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 Article has an altmetric score of 11

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 2

Autophagy is induced by cell-expressed Env, and Beclin 1 is accumulated during this process.

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Autophagy is induced by cell-expressed Env, and Beclin 1 is accumulated ...
(A) UC blood CD4+ T lymphocytes were purified by negative selection using the CD4+ Rosette separation technique. Cells were cocultured for 3 days with HEK or HEK.Env or treated with 1 μM Rapa and examined by TEM. Autophagic (vacuolated) cells were defined as cells that had 5 or more autophagic vacuoles. The percentage of autophagic cells and the number of vacuoles in the target cell sections were analyzed from at least 100 randomly chosen TEM fields by 2 investigators. Scale bars: 1 μm; 250 nm (indicated enlargements). (B) UC blood CD4+ T cells were transfected with GFP-LC3, cocultured with HIVNL4-3-infected or uninfected CEM cells, and examined by epifluorescence. Data are representative of 3 independent experiments; more than 100 cells were counted by 2 investigators. Cells with autophagosomes were defined as cells that had 5 or more LC3 spots in the cytoplasm. Magnification shown. (C) Beclin 1 expression was analyzed in UC blood CD4+ T cells cocultured with effector HEK cells with or without Env expression. Fold induction was calculated as the intensity of the Beclin 1 immunoblot obtained in cells cocultured with effector cells expressing Env compared with effector cells that do not express Env. Ratios were normalized to that obtained with anti-actin Ab. Data are representative of at least 3 independent experiments. **P < 0.01; ***P < 0.001.