SAMHD1 enhances nucleoside-analogue efficacy against HIV-1 in myeloid cells View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-12

AUTHORS

Paula Ordonez, Simone Kunzelmann, Harriet C T Groom, Melvyn W Yap, Simon Weising, Chris Meier, Kate N Bishop, Ian A Taylor, Jonathan P Stoye

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. More... »

PAGES

42824

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/srep42824

    DOI

    http://dx.doi.org/10.1038/srep42824

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1083852555

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/28220857


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    444 Structural Biology Science Technology Platform, The Francis Crick Institute, London, UK.
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    447 schema:name Faculty of Medicine, Imperial College London, London, UK.
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    450 https://www.grid.ac/institutes/grid.9026.d schema:alternateName University of Hamburg
    451 schema:name Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Germany.
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