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

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Abstract

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.

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Abbreviations

CD4c:

CD4 cytoplasmic domain

AIDS:

acquired immunodeficiency syndrome

HIV:

human immunodeficiency virus

DDHR:

death domain homology region

FADD:

Fas-associating protein with a DD

GITR:

glucocorticoid-induced TNFR family-related gene

Gal4AD:

Gal4 activating domain

PI:

propidium iodide

PS:

phosphatidyl-serine

RT:

room temperature

GST:

glutathione S-transferase

GSH:

glutathione

SD:

standard deviation

APC:

antigen presenting cells

Abs:

antibodies

AICD:

activation-induced cell death

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Acknowledgements

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.

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  1. Bénédicte Py

    Present address: Department of Cell Biology, Harvard Medical School, Boston, USA

Authors and Affiliations

  1. Institut Cochin, CNRS (UMR 8104), Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, 75014, Paris, France

    Bénédicte Py, Jérôme Bouchet, Guillaume Jacquot, Stéphane Basmaciogullari & Serge Benichou

  2. Inserm U567, Paris, France

    Bénédicte Py, Jérôme Bouchet, Guillaume Jacquot, Stéphane Basmaciogullari & Serge Benichou

  3. Institut Pasteur, Paris, France

    Nathalie Sol-Foulon & Olivier Schwartz

  4. Laboratoire Infections Rétrovirales et Signalisation Cellulaire, CNRS UMR 5121, Université Montpellier 1, Montpellier, France

    Martine Biard-Piechaczyk

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  1. Bénédicte Py
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Correspondence to Serge Benichou.

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Py, B., Bouchet, J., Jacquot, G. et al. The Siva protein is a novel intracellular ligand of the CD4 receptor that promotes HIV-1 envelope-induced apoptosis in T-lymphoid cells. Apoptosis 12, 1879–1892 (2007). https://doi.org/10.1007/s10495-007-0106-4

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