APOPTOSIS OF CD4(-CELLS INDUCED AFTER CONTACT WITH HIV-1-INFECTED OR NONINFECTED MACROPHAGES() T)

The hallmark of human immunodeficiency virus type 1 (HIV1) infection i s the relentless destruction of CD4(+) T lymphocytes. Indirect cell ki lling mechanisms are thought to play an outstanding role in lymphocyte depletion. One such proposed mechanism is the induction of apoptosis through cross-linking of the CD4 receptor by anti-CD4 antibodies or by the HIV1 envelope protein expressed at the surface of infected cells. Here we provide evidence that apoptosis is triggered in CD4(+) lympho blastoid cells (MT4) following cocultivation with monocyte-derived mac rophages (MDMs) productively infected with the monocytotropic isolate HIV1 PAR. Blocking virus replication by AZT abrogates apoptosis of MT4 cells. Infected MDMs do not transmit virus infection to target cells. DNA nucleosomal fragmentation occurs at 46-66 h after starting cocult ures. It is inhibited by the addition of neutralizing anti-gp120 monoc lonal antibody (mAb), implying that the gp120/CD4 interaction triggers the apoptotic: process. Cocultivating with MDMs, either infected or n ot, in the presence of anti-CD4 mAb Leu-3a, also leads to MT4 cell dea th, with DNA fragmentation being detected at 24-40 h. Leu-3a induced a poptosis does not require cross-linking of CD4 by anti-immunoglobulin, showing that MDMs provide an alternative to conventional cross-linkin g. Both the infected and the non-infected MDMs were found to stimulate H-3-thymidine incorporation in cocultivated MT4 cells.