Journal Article

HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase

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

2011

Overview

Antiretroviral role for SAMHD1 protein Mutations in SAMHD1 protein are associated with the human autoimmune disease Aicardi–Goutières syndrome, and SAMHD1 was recently shown to be responsible for restriction of HIV-1 replication in myeloid cells. Ian Taylor and colleagues reveal a previously unknown function of SAMHD1 that could explain its antivirus role. They provide a crystal structure of the catalytic core of SAMHD1 and show that it is a dGTP-stimulated triphosphohydrolase that hydrolyses dNTPs, the building blocks of DNA. This activity may prevent reverse transcription and viral synthesis of complementary DNA by keeping the concentration of cellular dNTPs at a low level. 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 2 , 3 and is the target of the lentiviral protein Vpx, which can relieve HIV-1 restriction 4 , 5 , 6 , 7 . 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 8 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/326/596 / 631/45/535 / 692/308 / 692/699/255/2514 / Allosteric Regulation / Analysis / Anti-HIV agents / Antiviral agents / Biocatalysis / Biological and medical sciences / Catalytic Domain / Crystal structure / Crystallography, X-Ray / Dendritic Cells - metabolism / Dendritic Cells - virology / Deoxyadenine Nucleotides - metabolism / Deoxycytosine Nucleotides - metabolism / Deoxyguanine Nucleotides - metabolism / Deoxyribonucleic acid / Deoxyribonucleotides / DNA / Enzymes / Fundamental and applied biological sciences. Psychology / Guanosine triphosphatase / HIV (Viruses) / HIV-1 - physiology / Humanities and Social Sciences / Humans / Hydrolysis / letter / Microbiology / Models, Biological / Models, Molecular / Monomeric GTP-Binding Proteins - chemistry / Monomeric GTP-Binding Proteins - genetics / Monomeric GTP-Binding Proteins - metabolism / multidisciplinary / Mutation (Biology) / Myeloid Cells - virology / NOD-like receptors / Nucleoside-Triphosphatase - chemistry / Nucleoside-Triphosphatase - genetics / Nucleoside-Triphosphatase - metabolism / Properties / Proteases / Protein Structure, Tertiary / Proteins / Replicative cycle, interference, host-virus relations, pathogenicity, miscellaneous strains / Reverse Transcription / SAM Domain and HD Domain-Containing Protein 1 / Science / Structure / Thymine Nucleotides - metabolism / Viral Regulatory and Accessory Proteins - metabolism / Virology / Virus Replication