Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4
Lucile Espert, … , Patrice Codogno, Martine Biard-Piechaczyk
Lucile Espert, … , Patrice Codogno, Martine Biard-Piechaczyk
Published August 1, 2006
Citation Information: J Clin Invest. 2006;116(8):2161-2172. https://doi.org/10.1172/JCI26185.
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Research Article AIDS/HIV

Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4

Abstract

HIV-1 envelope glycoproteins (Env), expressed at the cell surface, induce apoptosis of uninfected CD4+ T cells, contributing to the development of AIDS. Here we demonstrate that, independently of HIV replication, transfected or HIV-infected cells that express Env induced autophagy and accumulation of Beclin 1 in uninfected CD4+ T lymphocytes via CXCR4. The same phenomena occurred in a T cell line and in transfected HEK.293 cells that expressed both wild-type CXCR4 and a truncated form of CD4 that is unable to bind the lymphocyte-specific protein kinase Lck. Env-mediated autophagy is required to trigger CD4+ T cell apoptosis since blockade of autophagy at different steps, by either drugs (3-methyladenine and bafilomycin A1) or siRNAs specific for Beclin 1/Atg6 and Atg7 genes, totally inhibited the apoptotic process. Furthermore, CD4+ T cells still underwent Env-mediated cell death with autophagic features when apoptosis was inhibited. These results suggest that HIV-infected cells can induce autophagy in bystander CD4+ T lymphocytes through contact of Env with CXCR4, leading to apoptotic cell death, a mechanism most likely contributing to immunodeficiency.

Authors

Lucile Espert, Mélanie Denizot, Marina Grimaldi, Véronique Robert-Hebmann, Bernard Gay, Mihayl Varbanov, Patrice Codogno, Martine Biard-Piechaczyk

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Figure 1

Description of the cellular models.

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Description of the cellular models. In model 1, target CD4+ T cells (UC ...
In model 1, target CD4+ T cells (UC blood CD4+ T cells and a T cell line expressing CXCR4 and CD4.403) are cocultured with effector HEK cells with or without Env expression. In model 2, HEK/CD4.403/CXCR4 and HEK/CD4.403 cells are cocultured with effector T cells with or without Env expression. In model 3, target CD4+ T cells are cocultured with HIVNL4-3-infected or uninfected T cells. Expression of gp120 at the surface of HEK.Env, 8.E5, and HIVNL4-3-infected effector cells as well as parental HEK and CEM cells — used as negative controls — were analyzed by flow cytometry after incubation of the cells with PBS (white histograms) or with PBS containing anti-gp120 human polyclonal Ab (black histograms). Bound Ab was detected with a secondary FITC-labeled goat anti-human Ig. Expression analysis of the extracellular domains of CD4 and CXCR4 at the surface of target cells was performed after incubation of the cells with PBS (white histograms) or with anti-CD4 (black histograms) or anti-CXCR4 (gray histograms) mAb at 10 μg/ml. Bound mAb was detected with FITC-labeled goat anti-mouse Ig. The fluorescence intensity was recorded in the log mode on an EPICS XL4 cytofluorometer.