Caspase-dependent apoptosis of cells expressing the chemokine receptor CXCR4 is induced by cell membrane-associated human immunodeficiency virus type 1 envelope glycoprotein (gp120).
Human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins interact with CD4 and chemokine receptors on T cells to deliver signals that trigger either activation, anergy, or apoptosis. However, the molecular mechanisms driving these responses remain poorly understood. In this study we demonstrate that apoptosis is induced upon HIV-1 envelope binding to the chemokine receptor CXCR4. Cells expressing a mutant form of CXCR4 with a C-terminal deletion were also sensitive to HIV-1 envelope-mediated apoptosis, indicating that the cytoplasmic tail of CXCR4 is not required to induce the apoptotic pathway. The specificity of this process was analyzed using several inhibitors of gp120-CD4-CXCR4 interaction. Monoclonal antibodies directed against the gp120-binding site on CD4 (ST4) and against CXCR4 (MAB173) prevented the apoptotic signal in a dose-dependent manner. The cell death program was also inhibited by SDF-1alpha, the natural ligand of CXCR4, and by suramin, 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 gp120-binding on CXCR4 to trigger programmed cell death. Next, we investigated the intracellular signal involved in gp120-induced apoptosis. This cell death program was insensitive to pertussis toxin and did not involve activation of the stress- and apoptosis-related MAP kinases p38(MAPK) and SAPK/JNK 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 signaling pathway through CXCR4.
Biard-Piechaczyk
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M
Laboratoire Infections Rétrovirales et Signalisation Cellulaire, CNRS EP 2104, Institut de Biologie, 4 Boulevard Henri IV, Montpellier Cedex, 34060, France.
Robert-Hebmann
V
V
Richard
V
V
Roland
J
J
Hipskind
R A
RA
Devaux
C
C
D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000502:physiology*; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D004789:Enzyme Activation / Q000502:physiology; D015726:Giant Cells / Q000821:virology; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured
D015699:HIV Envelope Protein gp120; D008562:Membrane Glycoproteins; D019718:Receptors, CXCR4; D020169:Caspases