutes) in primary and enriched glial cell cultures as well a s in transformed microglial cells. This demonstrates that gp120 could be an effector of HIV-1-induced apoptosis in the CNS and act directly on neuronal and glial cells.