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

T Roumier1, H L A Vieira, M Castedo

  • 1Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France.

Cell Death and Differentiation
|October 31, 2002
PubMed

Insights

The HIV-1 Vpr protein kills cells via a caspase-independent mitochondrial pathway, not by activating caspases. Inhibiting mitochondrial membrane permeabilization reduces Vpr

Area of Science:

  • Virology
  • Cell Biology
  • Biochemistry

Background:

  • Previous studies suggested HIV-1 Vpr induces cell death by affecting adenine nucleotide translocase (ANT) and causing mitochondrial membrane permeabilization (MMP).
  • The precise mechanism of Vpr-mediated cytotoxicity, particularly its relationship with apoptosis and mitochondria, requires further elucidation.

Purpose of the Study:

  • To investigate the mechanism of cell death induced by the HIV-1 Vpr protein.
  • To determine whether Vpr-mediated cell killing involves caspase activation or relies on mitochondrial pathways.
  • To explore the role of mitochondrial membrane permeabilization (MMP) in Vpr-induced cytotoxicity.

Main Methods:

  • Assessing caspase activation in Vpr-expressing cells.
  • Utilizing knock-out cell lines for caspase activators (Apaf-1, caspase-9) and AIF.
  • Evaluating the impact of overexpressing MMP inhibitors (Bcl-2, vMIA) on Vpr-induced cell death.
  • Comparing the cytotoxic effects of Vpr and HIV-1 Env.

Main Results:

  • Vpr induced cell killing without activating caspases.
  • Knocking out Apaf-1, caspase-9, or AIF did not prevent Vpr-mediated cell death.
  • Overexpression of Bcl-2 or vMIA significantly reduced Vpr's cytotoxic effects.
  • Vpr and HIV-1 Env exhibited additive, but not synergistic, cytotoxic effects.

Conclusions:

  • HIV-1 Vpr induces apoptosis through a caspase-independent mitochondrial pathway.
  • Mitochondrial membrane permeabilization is a key event in Vpr-mediated cell killing.
  • Vpr's mechanism of cell death differs from pathways involving caspase activation or AIF.

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