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al., 1992). Thus, it was possible that in vivo ADCC takes place with NK e¨ec-
tor cells and gp120-bearing CD4
T cells and anti-gp120 antibodies leading to
apoptosis of NK cells and the destruction of CD4
T cells. This hypothesis was
tested in vitro. The ®ndings revealed that gp120-coated peripheral T lympho-
cytes serve as targets and are killed in ADCC. Further, the NK cells that
recover from the ADCC reaction show loss of cytotoxic function, acquire the
CD16
dim=ÿ
CD56
dim=ÿ
phenotype (as seen in vivo), and a signi®cant fraction of
NK cells are killed by apoptosis (Jewett et al., 1997). Further studies revealed
that endogenous TNF-a synthesis and secretion by NK cells play a pivotal role
in the induction of functional anergy and apoptosis in NK cells (Jewett et al.,
1997).
The mechanism for early immune dysfunction in HIV infection with normal
CD4 counts is not clear. It may be the result of inappropriate triggering of
activation-induced cell death in T cells from such individuals once stimulated
with speci®c antigens or certain mitogens. The depletion of CD4 T cells tends to
result in part by infection and by apoptosis. Several mechanisms have been
postulated, which include HIV Tat shown to enhance Fas sensitivity and en-
hance Fas ligand production; HIV Nef shown to result in activation and up-
regulation of Fas ligand; HIV Vpr shown to arrest cell cycle and also have a
direct e¨ect on the permeability of mitochondria; activation-induced cell death;
gp-120/160 shown to activate T cells and also up-regulate Fas sensitivity and
Fas ligand ( Badley et al., 2000); and apoptosis regulatory proteins, which
include cellular receptors, induce apoptosis after ligation of Fas, p55 TNF re-
ceptor I, and TRAIL/Apo-2L receptor 1 and 2. The magnitude of apoptosis
observed in HIV-infected patients correlates well with stage of HIV disease in
longitudinal and cross-sectional analyses ( Prati et al., 1997; Samuelsson et al.,
1997).
Investigations have examined the e¨ect of binding of CD4 molecules by HIV
envelope protein gp-120 and cross-linking by anti gp-120 antibody. Although
this cross-linking is insu½cient to induce apoptosis in normal T lymphocytes,
apoptosis is observed in CD4
T cells from HIV-infected individuals. There
was up-regulation of Fas and this correlated with apoptosis. Also, there was
induction of the cytokines IFN-g and TNF-a in the absence of IL-2 and IL-4.
Antibodies to IFN-g and TNF-a inhibited the up-regulation of Fas apoptosis in
T cells. It is possible that IFN-g and TNF-a in¯uence NK cells similar to the T
cells and lead to their destruction (Oyaizu et al., 1995).
Peripheral blood mononuclear cells ( PBMC) of HIV-infected adults are able
to lyse CD4 lymphocytes expressing gp120, the major envelope glycoprotein of
HIV-1, and the e¨ector cells responsible for the lysis were shown to be CD16
and NK cells armed with cytophilic HIV speci®c antibody ( Tanneau et al.,
1990; Tyler et al., 1989; Weinhold et al., 1998). ADCC against HIV-1-express-
ing CD4 lymphocytes in children at various stages of HIV infection were
examined. PBMC of vertically HIV-infected children were impaired in their
ability
to
lyse
HIV-expressing
CD4
lymphocytes.
In
contrast,
PBMC
of
