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L'autophagie induite par les glycoprotéines de l'enveloppe du VIH-1 dégrade les peroxysomes : rôle dans la mort des lymphocytes T CD4 non infectés

Abstract : The development of AIDS (Acquired ImmunoDeficiency Syndrome) in HIV-1 (Human Immunodeficiency Virus)-infected patients is characterized by a progressive decrease in the number of CD4 T cells. The majority of dying cells are noninfected and called bystander CD4 T cells. In 2006, our team demonstrated that the contact between infected cells (expressing the envelope glycoproteins (Env)) and non-infected cells (expressing the CD4 and CXCR4 receptors) was responsible for enhancing the autophagic pathway which lead to their cellular death by apoptosis. The autophagicpathway is involved in the degradation of cytoplasmic material after its sequestration into vacuoles wherein it will be degraded and then recycled. This process can be highly selective through the involvement of receptor proteins such asp62 or NBR1.We aim at understanding how Env-mediated autophagy can lead to apoptosis in bystander CD4 T cells. A precedent workof our team showed that the changes induced by Env in bystander CD4 T cells included the production of reactive oxygen species (ROS) leading to an oxidative stress state. We showed that the oxidative stress induced by Env is involved in thecellular death by apoptosis of bystander CD4 T cells. We also show that the autophagic process involved has to be a degradative process to lead these CD4 T cells to their death by apoptosis. Moreover, we have observed that Env-mediatedautophagy was degrading peroxisomal proteins. Peroxisomes are essential organelles in the cell responsible partly for the detoxification of ROS in the cell. Their number is regulated through a selective autophagic degradation known aspexophagy.Therefore, we hypothesized that Env induced a selective degradation by autophagy of the cell antioxidant system in bystander CD4 T cells. Since peroxisomes are responsible for regulating the cellular response to an oxidative stress state, their selective degradation could prevent the cell from overcoming this event and eventually lead to its death by apoptosis. In conclusion, we are showing that Env-mediated autophagy degrades important antioxidant systems which are a key survival factor necessary to the bystander CD4 T cells to reduce the oxidative stress induced by Env.
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Mathilde Galais. L'autophagie induite par les glycoprotéines de l'enveloppe du VIH-1 dégrade les peroxysomes : rôle dans la mort des lymphocytes T CD4 non infectés. Sciences agricoles. Université Montpellier, 2019. Français. ⟨NNT : 2019MONTT017⟩. ⟨tel-02464911⟩

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