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
EM Sloand, NS Young, P Kumar, FF Weichold, T Sato and JP Maciejewski
National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
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.
Volume 89,
Issue 4,
pp. 1357-1363,
02/15/1997
Copyright © 1997 by The American Society of Hematology
