Binding of human immunodeficiency virus type 1 gp120 to CXCR4 induces mitochondrial transmembrane depolarization and cytochrome c-mediated apoptosis independently of Fas signaling.
Apoptosis of CD4(+) T lymphocytes, induced by contact between human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (gp120) and its receptors, could contribute to the cell depletion observed in HIV-infected individuals. CXCR4 appears to play an important role in gp120-induced cell death, but the mechanisms involved in this apoptotic process remain poorly understood. To get insight into the signal transduction pathways connecting CXCR4 to apoptosis following gp120 binding, we used different cell lines expressing wild-type CXCR4 and a truncated form of CD4 that binds gp120 but lacks the ability to transduce signals. The present study demonstrates that (i) the interaction of cell-associated gp120 with CXCR4-expressing target cells triggers a rapid dissipation of the mitochondrial transmembrane potential resulting in the cytosolic release of cytochrome c from the mitochondria to cytosol, concurrent with activation of caspase-9 and -3; (ii) this apoptotic process is independent of Fas signaling; and (iii) cooperation with a CD4 signal is not required. In addition, following coculture with cells expressing gp120, a Fas-independent apoptosis involving mitochondria and caspase activation is also observed in primary umbilical cord blood CD4(+) T lymphocytes expressing high levels of CXCR4. Thus, this gp120-mediated apoptotic pathway may contribute to CD4(+) T-cell depletion in AIDS.
Roggero
R
R
Laboratoire Infections Rétrovirales et Signalisation Cellulaire CNRS EP 2104, Institut de Biologie, 34060 Montpellier Cedex, France.
Robert-Hebmann
V
V
Harrington
S
S
Roland
J
J
Vergne
L
L
Jaleco
S
S
Devaux
C
C
Biard-Piechaczyk
M
M
D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D003574:Cytochrome c Group / Q000502:physiology; D015699:HIV Envelope Protein gp120 / Q000502:physiology*; D015658:HIV Infections / Q000473:pathology / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000502:physiology; D019718:Receptors, CXCR4 / Q000502:physiology*; D015398:Signal Transduction; D019014:fas Receptor / Q000502:physiology
D003574:Cytochrome c Group; D015699:HIV Envelope Protein gp120; D019718:Receptors, CXCR4; D019014:fas Receptor