HIV-1 Env induces pexophagy and an oxidative stress leading to uninfected CD4 + T cell death

• Published in: Autophagy Vol. 17; no. 9; pp. 2465 - 2474
• Main Authors: Daussy, Coralie F, Galais, Mathilde, Pradel, Baptiste, Robert-Hebmann, Véronique, Sagnier, Sophie, Pattingre, Sophie, Biard-Piechaczyk, Martine, Espert, Lucile
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 02.09.2021
• Subjects: Autophagy; Brief Report; CD4-Positive T-Lymphocytes; Cell Death; HIV-1; Humans; Life Sciences; Macroautophagy; Oxidative Stress; T-Lymphocytes; peroxisomes; autophagy; ROS; Apoptosis; HIV-1 Env; Peroxisomes; Autophagy
• ISSN: 1554-8627; 1554-8635
• DOI: 10.1080/15548627.2020.1831814

The immunodeficiency observed in HIV-1-infected patients is mainly due to uninfected bystander CD4 T lymphocyte cell death. The viral envelope glycoproteins (Env), expressed at the surface of infected cells, play a key role in this process. Env triggers macroautophagy/autophagy, a process necessary for subsequent apoptosis, and the production of reactive oxygen species (ROS) in bystander CD4 T cells. Here, we demonstrate that Env-induced oxidative stress is responsible for their death by apoptosis. Moreover, we report that peroxisomes, organelles involved in the control of oxidative stress, are targeted by Env-mediated autophagy. Indeed, we observe a selective autophagy-dependent decrease in the expression of peroxisomal proteins, CAT and PEX14, upon Env exposure; the downregulation of either BECN1 or SQSTM1/p62 restores their expression levels. Fluorescence studies allowed us to conclude that Env-mediated autophagy degrades these entire organelles and specifically the mature ones. Together, our results on Env-induced pexophagy provide new clues on HIV-1-induced immunodeficiency. Ab: antibodies; AF: auranofin; AP: anti-proteases; ART: antiretroviral therapy; BafA : bafilomycin A ; BECN1: beclin 1; CAT: catalase; CD4: CD4 molecule; CXCR4: C-X-C motif chemokine receptor 4; DHR123: dihydrorhodamine 123; Env: HIV-1 envelope glycoproteins; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GFP-SKL: GFP-serine-lysine-leucine; HEK: human embryonic kidney; HIV-1: type 1 human immunodeficiency virus; HTRF: homogeneous time resolved fluorescence; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NAC: N-acetyl-cysteine; PARP: poly(ADP-ribose) polymerase; PEX: peroxin; ROS: reactive oxygen species; siRNA: small interfering ribonucleic acid; SQSTM1/p62: sequestosome 1.