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SAMHD1 enhances nucleosideanalogue efficacy against HIV-1 in myeloid cells

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Ordonez, P 
Kunzelmann, S 
Groom, HCT 
Yap, MW 
Weising, S 


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.



DNA metabolism, drug development, retrovirus

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Scientific Reports

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Nature Publishing Group
This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001042, FC001162, FC001178), the UK Medical Research Council (FC001042, FC001162, FC001178), and the Wellcome Trust (FC001042, FC001162, FC001178); and by the Wellcome Trust (108014/Z/15/Z and 108012/Z/15/Z).