, Volume 12, Issue 10, pp 1879–1892 | Cite as

The Siva protein is a novel intracellular ligand of the CD4 receptor that promotes HIV-1 envelope-induced apoptosis in T-lymphoid cells

  • Bénédicte Py
  • Jérôme Bouchet
  • Guillaume Jacquot
  • Nathalie Sol-Foulon
  • Stéphane Basmaciogullari
  • Olivier Schwartz
  • Martine Biard-Piechaczyk
  • Serge Benichou
Original Paper


In addition to its positive signaling function in the antigen presentation process, CD4 acts as the primary receptor for HIV-1. Contact between CD4 and the viral envelope leads to virus entry, but can also trigger apoptosis of uninfected CD4+ T-cells through a mechanism that is poorly understood. We show that Siva-1, a death domain-containing proapoptotic protein, associates with the cytoplasmic domain of CD4. This interaction is mediated by the cysteine-rich region found in the C-terminal part of the Siva-1 protein. Expression of Siva-1 specifically increases the susceptibility of both T-cell lines and unstimulated human primary CD4+ T-lymphocytes to CD4-mediated apoptosis triggered by the HIV-1 envelope, and results in activation of a caspase-dependent mitochondrial pathway. The same susceptibility is observed in T-cells expressing a truncated form of CD4 that is able to recruit Siva-1 but fails to associate with p56Lck, indicating that Siva-1 participates in a pathway independent of the p56Lck kinase activity. Altogether, these results suggest that Siva-1 might participate in the CD4-initiated signaling apoptotic pathway induced by the HIV-1 envelope in T-lymphoid cells.


Apoptosis CD4 HIV envelope Siva-1 T-lymphocytes 



CD4 cytoplasmic domain


acquired immunodeficiency syndrome


human immunodeficiency virus


death domain homology region


Fas-associating protein with a DD


glucocorticoid-induced TNFR family-related gene


Gal4 activating domain


propidium iodide




room temperature


glutathione S-transferase




standard deviation


antigen presenting cells




activation-induced cell death



This work was supported in part by INSERM, CNRS, Université Paris 5 and the French National Agency for AIDS Research and Sidaction (SB). We thank V.M. Dixit and D. Littman for the kind gift of reagents, and G. Bismuth, C. Hivroz, P.X. Petit, C. Devaux and J. Estaquier for active supports, discussion, and critical reading of the manuscript.

Supplementary material


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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Bénédicte Py
    • 1
    • 2
    • 3
  • Jérôme Bouchet
    • 1
    • 2
  • Guillaume Jacquot
    • 1
    • 2
  • Nathalie Sol-Foulon
    • 4
  • Stéphane Basmaciogullari
    • 1
    • 2
  • Olivier Schwartz
    • 4
  • Martine Biard-Piechaczyk
    • 5
  • Serge Benichou
    • 1
    • 2
  1. 1.Institut Cochin, CNRS (UMR 8104)Université Paris DescartesParisFrance
  2. 2.Inserm U567ParisFrance
  3. 3.Department of Cell BiologyHarvard Medical SchoolBostonUSA
  4. 4.Institut PasteurParisFrance
  5. 5.Laboratoire Infections Rétrovirales et Signalisation Cellulaire, CNRS UMR 5121Université Montpellier 1MontpellierFrance

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