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Cell Chem Biol. 2017 Nov 16;24(11):1377-1387.e3. doi: 10.1016/j.chembiol.2017.08.016. Epub 2017 Sep 28.

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

Author information

1
Section of Virology, Department of Medicine, Imperial College, London W2 1PG, UK.
2
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, UK.
3
Section of Virology, Department of Medicine, Imperial College, London W2 1PG, UK. Electronic address: c.bangham@imperial.ac.uk.

Abstract

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.

KEYWORDS:

2-oxoglutarate; HIF hydroxylase; HTLV-1; epigenetic regulation; glucose; hypoxia; latency; metabolism; virus

PMID:
28965728
PMCID:
PMC5696563
DOI:
10.1016/j.chembiol.2017.08.016
[Indexed for MEDLINE]
Free PMC Article

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