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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


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.


  1. 1

    Sharova, N. et al. Primate lentiviral Vpx commandeers DDB1 to counteract a macrophage restriction. PLoS Pathog. 4, e1000057 (2008).

    Article  Google Scholar 

  2. 2

    Hrecka, K. et al. Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature 474, 658–661 (2011).

    CAS  Article  Google Scholar 

  3. 3

    Laguette, N. et al. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature 474, 654–657 (2011).

    CAS  Article  Google Scholar 

  4. 4

    Li, N., Zhang, W. & Cao, X. Identification of human homologue of mouse IFN-γ induced protein from human dendritic cells. Immunol. Lett. 74, 221–224 (2000).

    CAS  Article  Google Scholar 

  5. 5

    Yan, N., Regalado-Magdos, A.D., Stiggelbout, B., Lee-Kirsch, M.A. & Lieberman, J. The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat. Immunol. 11, 1005–1013 (2010).

    CAS  Article  Google Scholar 

  6. 6

    Rice, G.I. et al. Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response. Nat. Genet. 41, 829–832 (2009).

    CAS  Article  Google Scholar 

  7. 7

    Crow, Y.J. et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nat. Genet. 38, 917–920 (2006).

    CAS  Article  Google Scholar 

  8. 8

    Zimmerman, M.D., Proudfoot, M., Yakunin, A. & Minor, W. Structural insight into the mechanism of substrate specificity and catalytic activity of an HD-domain phosphohydrolase: the 5′-deoxyribonucleotidase YfbR from Escherichia coli. J. Mol. Biol. 378, 215–226 (2008).

    CAS  Article  Google Scholar 

  9. 9

    Vorontsov, I.I. et al. Characterization of the deoxynucleotide triphosphate triphosphohydrolase (dNTPase) activity of the EF1143 protein from Enterococcus faecalis and crystal structure of the activator-substrate complex. J. Biol. Chem. 286, 33158–33166 (2011).

    CAS  Article  Google Scholar 

  10. 10

    Leshinsky-Silver, E. et al. A large homozygous deletion in the SAMHD1 gene causes atypical Aicardi-Goutieres syndrome associated with mtDNA deletions. Eur. J. Hum. Genet. 19, 287–292 (2011).

    Article  Google Scholar 

  11. 11

    Bourdon, A. et al. Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nat. Genet. 39, 776–780 (2007).

    CAS  Article  Google Scholar 

  12. 12

    Brahimi, N. et al. The first founder DGUOK mutation associated with hepatocerebral mitochondrial DNA depletion syndrome. Mol. Genet. Metab. 97, 221–226 (2009).

    CAS  Article  Google Scholar 

  13. 13

    Diamond, T.L. et al. Macrophage tropism of HIV-1 depends on efficient cellular dNTP utilization by reverse transcriptase. J. Biol. Chem. 279, 51545–51553 (2004).

    CAS  Article  Google Scholar 

  14. 14

    Woodside, A.M. & Guengerich, F.P. Effect of the O6 substituent on misincorporation kinetics catalyzed by DNA polymerases at O(6)-methylguanine and O(6)-benzylguanine. Biochemistry 41, 1027–1038 (2002).

    CAS  Article  Google Scholar 

  15. 15

    Collin, M. & Gordon, S. The kinetics of human immunodeficiency virus reverse transcription are slower in primary human macrophages than in a lymphoid cell line. Virology 200, 114–120 (1994).

    CAS  Article  Google Scholar 

  16. 16

    Furge, L.L. & Guengerich, F.P. Analysis of nucleotide insertion and extension at 8-oxo-7,8-dihydroguanine by replicative T7 polymerase exo- and human immunodeficiency virus-1 reverse transcriptase using steady-state and pre-steady-state kinetics. Biochemistry 36, 6475–6487 (1997).

    CAS  Article  Google Scholar 

  17. 17

    Ueno, T., Shirasaka, T. & Mitsuya, H. Enzymatic characterization of human immunodeficiency virus type 1 reverse transcriptase resistant to multiple 2′,3′-dideoxynucleoside 5′-triphosphates. J. Biol. Chem. 270, 23605–23611 (1995).

    CAS  Article  Google Scholar 

  18. 18

    Fletcher, T.M. III et al. Nuclear import and cell cycle arrest functions of the HIV-1 Vpr protein are encoded by two separate genes in HIV-2/SIV(SM). EMBO J. 15, 6155–6165 (1996).

    CAS  Article  Google Scholar 

  19. 19

    Kawamura, M., Sakai, H. & Adachi, A. Human immunodeficiency virus Vpx is required for the early phase of replication in peripheral blood mononuclear cells. Microbiol. Immunol. 38, 871–878 (1994).

    CAS  Article  Google Scholar 

  20. 20

    Wu, X., Conway, J.A., Kim, J. & Kappes, J.C. Localization of the Vpx packaging signal within the C terminus of the human immunodeficiency virus type 2 Gag precursor protein. J. Virol. 68, 6161–6169 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Sunseri, N., O'Brien, M., Bhardwaj, N. & Landau, N.R. Human immunodeficiency virus type 1 modified to package simian immunodeficiency virus Vpx efficiently infects macrophages and dendritic cells. J. Virol. 85, 6263–6274 (2011).

