Caspase-dependent apoptosis of cells expressing the chemokine receptor CXCR4 is induced by cell membrane-associated human immunodeficiency virus type1 envelope glycoprotein (gp120)
M. Biard-piechaczyk et al., Caspase-dependent apoptosis of cells expressing the chemokine receptor CXCR4 is induced by cell membrane-associated human immunodeficiency virus type1 envelope glycoprotein (gp120), VIROLOGY, 268(2), 2000, pp. 329-344
Human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins interact
with CD4 and chemokine receptors on T cells to deliver signals that trigge
r either activation, anergy, or apoptosis. However, the molecular mechanism
s driving these responses remain poorly understood. In this study we demons
trate that apoptosis is induced upon HIV-I envelope binding to the chemokin
e receptor CXCR4. Cells expressing a mutant form of CXCR4 with a C-terminal
deletion were also sensitive to HIV-1 envelope-mediated apoptosis, indicat
ing that the cytoplasmic tail of CXCR4 is not required to induce the apopto
tic pathway. The specificity of this process was analyzed using several inh
ibitors of gp120-CD4-CXCR4 interaction. Monoclonal antibodies directed agai
nst the gp120-binding site on CD4 (ST4) and against CXCR4 (MAB173) prevente
d the apoptotic signal in a dose-dependent manner. The cell death program w
as also inhibited by SDF-1 alpha, the natural ligand of CXCR4, and by suram
in, a G protein inhibitor that binds with a high affinity to the V3 loop of
HIV-1 gp120 envelope protein. These results highlight the role played by g
p120-binding on CXCR4 to trigger programmed cell death. Next, we investigat
ed the intracellular signal involved in gp120-induced apoptosis. This cell
death program was insensitive to pertussis toxin and did not involve activa
tion of the stress- and apoptosis-related MAP kinases p38(MAPK) and SAPK/JN
K but was inhibited by a broad spectrum caspase inhibitor (z-VAD.fmk) and a
relatively selective inhibitor of caspase 3 (z-DEVD.fmk). Altogether, our
results demonstrate that HIV induces a caspase-dependent apoptotic signalin
g pathway through CXCR4. (C) 2000 Academic Press.