Glucose Metabolism and Oxygen Availability Govern Reactivation of the Latent Human Retrovirus HTLV-1.
The human retrovirus HTLV-1 causes a hematological malignancy or neuroinflammatory disease in ∼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.
['Kulkarni|Anurag|A|', 'Mateus|Manuel|M|', 'Thinnes|Cyrille C|CC|', 'McCullagh|James S|JS|', 'Schofield|Christopher J|CJ|', 'Taylor|Graham P|GP|', 'Bangham|Charles R M|CRM|']
D000600:Amino Acids, Dicarboxylic D051784:Aryl Hydrocarbon Receptor Nuclear Translocator D015496:CD4-Positive T-Lymphocytes D015687:Cell Hypoxia D002478:Cells, Cultured D002952:Citric Acid Cycle D045222:Electron Transport Chain Complex Proteins D044127:Epigenesis, Genetic D005947:Glucose D006019:Glycolysis D006657:Histones D015368:Human T-lymphotropic virus 1 D006801:Humans D051795:Hypoxia-Inducible Factor 1, alpha Subunit D007656:Ketoglutaric Acids D007963:Leukocytes, Mononuclear D008928:Mitochondria D010100:Oxygen D017735:Virus Latency D014779:Virus Replication
glucose metabolism HTLV-1 hypoxia latency 2-oxoglutarate HIF hydroxylase epigenetic regulation virus