Primary macrophages infected by human immunodeficiency virus trigger CD95-mediated apoptosis of uninfected astrocytes

Infection of macrophages (M/M) by human immunodeficiency virus (HIV) is a m ain pathogenetic event leading to neuronal dysfunction and death in patient s with AIDS dementia complex. Alteration of viability of neurons and astroc ytes occurs in vivo even without their infection, thus it is conceivable th at HIV-infected M/M may affect viability of such cells even without direct infection. To assess this hypothesis, we studied the effects of HIV-infecte d M/M on an astrocytic cell-line lacking CD4-receptor expression. Exposure to supernatants of HIV-infected M/M triggers complete disruption and apopto tic death of astrocytic cells. This effect is not related to HIV transmissi on from infected M/M, because HIV-DNA and p24 production in astrocytic cell s remained negative. Apoptotic death of astrocytes is mainly mediated by Fa s ligand released in supernatants of HIV-infected M/M (as demonstrated by c omplete reversal of such phenomenon by adding neutralizing antibodies again st CD95 receptor). Treatment of astrocytic cells with recombinant (biologic ally active) Tat induces <10% apoptosis, and gp120 was totally ineffective. Treatment of HIV-infected M/M with AZT completely reverses the proapoptoti c effect of their supernatants on astrocytes, thus demonstrating that produ ctive virus replication within M/M is required for the induction of astrocy tic cell death. Taken together, data suggest that homeostasis of astrocytes may be affected by HIV-infected M/M in the absence of productive infection of target cells. This phenomenon may help to explain the cellular damage f ound in HIV-infected patients also in areas of the brain not strictly adjac ent to HIV-infected M/M.