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

Nature Immunology volume 13, pages 223228 (2012) | Download Citation

  • An Erratum to this article was published on 18 May 2012
  • A Corrigendum to this article was published on 19 July 2013

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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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.).

Author information

Author notes

    • Hichem Lahouassa
    •  & Waaqo Daddacha

    These authors contributed equally to this work.

Affiliations

  1. Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France.

    • Hichem Lahouassa
    • , Diana Ayinde
    • , Loïc Dragin
    • , Claire Maudet
    • , Matthieu Bertrand
    • , Catherine Transy
    •  & Florence Margottin-Goguet
  2. Centre National de la Recherche Scientifique UMR8104, Paris, France.

    • Hichem Lahouassa
    • , Diana Ayinde
    • , Loïc Dragin
    • , Claire Maudet
    • , Matthieu Bertrand
    • , Catherine Transy
    •  & Florence Margottin-Goguet
  3. Université of Paris Descartes, Paris, France.

    • Hichem Lahouassa
    • , Diana Ayinde
    • , Loïc Dragin
    • , Claire Maudet
    • , Matthieu Bertrand
    • , Catherine Transy
    •  & Florence Margottin-Goguet
  4. Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA.

    • Waaqo Daddacha
    •  & Baek Kim
  5. Department of Microbiology, New York University School of Medicine, New York, New York, USA.

    • Henning Hofmann
    • , Eric C Logue
    • , Nicolin Bloch
    •  & Nathaniel R Landau
  6. Virologisches Institut, Klinische und Molekulare Virologie, Universitat Erlangen-Nurnberg, Erlangen, Germany.

    • Thomas Gramberg
  7. Institut Pasteur, Unité de Régulation des Infections Rétrovirales, Paris, France.

    • Gianfranco Pancino
  8. Laboratoire d'Architecture et Fonction des Macromolécules Biologiques, UMR6098, Centre National de la Recherche Scientifique–Université d'Aix-Marseille, Marseille, France.

    • Stéphane Priet
    •  & Bruno Canard
  9. Institut de Génétique Humaine, Laboratoire de Virologie Moléculaire, Centre National de la Recherche Scientifique UPR1142, Montpellier, France.

    • Nadine Laguette
    •  & Monsef Benkirane
  10. Department of Pharmacy, Kyung Hee University, Seoul, South Korea.

    • Baek Kim

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

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

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DOI

https://doi.org/10.1038/ni.2236

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