Mitochondrial Functions Are Compromised in CD4 T Cells From ART-Controlled PLHIV

Abstract

The hallmark of HIV/AIDS is a gradual depletion of CD4 T cells. Despite effective control by antiretroviral therapy (ART), a significant subgroup of people living with HIV (PLHIV) fails to achieve complete immune reconstitution, deemed as immune non-responders (INRs). The mechanisms underlying incomplete CD4 T cell recovery in PLHIV remain unclear. In this study, CD4 T cells from PLHIV were phenotyped and functionally characterized, focusing on their mitochondrial functions. The results show that while total CD4 T cells are diminished, cycling cells are expanded in PLHIV, especially in INRs. HIV-INR CD4 T cells are more activated, displaying exhausted and senescent phenotypes with compromised mitochondrial functions. Transcriptional profiling and flow cytometry analysis showed remarkable repression of mitochondrial transcription factor A (mtTFA) in CD4 T cells from PLHIV, leading to abnormal mitochondrial and T cell homeostasis. These results demonstrate a sequential cellular paradigm of T cell over-activation, proliferation, exhaustion, senescence, apoptosis, and depletion, which correlates with compromised mitochondrial functions. Therefore, reconstituting the mtTFA pathway may provide an adjunctive immunological approach to revitalizing CD4 T cells in ART-treated PLHIV, especially in INRs.

Oxidative Stress Induces Mitochondrial Compromise in CD4 T Cells From Chronically HCV-Infected Individuals

“…MG is a selective dye that binds to free thiol groups of cysteine residues, which are naturally enriched in mitochondrial proteins, and thus is a measurement of mitochondrial density/mass. As shown in Figures 1C, D, the MFI of MG was significantly decreased in total, naïve, memory, non-cycling, cycling naïve, cycling memory, non-cycling naïve, and non-cycling memory CD4 cell subpopulations from HCV patients -similar to our previous findings in CD4 T cells from ART-controlled people living with HIV (PLHIV) (29). These results suggest that mitochondrial biogenesis and fitness are reduced in CD4 T cells from chronically HCV-infected individuals.…”

“…We have previously shown increased oxidative stress, apoptosis, and DNA damage, as well as shortened telomeres in CD4 T cells from chronically HCVinfected individuals compared to age-matched HS (19,20,22,23). We and others have also demonstrated dysregulated T cell homeostasis of CD4 T cell subpopulations, including naïve (CD45RA + ), memory (CD45RA -), cycling (CD71 + ), and noncycling (CD71 -) cells following chronic viral infection (19,20,29,35). Given the critical role of mitochondria on cellular metabolism and viability, we examined T cell homeostasis and mitochondrial functions in CD4 T cell subpopulations in PBMCs by measuring MO for the level of intracellular ROS and MG for mitochondrial mass.…”

Selective oxidative stress induces dual damage to telomeres and mitochondria in human T cells

“…Recent studies have highlighted the importance of shortened telomeres and impaired mitochondria in the age-related decline of cellular functions in the elderly (Buck et al, 2016;Kirkwood, 2005;Ron-Harel et al, 2015;Tedone et al, 2019). Notably, this natural aging phenotype is recapitulated in T cells derived from individuals with chronic viral infection (e.g., hepatitis C virus [HCV] or human immunodeficiency virus [HIV]) or inflammation (e.g., rheumatoid arthritis [RA]), which also exhibit shortened telomeres and impaired mitochondria (Blanco et al, 2015;Costenbader et al, 2011;Galluzzi et al, 2017;Lee & Bae, 2018;Lopez-Armada et al, 2013;Younes et al, 2018;Zhao et al, 2018Zhao et al, , 2019Zhao et al, , 2021. To date, how telomeres and mitochondria are dysregulated to drive T cell aging and dysfunction during infection and/or inflammation remains largely unknown and warrants further investigation.…”

“…Telomere integrity protects the ends of chromosomes and preserves genomic stability, whereas telomere erosion is a hallmark of cell aging that promotes cell dysfunction or apoptosis (Arkus, 2005;Arnoult & Karlseder, 2015;Carneiro et al, 2016;Cavanagh et al, 2012). We have recently shown accelerated telomere erosion and mitochondrial dysfunction in T cells from virus-infected individuals, indicating excessive cell proliferative turnover or increased irreparable DNA damage (Cao et al, 2020;Dang et al, 2020;Ji et al, 2019;Khanal et al, 2020;Nguyen et al, 2018;Schank et al, 2020Schank et al, , 2021Zhao et al, 2018Zhao et al, , 2019Zhao et al, , 2021. Additionally, we have discovered that telomeric DNA damage induces a profound p53associated inhibition of the master mitochondrial regulators, peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1α) or mitochondrial transcription factor A (mtTFA), which is associated with mitochondrial compromise due to impaired oxidative phosphorylation and ATP generation (Schank et al, 2020(Schank et al, , 2021Zhao et al, 2021).…”

“…We have recently shown accelerated telomere erosion and mitochondrial dysfunction in T cells from virus-infected individuals, indicating excessive cell proliferative turnover or increased irreparable DNA damage (Cao et al, 2020;Dang et al, 2020;Ji et al, 2019;Khanal et al, 2020;Nguyen et al, 2018;Schank et al, 2020Schank et al, , 2021Zhao et al, 2018Zhao et al, , 2019Zhao et al, , 2021. Additionally, we have discovered that telomeric DNA damage induces a profound p53associated inhibition of the master mitochondrial regulators, peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1α) or mitochondrial transcription factor A (mtTFA), which is associated with mitochondrial compromise due to impaired oxidative phosphorylation and ATP generation (Schank et al, 2020(Schank et al, , 2021Zhao et al, 2021). Nevertheless, how telomeres are damaged and what the impacts of telomeric DNA damage are on mitochondrial functions during the T cell aging process in the setting of chronic infection and/or inflammation remain unclear.…”