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

• Published in: Scientific reports 2017-02, Vol.7 (1), p.42824, Article 42824
• Main Authors: Ordonez, Paula, Kunzelmann, Simone, Groom, Harriet C. T., Yap, Melvyn W., Weising, Simon, Meier, Chris, Bishop, Kate N., Taylor, Ian A., Stoye, Jonathan P.
• Format: Article
• Language: English
• Subjects: 13/106; 13/31; 42; 631/326/596/1787; 631/337/1644; 692/308/153; Acquired immune deficiency syndrome; Acyclovir - pharmacology; Adenine Nucleotides - pharmacology; AIDS; Allosteric Regulation; Antiviral agents; Arabinonucleosides - pharmacology; Cancer; Cell Line; Clofarabine; Cytomegalovirus; Dendritic cells; Enzymes; Epstein-Barr virus; Ganciclovir; Ganciclovir - pharmacology; Herpes viruses; HIV; HIV-1 - physiology; Human immunodeficiency virus; Humanities and Social Sciences; Humans; Infections; Kinases; Laboratories; Lymphocytes T; Macrophages; multidisciplinary; Myeloid cells; Myeloid Cells - virology; Nucleoside analogs; Nucleotide analogs; Nucleotides - chemistry; Nucleotides - metabolism; Nucleotides - pharmacology; Phosphorylation; Proteins; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Reverse transcription; SAM Domain and HD Domain-Containing Protein 1 - metabolism; Science; Virus Replication - drug effects
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep42824

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.