Glucose Metabolism and Oxygen Availability Govern Reactivation of the Latent Human Retrovirus HTLV-1

• Published in: Cell chemical biology Vol. 24; no. 11; pp. 1377 - 1387.e3
• Main Authors: Kulkarni, Anurag, Mateus, Manuel, Thinnes, Cyrille C., McCullagh, James S., Schofield, Christopher J., Taylor, Graham P., Bangham, Charles R.M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 16.11.2017; Cell Press
• Subjects: 2-oxoglutarate; Amino Acids, Dicarboxylic - pharmacology; Aryl Hydrocarbon Receptor Nuclear Translocator - metabolism; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - virology; Cell Hypoxia; Cells, Cultured; Citric Acid Cycle - drug effects; Electron Transport Chain Complex Proteins - metabolism; Epigenesis, Genetic; epigenetic regulation; glucose; Glucose - metabolism; Glycolysis - drug effects; HIF hydroxylase; Histones - genetics; Histones - metabolism; HTLV-1; Human T-lymphotropic virus 1 - genetics; Human T-lymphotropic virus 1 - physiology; Humans; hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Ketoglutaric Acids - pharmacology; latency; Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - virology; metabolism; Mitochondria - drug effects; Mitochondria - metabolism; Oxygen - metabolism; virus; Virus Latency; Virus Replication - drug effects; hypoxia; glucose; latency; 2-oxoglutarate; HTLV-1; metabolism; virus; epigenetic regulation; HIF hydroxylase
• ISSN: 2451-9456; 2451-9448; 2451-9456
• DOI: 10.1016/j.chembiol.2017.08.016

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. [Display omitted] •Physiological (1%) hypoxia enhances HTLV-1 plus-strand transcription•HTLV-1 transcription is hypoxia regulated but HIF independent•Inhibition of glycolysis or the mitochondrial ETC suppresses HTLV-1 transcription•Extracellular glucose concentration regulates HTLV-1 reactivation from latency The human leukemia virus HTLV-1 remains dormant most of the time in the infected person, but is intermittently reactivated by unknown mechanisms. Kulkarni et al. show that fluctuations in glucose metabolism and oxygen availability are two major factors that govern the reactivation of HTLV-1 from dormancy.