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Mitochondrial control of cell death induced by HIV-1-encoded proteins
K F Ferri1, E Jacotot, J Blanco
1Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France.
Abstract:
In most examples of physiological or pathological cell death, mitochondrial membrane permeabilization (MMP) constitutes an early critical event of the lethal process. Signs of MMP that precede nuclear apoptosis include the translocation of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria to an extra-mitochondrial localization, as well as the dissipation of the mitochondrial transmembrane potential. MMP also occurs in HIV-1-induced apoptosis. Different HIV-1 encoded proteins (Env, Vpr, Tat, PR) can directly or indirectly trigger MMP, thereby causing cell death. The gp120/gp41 Env complex constitutes an example for an indirect MMP inducer. Env expressed on the plasma membrane of HIV-1 infected (or Env-transfected) cells mediates cell fusion with CD4/CXCR4-expressing uninfected cells. After a cell type-dependent latency period, syncytia then undergo MMP and apoptosis. Vpr exemplifies a direct MMP inducer. Vpr binds to the adenine nucleotide translocator (ANT), a mitochondrial inner membrane protein which also interacts with apoptosis-regulatory proteins from the Bcl-2/Bax family. Binding of Vpr to ANT favors formation of a non-specific pore leading to MMP. The structural motifs of the Vpr protein involved in MMP are conserved among most pathogenic HIV-1 isolates and determine the cytotoxic effect of Vpr. These data suggest the possibility that viruses employ multiple strategies to regulate host cell apoptosis by targeting mitochondria.
Insights
Human immunodeficiency virus type 1 (HIV-1) proteins trigger mitochondrial membrane permeabilization (MMP), a key event in cell death. Viruses utilize diverse strategies to induce apoptosis by targeting mitochondria.
Area of Science:
- Cellular biology
- Virology
- Biochemistry
Background:
- Mitochondrial membrane permeabilization (MMP) is a critical early event in physiological and pathological cell death.
- MMP involves cytochrome c and apoptosis-inducing factor (AIF) translocation and mitochondrial transmembrane potential dissipation.
- MMP is implicated in human immunodeficiency virus type 1 (HIV-1)-induced apoptosis.
Purpose of the Study:
- To investigate how HIV-1 encoded proteins induce MMP and subsequent apoptosis.
- To elucidate the mechanisms by which HIV-1 proteins like Env and Vpr trigger MMP.
Main Methods:
- Analysis of MMP markers (cytochrome c and AIF translocation, mitochondrial potential dissipation).
- Investigation of HIV-1 Env-mediated cell fusion and syncytia formation.
- Examination of Vpr protein binding to adenine nucleotide translocator (ANT) and its role in pore formation.
Main Results:
- HIV-1 proteins (Env, Vpr, Tat, PR) can directly or indirectly induce MMP.
- The Env complex indirectly induces MMP via cell fusion, leading to apoptosis in syncytia.
- Vpr directly induces MMP by binding to ANT, promoting pore formation and cell death.
Conclusions:
- HIV-1 employs multiple strategies to induce host cell apoptosis by targeting mitochondria.
- Vpr's conserved structural motifs are crucial for its MMP-inducing and cytotoxic effects.
- Understanding these viral strategies may offer insights into therapeutic interventions for HIV-1 infection.