title: Role of Fas ligand and receptor in the mechanism of T-cell depletion in acquired immunodeficiency syndrome: effect on CD4+ lymphocyte depletion and human immunodeficiency virus replication.
abstract: Direct killing of CD4+ lymphocytes by human immunodeficiency virus-1 (HIV-1) probably cannot account for the magnitude of the loss of these cells during the course of HIV-1 infection. Experimental evidence supports a pathophysiologic role of the apoptotic process in depletion of CD4 cells in acquired immunodeficiency syndrome (AIDS). The Fas-receptor/Fas-ligand (Fas-R/Fas-L) system mediates signals for apoptosis of susceptible lymphocytes and lympoblastoid cell lines. A number of investigators have recently reported increased expression of the Fas receptor in individuals with HIV infection, along with increased sensitivity of their lymphocytes to anti-Fas antibody mimicking Fas ligand. We attempted to determine the role of Fas-mediated apoptosis in disease progression and viral replication. Increased Fas-receptor (CD95) expression on CD4+ and CD8+ lymphocytes was found in a large group of HIV-1-infected patients compared with normal controls; individuals with a diagnosis of AIDS and a history of opportunistic infection had significantly more Fas receptor expression than did asymptomatic HIV-infected persons and normal blood donor controls (P < .01). Triggering of the Fas-R by agonistic anti-Fas monoclonal antibody, CH11, was preferentially associated with apoptosis in the CD4+ cells; this effect was more pronounced in lymphocytes derived from HIV+ individuals. Soluble and membrane-bound forms of Fas-L were produced in greater amounts in peripheral blood mononuclear cells (PBMC) cultures and in plasma obtained from HIV-1-infected persons than from normal controls. Furthermore, triggering of lymphocytes from HIV-infected persons by CH11 increased levels of interleukin-1beta converting enzyme (ICE), a protein associated with apoptosis. When PBMC were cultured in the presence of CH11, p24 production per number of viable cells was decreased as compared with the same PBMC without CH11 (P < .01). These findings suggest that multiple mechanisms, including increased production of Fas-L by infected PBMC, increased Fas-R expression, and induction of a protease of ICE family, may play roles in the apoptotic depletion of CD4+ cells in HIV infection.
authors.affiliation: National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Sloand
authors.forename: N S
authors.initials: NS
authors.lastname: Young
authors.forename: P
authors.initials: P
authors.lastname: Kumar
authors.forename: F F
authors.initials: FF
authors.lastname: Weichold
authors.forename: T
authors.initials: T
authors.lastname: Sato
authors.forename: J P
authors.initials: JP
authors.lastname: Maciejewski
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology*; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D020170:Caspase 1; D002453:Cell Cycle; D015331:Cohort Studies; D003546:Cysteine Endopeptidases / Q000096:biosynthesis; D004790:Enzyme Induction; D053222:Fas Ligand Protein; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000502:physiology*; D010835:Phytohemagglutinins / Q000494:pharmacology; D015398:Signal Transduction; D014779:Virus Replication; D019014:fas Receptor / Q000502:physiology*
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D010835:Phytohemagglutinins; D019014:fas Receptor; D003546:Cysteine Endopeptidases; D020170:Caspase 1