The human retrovirus HTLV-1 causes a haematological 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 enhances 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.
