Format

Send to

Choose Destination
Sci Rep. 2017 Feb 21;7:42824. doi: 10.1038/srep42824.

SAMHD1 enhances nucleoside-analogue efficacy against HIV-1 in myeloid cells.

Author information

1
Retrovirus-Host Interactions Laboratory, The Francis Crick Institute, London, UK.
2
Structural Biology Science Technology Platform, The Francis Crick Institute, London, UK.
3
Infection and Replication of Retroviruses Laboratory, The Francis Crick Institute, London, UK.
4
Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Germany.
5
Macromolecular Structure Laboratory, The Francis Crick Institute, London, UK.
6
Faculty of Medicine, Imperial College London, London, UK.

Abstract

SAMHD1 is an intracellular enzyme that specifically degrades deoxynucleoside triphosphates into component nucleoside and inorganic triphosphate. In myeloid-derived dendritic cells and macrophages as well as resting T-cells, SAMHD1 blocks HIV-1 infection through this dNTP triphosphohydrolase activity by reducing the cellular dNTP pool to a level that cannot support productive reverse transcription. We now show that, in addition to this direct effect on virus replication, manipulating cellular SAMHD1 activity can significantly enhance or decrease the anti-HIV-1 efficacy of nucleotide analogue reverse transcription inhibitors presumably as a result of modulating dNTP pools that compete for recruitment by viral polymerases. Further, a variety of other nucleotide-based analogues, not normally considered antiretrovirals, such as the anti-herpes drugs Aciclovir and Ganciclovir and the anti-cancer drug Clofarabine are now revealed as potent anti-HIV-1 agents, under conditions of low dNTPs. This in turn suggests novel uses for nucleotide analogues to inhibit HIV-1 in differentiated cells low in dNTPs.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center