Keywords :
Amino Acids, Dicarboxylic/pharmacology; Aryl Hydrocarbon Receptor Nuclear Translocator/metabolism; CD4-Positive T-Lymphocytes/cytology/metabolism/virology; Cell Hypoxia; Cells, Cultured; Citric Acid Cycle/drug effects; Electron Transport Chain Complex Proteins/metabolism; Epigenesis, Genetic; Glucose/metabolism; Glycolysis/drug effects; Histones/genetics/metabolism; Human T-lymphotropic virus 1/genetics/physiology; Humans; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism; Ketoglutaric Acids/pharmacology; Leukocytes, Mononuclear/cytology/metabolism/virology; Mitochondria/drug effects/metabolism; Oxygen/metabolism; Virus Latency; Virus Replication/drug effects; 2-oxoglutarate; HIF hydroxylase; HTLV-1; epigenetic regulation; glucose; hypoxia; latency; metabolism; virus
Abstract :
[en] The human retrovirus HTLV-1 causes a hematological malignancy or neuroinflammatory disease in approximately 10% of infected individuals. HTLV-1 primarily infects CD4(+) T lymphocytes and persists as a provirus integrated in their genome. HTLV-1 appears transcriptionally latent in freshly isolated cells; however, the chronically active anti-HTLV-1 cytotoxic T cell response observed in infected individuals indicates frequent proviral expression in vivo. The kinetics and regulation of HTLV-1 proviral expression in vivo are poorly understood. By using hypoxia, small-molecule hypoxia mimics, and inhibitors of specific metabolic pathways, we show that physiologically relevant levels of hypoxia, as routinely encountered by circulating T cells in the lymphoid organs and bone marrow, significantly enhance HTLV-1 reactivation from latency. Furthermore, culturing naturally infected CD4(+) T cells in glucose-free medium or chemical inhibition of glycolysis or the mitochondrial electron transport chain strongly suppresses HTLV-1 plus-strand transcription. We conclude that glucose metabolism and oxygen tension regulate HTLV-1 proviral latency and reactivation in vivo.
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