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HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase

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 cells2,3 and is the target of the lentiviral protein Vpx, which can relieve HIV-1 restriction4,5,6,7. 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-α8. 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.

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Figure 1: Examination of SAMHD1 deoxyribonucleoside triphosphate hydrolysis activity.
Figure 2: SAMHD1 is allosterically activated to cleave dATP, dCTP and TTP by dGTP.
Figure 3: Crystal structure of the extended HD domain of human SAMHD1.
Figure 4: Model for SAMHD1 function.

Accession codes

Primary accessions

Protein Data Bank

Data deposits

The coordinates and structure factors of SAMHD1c have been deposited in the Protein Data Bank under accession number 3U1N.

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Acknowledgements

We thank S. Gamblin for comments on the manuscript and we acknowledge the Diamond Light Source for synchrotron access. This work was supported by the UK Medical Research Council, file references U117565647 (I.A.T.) and U117512710 (J.P.S.). Y.J.C. acknowledges the European Union Seventh Framework Programme (FP7/2007-2013) grant agreement number 241779 (NIMBL: http://www.NIMBL.eu/), and the European Leukodystrophy Association. Y.J.C. and M.W. acknowledge the Manchester National Institute for Health Research Biomedical Research Centre.

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D.C.G., V.E.-A., J.J.H., H.C. T. G., E.C., P.A.W., G.K., L.F.H., M.W.Y., I.A.T. and M.W. performed experiments. All authors contributed to data analysis, experimental design and manuscript writing.

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Correspondence to Ian A. Taylor or Michelle Webb.

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The authors declare no competing financial interests.

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Goldstone, D., Ennis-Adeniran, V., Hedden, J. et al. HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature 480, 379–382 (2011). https://doi.org/10.1038/nature10623

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