Mechanisms of apoptosis induction by the HIV-1 envelope.
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-kappaB kinase, IKK), as well as the activation of several transcription factors (NF-kappaB, 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.
Perfettini
J-L
JL
CNRS-UMR8125, Institut Gustave Roussy, 39 rue Camille-Desmoulins, Villejuif, France.
Castedo
M
M
Roumier
T
T
Andreau
K
K
Nardacci
R
R
Piacentini
M
M
Kroemer
G
G
D000818:Animals; D017209:Apoptosis; D015704:CD4 Antigens / Q000187:drug effects; D002478:Cells, Cultured; D016336:Gene Products, vpr / Q000494:pharmacology; D015726:Giant Cells / Q000187:drug effects / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology* / Q000502:physiology; D015497:HIV-1 / Q000472:pathogenicity; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019713:Receptors, CCR5 / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000187:drug effects; D019707:Receptors, Chemokine / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction; D054325:vpr Gene Products, Human Immunodeficiency Virus
D015704:CD4 Antigens; D016336:Gene Products, vpr; D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D054325:vpr Gene Products, Human Immunodeficiency Virus