UP-REGULATION OF FAS LIGAND EXPRESSION BY HUMAN-IMMUNODEFICIENCY-VIRUS IN HUMAN MACROPHAGES MEDIATES APOPTOSIS OF UNINFECTED T-LYMPHOCYTES

Apoptosis has been proposed to mediate CD4(+) T-cell depletion in huma n immunodeficiency virus (HIV)-infected individuals. Interaction of Fa s ligand (FasL) with Fas (CD95) results in lymphocyte apoptosis, and i ncreased susceptibility to Fas-mediated apoptosis has been demonstrate d in lymphocytes from HN-infected individuals. Cells undergoing apopto sis in lymph nodes from HIV-infected individuals do not harbor virus, and therefore a bystander effect has been postulated to mediate apopto sis of uninfected cells. These data raise the possibility that antigen -presenting cells are a source of Fast and that HIV infection of cells such as macrophages may induce or increase Fast expression, In this r eport, we demonstrate that HIV infection of monocytic cells not only i ncreases the surface expression of Fas but also results in the de novo expression of FasL. Interference with the FasL-Fas interaction by ant i-Fas blocking antibodies abrogates HIV-induced apoptosis of monocytic cells. Human monocyte-derived macrophages from healthy donors contain detectable Fast mRNA, which is further upregulated following HIV infe ction with monocytotropic strains. HIV-infected human macrophages resu lt in the apoptotic death of Jurkat T cells and peripheral blood T lym phocytes. Interruption of the FasL-Fas interaction abrogates the HIV-i nfected macrophage-dependent death of T lymphocytes. These results pro vide evidence that human macrophages can provide a source of Fast, esp ecially following HIV infection, and can thus participate in lymphocyt e depletion in HIV-infected individuals.