HIV and Apoptosis

While a main feature of HIV-1 pathogenesis is the death of CD4 ϩ T cells due to apoptosis, the mechanisms of apop-tosis are highly controversial (1, 2). Several HIV-1 proteins have been implicated in apoptosis regulation, among them viral protein R (Vpr), a small (‫ف‬ 14 kD) HIV-1 accessory protein that is packed in the nucleocapsid through its interaction with the Pr55 Gag precursor (3). In addition to its roles in apoptosis and virus assembly, several other activities have been ascribed to Vpr–protein interaction, including: (a) translocation of the HIV-1 preintegration complex through the nuclear pore, a necessary step for the replica-tion of HIV-1 in nondividing cells—Vpr appears to participate in this process by binding to kariopherin ␣ ; (b) induction of cell cycle arrest, likely by Vpr binding to and inactivating MOV34, an upstream positive regulator of the p34–cyclin B complex shown to be essential for the G2–M phase transition; (c) stimulation of viral gene expression through physical interaction of Vpr with transcription factors and/or as a consequence of its effect on cell cycle. The ability of Vpr to exert so many effects through direct pro-tein–protein interactions, followed by changes in target protein activity, can be explained by thinking of Vpr as a chaperone, as recently suggested by the fact that Vpr can substitute for hsp70, a cellular chaperone (4). Thus, Vpr seems to possess structural features that allow for binding to more than one protein with sufficient energy to cause changes in activity (presumably in conformation) of target proteins. In this issue (5), Jacotot et al. extend their previous finding (6) that the mitochondrial adenine nucleotide transloca-tor (ANT), a proposed component of the permeability transition pore, constitutes a novel Vpr target. Here, they present a large number of experiments to test the idea that this physical interaction of Vpr and ANT is central to Vpr-induced apoptosis. First, in pure lipid bilayer membranes, they demonstrate that adding an apoptogenic peptide derived from Vpr (Vpr 52–96) and ANT together leads to channel formation. The channels they measure could easily be large enough to permeabilize (although channel selectiv-ity remains to be determined) the inner mitochondrial membrane, leading to uncoupling of mitochondrial respiration , loss of transmembrane potential, swelling of the matrix , and release of intermembrane proteins, activities of Vpr 52–96 that they independently demonstrate on isolated mitochondria. Second, based on the ability of PA10, a voltage dependent anion channel (VDAC) …