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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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.
KeywordsApoptosis 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
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.
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