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Sequential involvement of Cdk1, mTOR and p53 in apoptosis induced by the HIV-1 envelope
Maria Castedo1, Thomas Roumier, Julià Blanco
1Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, , France.
Abstract:
Syncytia arising from the fusion of cells expressing the HIV-1-encoded Env gene with cells expressing the CD4/CXCR4 complex undergo apoptosis following the nuclear translocation of mammalian target of rapamycin (mTOR), mTOR-mediated phosphorylation of p53 on Ser15 (p53(S15)), p53-dependent upregulation of Bax and activation of the mitochondrial death pathway. p53(S15) phosphorylation is only detected in syncytia in which nuclear fusion (karyogamy) has occurred. Karyogamy is secondary to a transient upregulation of cyclin B and a mitotic prophase-like dismantling of the nuclear envelope. Inhibition of cyclin-dependent kinase-1 (Cdk1) prevents karyogamy, mTOR activation, p53(S15) phosphorylation and apoptosis. Neutralization of p53 fails to prevent karyogamy, yet suppresses apoptosis. Peripheral blood mononuclear cells from HIV-1-infected patients exhibit an increase in cyclin B and mTOR expression, correlating with p53(S15) phosphorylation and viral load. Cdk1 inhibition prevents the death of syncytia elicited by HIV-1 infection of primary CD4 lymphoblasts. Thus, HIV-1 elicits a pro-apoptotic signal transduction pathway relying on the sequential action of cyclin B-Cdk1, mTOR and p53.
Insights
HIV-1 infection triggers cell death through a pathway involving cyclin B-Cdk1, mammalian target of rapamycin (mTOR), and p53. This process leads to syncytia apoptosis, a key event in HIV pathogenesis.
Area of Science:
- Virology
- Cell Biology
- Immunology
Background:
- Cell fusion, forming syncytia, is a hallmark of HIV-1 infection.
- Apoptosis, or programmed cell death, plays a critical role in HIV pathogenesis.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying HIV-1-induced syncytia apoptosis.
- To identify key signaling molecules and pathways involved in HIV-1-mediated cell death.
Main Methods:
- Investigated syncytia formation and apoptosis in cells expressing HIV-1 Env and CD4/CXCR4.
- Utilized inhibitors of cyclin-dependent kinase-1 (Cdk1) and p53 neutralization.
- Analyzed protein expression (mTOR, p53, cyclin B) and phosphorylation (p53(S15)) in primary cells from HIV-1-infected patients.
Main Results:
- HIV-1 syncytia undergo apoptosis via nuclear translocation of mammalian target of rapamycin (mTOR) and p53 phosphorylation at Ser15 (p53(S15)).
- Karyogamy (nuclear fusion) is essential for p53(S15) phosphorylation and apoptosis, preceded by cyclin B upregulation and nuclear envelope breakdown.
- Cdk1 inhibition blocks karyogamy, mTOR activation, p53(S15) phosphorylation, and syncytia apoptosis, while p53 neutralization inhibits apoptosis but not karyogamy.
- Elevated cyclin B, mTOR, and p53(S15) phosphorylation correlate with viral load in HIV-1-infected patients.
Conclusions:
- HIV-1 infection activates a pro-apoptotic cascade involving cyclin B-Cdk1, mTOR, and p53.
- This pathway culminates in the activation of the mitochondrial death pathway and syncytia apoptosis.
- Targeting Cdk1 or p53 may offer therapeutic strategies to mitigate HIV-1-induced cell death.