Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4.
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.
Espert
Lucile
L
Laboratoire Infections Rétrovirales et Signalisation Cellulaire, CNRS UMR 5121, Institut de Biologie, Montpellier, France.
Denizot
Mélanie
M
Grimaldi
Marina
M
Robert-Hebmann
Véronique
V
Gay
Bernard
B
Varbanov
Mihayl
M
Codogno
Patrice
P
Biard-Piechaczyk
Martine
M
D017209:Apoptosis; D001343:Autophagy / Q000276:immunology*; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D016923:Cell Death / Q000276:immunology; D002460:Cell Line; D018920:Coculture Techniques; D015686:Gene Products, env; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D007668:Kidney; D019718:Receptors, CXCR4 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
D015686:Gene Products, env; D015699:HIV Envelope Protein gp120; D019718:Receptors, CXCR4