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

  title={Mitochondrial Control of Cell Death Induced by HIV‐1‐Encoded Proteins},
  author={Karine F. Ferri and Etienne Daniel Jacotot and Juli{\`a} Blanco and Jos{\'e} A. Est{\'e} and Guido Kroemer},
  journal={Annals of the New York Academy of Sciences},
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… 

Mitochondrial Apoptosis Induced by the HIV‐1 Envelope

In several models of Env‐induced apoptosis, early signs of mitochondrial membrane permeabilization (MMP) become manifest and may involve an elevation of cytosolic Ca2+, reactive oxygen species and/or the transcriptional activation of p53, with the consequent expression of pro‐apoptotic proteins such as Bax, which permeabilizes mitochondrial membranes.

The C-terminal moiety of HIV-1 Vpr induces cell death via a caspase-independent mitochondrial pathway

It appears that Vpr induces apoptosis through a caspase-independent mitochondrial pathway, and HIV-1-Env, which causes MMP through an indirect pathway, exhibit additive (but not synergic) cytotoxic effects.

HIV gp41‐induced apoptosis is mediated by caspase‐3‐dependent mitochondrial depolarization, which is inhibited by HIV protease inhibitor nelfinavir

Using an in vitro model of coculture of Env‐expressing cells as effectors and CD4+ T cells as targets, it is found that apoptosis mediated by Env glycoprotein in bystander cells in fact correlates with gp41‐induced hemifusion and it is shown that virion‐induced apoptosis is gp 41‐dependent.

HIV-1 protease-induced apoptosis

It is shown that expression of active HIV-1 PR induces death in HeLa and HEK-293 cells via the mitochondrial apoptotic pathway, which is caused either by a direct effect of HIV- 1 PR on mitochondrial membrane integrity or by its interaction with cellular protein BCA3.

HIV-1 Vpr Triggers Mitochondrial Destruction by Impairing Mfn2-Mediated ER-Mitochondria Interaction

The results suggest that Vpr-mediated cellular damage may occur on an alternative protein transport pathway from the ER, via MAM to the mitochondria, which are modulated by Mfn2 and DRP1.

HIV‐1 Tat targets microtubules to induce apoptosis, a process promoted by the pro‐apoptotic Bcl‐2 relative Bim

The findings reveal a strategy by which Tat induces apoptosis by targeting the microtubule network, and HIV‐1 Tat joins a growing list of pathogen‐derived proteins that target the cytoskeleton of host cells.

Visna/maedi virus-induced apoptosis involves the intrinsic mitochondrial pathway

VMV apoptosis is mediated in part by the activation of p53 and the intrinsic mitochondrial apoptotic pathway, which seems to be regulated by the p53 pathway.

Newcastle Disease Virus Exerts Oncolysis by both Intrinsic and Extrinsic Caspase-Dependent Pathways of Cell Death

It is demonstrated that genetically modified, recombinant NDV strains are cytotoxic to human tumor cell lines of ecto-, endo-, and mesodermal origin and that recombinantNDV could be developed as a cancer virotherapy agent, either alone or in combination with therapeutic transgenes.

Mitochondrial Membrane Permeabilization in Physiological and Pathological Cell Death

MMP is regulated by pro-and anti-apoptotic members of a Bax/Bcl-2 family of proteins, via a process that may involve sessile mitochondrial proteins organized in the two membrane-spanning permeability transition pore complex (PTPC).

A flavivirus protein M-derived peptide directly permeabilizes mitochondrial membranes, triggers cell death and reduces human tumor growth in nude mice

Findings support the notion of using viral genomes as valuable sources to discover mitochondria-targeted sequences that may lead to the development of new anticancer compounds.



The HIV-1 Viral Protein R Induces Apoptosis via a Direct Effect on the Mitochondrial Permeability Transition Pore

Coincubation of purified organelles revealed that nuclear apoptosis is only induced by Vpr when mitochondria are present yet can be abolished by PTPC inhibitors, suggesting that Vpr induces apoptosis via a direct effect on the mitochondrial PTPC.

Apoptosis Control in Syncytia Induced by the HIV Type 1–Envelope Glycoprotein Complex

The results establish that the following molecular sequence governs apoptosis of Env-induced syncytia: Bax-mediated/Bcl-2–inhibited MMP → AIF release → Cyt-c release → caspase activation → nuclear apoptosis.

[Mitochondrial control of apoptosis].

  • G. Kroemer
  • Biology
    Bulletin de l'Academie nationale de medecine
  • 2001

Molecular Ordering in HIV-induced Apoptosis

Dysregulated apoptosis may underlie the etiology of T cell depletion by human immunodeficiency virus type 1 (HIV-1). We show that HIV-induced apoptosis is preceded by an exponential increase in

Mitochondrion as a novel target of anticancer chemotherapy.

The design of mitochondrion-targeted cytotoxic drugs may constitute a novel strategy for overcoming apoptosis resistance.

Mitochondrio‐nuclear translocation of AIF in apoptosis and necrosis

  • E. DaugasS. Susin G. Kroemer
  • Biology
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 2000
Data are compatible with the hypothesis that AIF is a caspase‐independent mitochondrial death effector responsible for partial chromatinolysis, and in conditions of ATP depletion, AIF translocation correlates with the appearance of large‐scale DNA fragmentation.

Bcl-2 inhibits the mitochondrial release of an apoptogenic protease

It is shown that mitochondria contain a pre-formed approximately 50-kD protein which is released upon delta psi m disruption and which, in a cell-free in vitro system, causes isolated nuclei to undergo apoptotic changes such as chromatin condensation and internucleosomal DNA fragmentation, and the effect of Bcl-2 on the formation, release, and action of AIF.

Both necrosis and apoptosis contribute to HIV-1-induced killing of CD4 cells.

Although lymphoblastoid and monocytoid cells acutely infected by HIV-1 had increased levels of fragmented DNA, a marker of apoptotic cell death, few had condensed chromatin and fragmented nuclei, the morphological features of apoptosis.

Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC

The results indicate that the Bcl-2 family of proteins bind to the VDAC in order to regulate the mitochondrial membrane potential and the release of cytochrome c during apoptosis.

The mitochondrial death/life regulator in apoptosis and necrosis.

The acquisition of the biochemical and ultrastructural features of apoptosis critically relies on the liberation of apoptogenic proteases or protease activators from mitochondria.