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SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates

A Corrigendum to this article was published on 19 July 2013

An Erratum to this article was published on 18 May 2012

This article has been updated

Abstract

SAMHD1 restricts the infection of dendritic and other myeloid cells by human immunodeficiency virus type 1 (HIV-1), but in lentiviruses of the simian immunodeficiency virus of sooty mangabey (SIVsm)–HIV-2 lineage, SAMHD1 is counteracted by the virion-packaged accessory protein Vpx. Here we found that SAMHD1 restricted infection by hydrolyzing intracellular deoxynucleoside triphosphates (dNTPs), lowering their concentrations to below those required for the synthesis of the viral DNA by reverse transcriptase (RT). SAMHD1-mediated restriction was alleviated by the addition of exogenous deoxynucleosides. An HIV-1 with a mutant RT with low affinity for dNTPs was particularly sensitive to SAMHD1-mediated restriction. Vpx prevented the SAMHD1-mediated decrease in dNTP concentration and induced the degradation of human and rhesus macaque SAMHD1 but had no effect on mouse SAMHD1. Nucleotide-pool depletion could be a general mechanism for protecting cells from infectious agents that replicate through a DNA intermediate.

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Figure 1: Knockdown of SAMHD1 and treatment with Vpx enhance the dNTP pool in PMA-treated THP-1 cells.
Figure 2: Vpx increases the intracellular pool of dNTPs in MDMs.
Figure 3: SAMHD1 diminishes the intracellular dNTP pool, and human and rhesus SAMHD1, but not mouse SAMHD1 homologs, are counteracted by Vpx.
Figure 4: Vpx restores the infectivity of HIV-1 expressing mutant RT with lower affinity for dNTPs.
Figure 5: The salvage pathway of dNTP synthesis partially restores the infectivity of Δvpx SIVmac in MDMs.

Change history

  • 04 April 2012

    In the version of this article initially published, the number for Baek Kim's second affiliation is incorrect in the author list. The correct number is 10. The error has been corrected in the HTML and PDF versions of the article.

  • 15 January 2013

    In the version of this article initially published, the Author Contributions statement was incomplete. The correct statement should include the following: "C.T. raised the original idea that Vpx may increase the amount of nucleotides." The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank L. Stouvenel, K. Labroquère and M. Andrieu for flow cytometry, and J. Hollenbaugh and S. Dewhurst for critical reading of the manuscript. Supported by the Agence Nationale de la Recherche sur le SIDA et les Hépatites Virales (M.Ben., F.M.-G. and H.L.), SIDACTION (M.Ber., F.M.-G. and N.L.), Fondation de France, Mairie de Paris, the American Foundation for AIDS Research, the US National Institutes of Health (AI049781 and A1077401 to B.K.; A1067059 to N.R.L.; and F31 GM095190 to W.D.), the European Research Council (250333 to M.Ben.), Paris Diderot University (C.M. and D.A.) and the Ministère de l'Enseignement Supérieur et de la Recherche (C.M. and D.A.).

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Contributions

C.T. raised the original idea that Vpx may increase the amount of nucleotides; H.L., W.D., H.H., M.Ben., N.R.L., N.B., C.T., B.K. and F.M.-G. conceived of and did the experiments; H.L., M.Ben., C.T., B.K., N.R.L. and F.M.-G. wrote the paper; and D.A., E.C.L., L.D., C.M., T.G., G.P., N.L., M.Ber., B.C. and S.P. designed and did some of the experiments.

Corresponding authors

Correspondence to Nathaniel R Landau, Baek Kim or Florence Margottin-Goguet.

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Lahouassa, H., Daddacha, W., Hofmann, H. et al. SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nat Immunol 13, 223–228 (2012). https://doi.org/10.1038/ni.2236

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