HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase

David C Goldstone, Valerie Ennis-Adeniran, Joseph J Hedden, Harriet C T Groom, Gillian I Rice, Evangelos Christodoulou, Philip A Walker, Geoff Kelly, Lesley F Haire, Melvyn W Yap, Luiz Pedro S de Carvalho, Jonathan P Stoye, Yanick J Crow, Ian A Taylor, Michelle Webb

Research output: Contribution to journalArticlepeer-review

Abstract

SAMHD1, an analogue of the murine interferon (IFN)-γ-induced gene Mg11 (ref. 1), has recently been identified as a human immunodeficiency virus-1 (HIV-1) restriction factor that blocks early-stage virus replication in dendritic and other myeloid cells and is the target of the lentiviral protein Vpx, which can relieve HIV-1 restriction. SAMHD1 is also associated with Aicardi-Goutières syndrome (AGS), an inflammatory encephalopathy characterized by chronic cerebrospinal fluid lymphocytosis and elevated levels of the antiviral cytokine IFN-α. The pathology associated with AGS resembles congenital viral infection, such as transplacentally acquired HIV. Here we show that human SAMHD1 is a potent dGTP-stimulated triphosphohydrolase that converts deoxynucleoside triphosphates to the constituent deoxynucleoside and inorganic triphosphate. The crystal structure of the catalytic core of SAMHD1 reveals that the protein is dimeric and indicates a molecular basis for dGTP stimulation of catalytic activity against dNTPs. We propose that SAMHD1, which is highly expressed in dendritic cells, restricts HIV-1 replication by hydrolysing the majority of cellular dNTPs, thus inhibiting reverse transcription and viral complementary DNA (cDNA) synthesis.

Original languageEnglish
Pages (from-to)379-82
Number of pages4
JournalNature
Volume480
Issue number7377
DOIs
Publication statusPublished - 6 Nov 2011

Keywords

  • Allosteric Regulation
  • Biocatalysis
  • Catalytic Domain
  • Crystallography, X-Ray
  • Dendritic Cells
  • Deoxyadenine Nucleotides
  • Deoxycytosine Nucleotides
  • Deoxyguanine Nucleotides
  • HIV-1
  • Humans
  • Hydrolysis
  • Models, Biological
  • Models, Molecular
  • Monomeric GTP-Binding Proteins
  • Myeloid Cells
  • Nucleoside-Triphosphatase
  • Protein Structure, Tertiary
  • Reverse Transcription
  • SAM Domain and HD Domain-Containing Protein 1
  • Thymine Nucleotides
  • Viral Regulatory and Accessory Proteins
  • Virus Replication
  • Journal Article
  • Research Support, Non-U.S. Gov't

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