Binding of Human Immunodeficiency Virus Type 1 gp120 to CXCR4 Induces Mitochondrial Transmembrane Depolarization and Cytochromec-Mediated Apoptosis Independently of Fas Signaling

Abstract

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.

Mechanisms of apoptosis induction by the HIV-1 envelope

“…32 Cell lines transfected with a truncated form of CD4 that binds gp120 but lacks the ability to transduce signals (due to absence of the cytoplasmic domain of CD4), still manifest DCm dissipation in response to gp120 acting on CXCR4. 16 The signal triggered by gp120 involves chemokine receptorsin neurons mainly CXCR4, 16,17 and downstream of such receptors, pertussis toxin-sensitive G proteins, 17 the p38 mitogen-activated protein kinase pathway, 38 and/or a rapid cytosolic Ca 2 þ increase 39 ( Figure 2). Gp120 induces apoptosis of cultured neurons and sensitizes them to oxidative stress and excitotoxins.…”

“…Cell killing may be secondary to fusion of the interacting cells, but it may also affect single cells 16,19,[43][44][45][46] (Figure 3). Apparently, the 'decision' whether cell fusion occurs or not is governed at the level of the CD4/ coreceptor-expressing cell, through yet-to-be-elucidated mechanisms, since different cell lines expressing such coreceptors (e.g.…”

“…The putative implication of membrane protein transfer and/or specific receptor-mediated death signals is also depicted and whether a simple membrane perturbation or more specific signals lead to cell death. The exact cellular signals involved in target cell killing remain largely unexplored apart from the fact that they do not involve CD95 16 and that they act in a rapid, pertussis toxin-resistant fashion, 43 leading to DC m loss and subsequent plasma membrane permeabilization. 19,43,45 Overexpression of Bcl-2 can inhibit single cell killing 45 and, as mentioned above, inhibition of caspases diverts single cell killing to syncytium formation, 43 suggesting that the process does follow canonical apoptotic signaling pathways (Figure 3).…”

“…[12][13][14][15] The Env glycoprotein (gp) precursor protein (gp160) undergoes proteolytic maturation to generate gp41 (membrane inserted) and gp120 (membrane inserted or shed from the cell surface). Soluble gp120 can stimulate proapoptotic signal via an action on chemokine receptors (CXCR4 for lymphotropic Env variants, CCR5 for monocytotropic Env variants) 12,16,17 (Figure 1). Although soluble gp120 has been detected in body fluids, it has been doubted whether it would reach concentrations high enough to induce cell death in vivo.…”

Autophagie et destruction des lymphocytes T CD4 par le VIH-1

“…Malgré de nombreux travaux réalisés, la nature des premiers signaux induits directement par le virus et conduisant à la mort cellulaire n'a toujours pas été identifiée. Les résultats obtenus dans notre équipe montrent que l'interaction entre Env et CXCR4 active une voie de signalisation conduisant à la voie intrinsèque d'apoptose (relargage de cytochrome c de la mitochondrie, activation des caspases 9 puis 3), et ainsi à la mort des cellules T CD4 par apoptose sans infection ni réplication virale [13]. Cependant, les expé-riences montrent que la mort cellulaire induite par Env n'est pas totalement bloquée lorsque l'apoptose est inhibée par un inhibiteur géné-ral des caspases (z-VAD).…”