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Published on: May 14, 2017
ROS-Induced Mitochondrial Dysfunction in CD4 T Cells from ART-Controlled People Living with HIV
Madison Schank1,2, Juan Zhao1,2, Ling Wang1,2
1Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
Abstract:
We have previously demonstrated mitochondrial dysfunction in aging CD4 T cells from antiretroviral therapy (ART)-controlled people living with HIV (PLWH). However, the underlying mechanisms by which CD4 T cells develop mitochondrial dysfunction in PLWH remain unclear. In this study, we sought to elucidate the mechanism(s) of CD4 T cell mitochondrial compromise in ART-controlled PLWH. We first assessed the levels of reactive oxygen species (ROS), and we observed significantly increased cellular and mitochondrial ROS levels in CD4 T cells from PLWH compared to healthy subjects (HS). Furthermore, we observed a significant reduction in the levels of proteins responsible for antioxidant defense (superoxide dismutase 1, SOD1) and ROS-mediated DNA damage repair (apurinic/apyrimidinic endonuclease 1, APE1) in CD4 T cells from PLWH. Importantly, CRISPR/Cas9-mediated knockdown of SOD1 or APE1 in CD4 T cells from HS confirmed their roles in maintaining normal mitochondrial respiration via a p53-mediated pathway. Reconstitution of SOD1 or APE1 in CD4 T cells from PLWH successfully rescued mitochondrial function as evidenced by Seahorse analysis. These results indicate that ROS induces mitochondrial dysfunction, leading to premature T cell aging via dysregulation of SOD1 and APE1 during latent HIV infection.
Insights
Reactive oxygen species (ROS) cause mitochondrial dysfunction and premature aging in CD4 T cells of people with HIV (PLWH) by reducing antioxidant proteins SOD1 and APE1. Restoring these proteins improves mitochondrial function.
Area of Science:
- Immunology
- Cellular Biology
- Virology
Background:
- Mitochondrial dysfunction is observed in aging CD4 T cells of people living with HIV (PLWH) on antiretroviral therapy (ART).
- The precise mechanisms driving CD4 T cell mitochondrial compromise in PLWH are not fully understood.
Purpose of the Study:
- To investigate the mechanisms underlying CD4 T cell mitochondrial dysfunction in ART-controlled PLWH.
- To determine the role of reactive oxygen species (ROS) and specific antioxidant proteins in this process.
Main Methods:
- Assessed cellular and mitochondrial ROS levels in CD4 T cells from PLWH and healthy subjects (HS).
- Quantified levels of superoxide dismutase 1 (SOD1) and apurinic/apyrimidinic endonuclease 1 (APE1) proteins.
- Utilized CRISPR/Cas9 to knock down SOD1 or APE1 in HS CD4 T cells to study their role in mitochondrial respiration via a p53-mediated pathway.
- Reconstituted SOD1 or APE1 in PLWH CD4 T cells and assessed mitochondrial function using Seahorse analysis.
Main Results:
- CD4 T cells from PLWH exhibited significantly elevated cellular and mitochondrial ROS levels compared to HS.
- Levels of SOD1 and APE1 were significantly reduced in CD4 T cells from PLWH.
- Knockdown of SOD1 or APE1 in HS CD4 T cells impaired mitochondrial respiration, confirming their importance via a p53 pathway.
- Reconstitution of SOD1 or APE1 in PLWH CD4 T cells restored mitochondrial function.
Conclusions:
- Elevated ROS levels contribute to mitochondrial dysfunction and premature aging of CD4 T cells in PLWH.
- Downregulation of SOD1 and APE1 plays a critical role in ROS-induced mitochondrial compromise.
- Targeting ROS and restoring SOD1/APE1 levels may offer therapeutic strategies to mitigate T cell aging in HIV infection.
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