title: SAMHD1 enhances nucleoside-analogue efficacy against HIV-1 in myeloid cells.
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.
authors.affiliation: Retrovirus-Host Interactions Laboratory, The Francis Crick Institute, London, UK.
authors.forename: Paula
authors.initials: P
authors.lastname: Ordonez
authors.affiliation: Structural Biology Science Technology Platform, The Francis Crick Institute, London, UK.
authors.forename: Simone
authors.initials: S
authors.lastname: Kunzelmann
authors.affiliation: Infection and Replication of Retroviruses Laboratory, The Francis Crick Institute, London, UK.
authors.forename: Harriet C T
authors.initials: HC
authors.lastname: Groom
authors.affiliation: Retrovirus-Host Interactions Laboratory, The Francis Crick Institute, London, UK.
authors.forename: Melvyn W
authors.initials: MW
authors.lastname: Yap
authors.affiliation: Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Weising
authors.affiliation: Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Germany.
authors.forename: Chris
authors.initials: C
authors.lastname: Meier
authors.affiliation: Infection and Replication of Retroviruses Laboratory, The Francis Crick Institute, London, UK.
authors.forename: Kate N
authors.initials: KN
authors.lastname: Bishop
authors.affiliation: Macromolecular Structure Laboratory, The Francis Crick Institute, London, UK.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Taylor
authors.affiliation: Retrovirus-Host Interactions Laboratory, The Francis Crick Institute, London, UK.|Faculty of Medicine, Imperial College London, London, UK.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Stoye
mesh_terms: D000212:Acyclovir / Q000494:pharmacology; D000227:Adenine Nucleotides / Q000494:pharmacology; D000494:Allosteric Regulation; D001087:Arabinonucleosides / Q000494:pharmacology; D002460:Cell Line; D000077866:Clofarabine; D015774:Ganciclovir / Q000494:pharmacology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D022423:Myeloid Cells / Q000821:virology; D009711:Nucleotides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D000076106:SAM Domain and HD Domain-Containing Protein 1 / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D009711:Nucleotides; D018894:Reverse Transcriptase Inhibitors; D000077866:Clofarabine; D000076106:SAM Domain and HD Domain-Containing Protein 1; D015774:Ganciclovir; D000212:Acyclovir