Abstract
The envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) can induce apoptosis by a cornucopia of distinct mechanisms. A soluble Env derivative, gp120, can kill cells through signals that are transmitted by chemokine receptors such as CXCR4. Cell surface-bound Env (gp120/gp41), as present on the plasma membrane of HIV-1-infected cells, can kill uninfected bystander cells expressing CD4 and CXCR4 (or similar chemokine receptors, depending on the Env variant) by at least three different mechanisms. First, a transient interaction involving the exchange of lipids between the two interacting cells (‘the kiss of death’) may lead to the selective death of single CD4-expressing target cells. Second, fusion of the interacting cells may lead to the formation of syncytia which then succumb to apoptosis in a complex pathway involving the activation of several kinases (cyclin-dependent kinase-1, Cdk1; checkpoint kinase-2, Chk2; mammalian target of rapamycin, mTOR; p38 mitogen-activated protein kinase, p38 MAPK; inhibitor of NF-κB kinase, IKK), as well as the activation of several transcription factors (NF-κB, p53), finally resulting in the activation of the mitochondrial pathway of apoptosis. Third, if the Env-expressing cell is at an early stage of imminent apoptosis, its fusion with a CD4-expressing target cell can precipitate the death of both cells, through a process that may be considered as contagious apoptosis and which does not involve Cdk1, mTOR, p38 nor p53, yet does involve mitochondria. Activation of some of the above- mentioned lethal signal transducers have been detected in patients’ tissues, suggesting that HIV-1 may indeed trigger apoptosis through molecules whose implication in Env-induced killing has initially been discovered in vitro.
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Abbreviations
- AIDS:
-
acquired immunodeficiency syndrome
- Cdk1:
-
cyclin-dependent kinase-1
- Cyt c:
-
cytochrome c
- Env:
-
envelope glycoprotein complex
- HIV-1:
-
human immunodeficiency virus-1
- mTOR:
-
mammalian target of rapamycin
- p38T180/Y182P:
-
p38 with phosphorylated threonine 180 and tyrosine 182
- p53S15P:
-
p53 with phosphorylated serine 15
- p53S46P:
-
p53 with phosphorylated serine 46
- siRNA:
-
small interfering RNA
- Z-VAD.fmk:
-
N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone
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This work has been supported by ANRS, Sidaction, as well as the European Union (Active p53).
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Perfettini, JL., Castedo, M., Roumier, T. et al. Mechanisms of apoptosis induction by the HIV-1 envelope. Cell Death Differ 12 (Suppl 1), 916–923 (2005). https://doi.org/10.1038/sj.cdd.4401584
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DOI: https://doi.org/10.1038/sj.cdd.4401584
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