Mitochondrial Control of Cell Death Induced by HIV‐1‐Encoded Proteins

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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.