ArticleCell death & disease2020
Inhibition of topoisomerase IIA (Top2α) induces telomeric DNA damage and T cell dysfunction during chronic viral infection.
Article in Cell death & disease, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 30 citations in OpenAlex.
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- Chronic viral infections and their role in shaping the tumor immune microenvironment.Frontiers in immunology · 2026Review
- The Immunogenic Role of Self-DNA in T Cell Immunity.Clinical reviews in allergy & immunology · 2025Review
- Circulating GDF-15: a biomarker for metabolic dysregulation and aging in people living with HIV.Frontiers in aging · 2024Article
- HCV and HCC Tango-Deciphering the Intricate Dance of Disease: A Review Article.International journal of molecular sciences · 2023Review
- A ciprofloxacin derivative with four mechanisms of action overcomes paclitaxel resistance in p53-mutant and MDR1 gene-expressing type II human endometrial cancer.Biomaterials · 2023Article
- ROS-Induced Mitochondrial Dysfunction in CD4 T Cells from ART-Controlled People Living with HIV.Viruses · 2023Article
- Divergent CD4Frontiers in immunology · 2023Article
- TRF2 inhibition rather than telomerase disruption drives CD4T cell dysfunction during chronic viral infection.Journal of cell science · 2022Article
- Computational investigation of benzalacetophenone derivatives against SARS-CoV-2 as potential multi-target bioactive compounds.Computers in biology and medicine · 2022Article
- Mitochondrial topoisomerase 1 inhibition induces topological DNA damage and T cell dysfunction in patients with chronic viral infection.Frontiers in cellular and infection microbiology · 2022Article
- Selective oxidative stress induces dual damage to telomeres and mitochondria in human T cells.Aging cell · 2021Article
- The Impact of HIV- and ART-Induced Mitochondrial Dysfunction in Cellular Senescence and Aging.Cells · 2021Review
- Oxidative Stress Induces Mitochondrial Compromise in CD4 T Cells From Chronically HCV-Infected Individuals.Frontiers in immunology · 2021Article
- Mitochondrial Functions Are Compromised in CD4 T Cells From ART-Controlled PLHIV.Frontiers in immunology · 2021Article
- Long Non-coding RNA GAS5 Regulates T Cell Functions via miR21-Mediated Signaling in People Living With HIV.Frontiers in immunology · 2021Article
- Telomeric injury by KML001 in human T cells induces mitochondrial dysfunction through the p53-PGC-1α pathway.Cell death & disease · 2020Article
- Telomere and ATM Dynamics in CD4 T-Cell Depletion in Active and Virus-Suppressed HIV Infections.Journal of virology · 2020Article
- A Matter of Life or Death: Productively Infected and Bystander CD4 T Cells in Early HIV Infection.Frontiers in immunology · 2020Article
Corrections and comments
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Authors and funding
19 authors at 3 institutions in 1 country.
Funding
Abstract
T cells play a critical role in controlling viral infection; however, the mechanisms regulating their responses remain incompletely understood. Here, we investigated the role of topoisomerase IIA (Top2α, an enzyme that is essential in resolving entangled DNA strands during replication) in telomeric DNA damage and T cell dysfunction during viral infection. We demonstrated that T cells derived from patients with chronic viral (HBV, HCV, and HIV) infection had lower Top2α protein levels and enzymatic activity, along with an accumulation of the Top2α cleavage complex (Top2cc) in genomic DNA. In addition, T cells from virally infected subjects with lower Top2α levels were vulnerable to Top2α inhibitor-induced cell apoptosis, indicating an important role for Top2α in preventing DNA topological disruption and cell death. Using Top2α inhibitor (ICRF193 or Etoposide)-treated primary T cells as a model, we demonstrated that disrupting the DNA topology promoted DNA damage and T cell apoptosis via Top2cc accumulation that is associated with protein-DNA breaks (PDB) at genomic DNA. Disruption of the DNA topology was likely due to diminished expression of tyrosyl-DNA phosphodiesterase 2 (TDP2), which was inhibited in T cells in vitro by Top2α inhibitor and in vivo by chronic viral infection. These results suggest that immune-evasive viruses (HBV, HCV, and HIV) can disrupt T cell DNA topology as a mechanism of dysregulating host immunity and establishing chronic infection. Thus, restoring the DNA topologic machinery may serve as a novel strategy to protect T cells from unwanted DNA damage and to maintain immune competence.
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