    CAS  Article  Google Scholar 

  22. 22

    Goujon, C. et al. With a little help from a friend: increasing HIV transduction of monocyte-derived dendritic cells with virion-like particles of SIV(MAC). Gene Ther. 13, 991–994 (2006).

    CAS  Article  Google Scholar 

  23. 23

    Goujon, C. et al. Characterization of simian immunodeficiency virus SIVSM/human immunodeficiency virus type 2 Vpx function in human myeloid cells. J. Virol. 82, 12335–12345 (2008).

    CAS  Article  Google Scholar 

  24. 24

    O'Brien, W.A. et al. Kinetics of human immunodeficiency virus type 1 reverse transcription in blood mononuclear phagocytes are slowed by limitations of nucleotide precursors. J. Virol. 68, 1258–1263 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Meyerhans, A. et al. Restriction and enhancement of human immunodeficiency virus type 1 replication by modulation of intracellular deoxynucleoside triphosphate pools. J. Virol. 68, 535–540 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Jamburuthugoda, V.K., Chugh, P. & Kim, B. Modification of human immunodeficiency virus type 1 reverse transcriptase to target cells with elevated cellular dNTP concentrations. J. Biol. Chem. 281, 13388–13395 (2006).

    CAS  Article  Google Scholar 

  27. 27

    Nordlund, P. & Reichard, P. Ribonucleotide reductases. Annu. Rev. Biochem. 75, 681–706 (2006).

    CAS  Article  Google Scholar 

  28. 28

    Kennedy, E.M. et al. Ribonucleoside triphosphates as substrate of human immunodeficiency virus type 1 reverse transcriptase in human macrophages. J. Biol. Chem. 285, 39380–39391 (2010).

    CAS  Article  Google Scholar 

  29. 29

    Diamond, T.L. et al. Mechanistic understanding of an altered fidelity simian immunodeficiency virus reverse transcriptase mutation, V148I, identified in a pig-tailed macaque. J. Biol. Chem. 278, 29913–29924 (2003).

    CAS  Article  Google Scholar 

  30. 30

    Goldstone, D.C. et al. HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature. 480, 379–382 (2011).

    CAS  Article  Google Scholar 

  31. 31

    Powell, R.D., Holland, P.J., Hollis, T. & Perrino, F.W. The Aicardi-Goutieres syndrome gene and HIV-1 restriction factor SAMHD1 is a dGTP-regulated deoxynucleotide triphosphohydrolase. J. Biol. Chem. 286, 43596–43600 (2011).

    CAS  Article  Google Scholar 

  32. 32

    Manel, N. et al. A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells. Nature 467, 214–217 (2010).

    CAS  Article  Google Scholar 

  33. 33

    Lafuse, W.P., Brown, D., Castle, L. & Zwilling, B.S. Cloning and characterization of a novel cDNA that is IFN-gamma-induced in mouse peritoneal macrophages and encodes a putative GTP-binding protein. J. Leukoc. Biol. 57, 477–483 (1995).

    CAS  Article  Google Scholar 

  34. 34

    Schröfelbauer, B., Hakata, Y. & Landau, N.R. HIV-1 Vpr function is mediated by interaction with the damage-specific DNA-binding protein DDB1. Proc. Natl. Acad. Sci. USA 104, 4130–4135 (2007).

    Article  Google Scholar 

  35. 35

    Le Rouzic, E. et al. HIV1 Vpr arrests the cell cycle by recruiting DCAF1/VprBP, a receptor of the Cul4–DDB1 ubiquitin ligase. Cell Cycle 6, 182–188 (2007).

    CAS  Article  Google Scholar 

  36. 36

    Gibbs, J.S. et al. Progression to AIDS in the absence of a gene for vpr or vpx. J. Virol. 69, 2378–2383 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Berger, G. et al. APOBEC3A is a specific inhibitor of the early phases of HIV-1 infection in myeloid cells. PLoS Pathog. 7, e1002221 (2011).

    CAS  Article  Google Scholar 

  38. 38

    Lembo, D. & Brune, W. Tinkering with a viral ribonucleotide reductase. Trends Biochem. Sci. 34, 25–32 (2009).

    CAS  Article  Google Scholar 

  39. 39

    Zhang, Y. et al. Productive infection of primary macrophages with human herpesvirus 7. J. Virol. 75, 10511–10514 (2001).

    CAS  Article  Google Scholar 

  40. 40

    Triques, K. & Stevenson, M. Characterization of restrictions to human immunodeficiency virus type 1 infection of monocytes. J. Virol. 78, 5523–5527 (2004).

    CAS  Article  Google Scholar 

  41. 41

    Chowdhury, K., Kaushik, N., Pandey, V.N. & Modak, M.J. Elucidation of the role of Arg 110 of murine leukemia virus reverse transcriptase in the catalytic mechanism: biochemical characterization of its mutant enzymes. Biochemistry 35, 16610–16620 (1996).

    CAS  Article  Google Scholar 

  42. 42

    Shi, Q., Singh, K., Srivastava, A., Kaushik, N. & Modak, M.J. Lysine 152 of MuLV reverse transcriptase is required for the integrity of the active site. Biochemistry 41, 14831–14842 (2002).

    CAS  Article  Google Scholar 

  43. 43

    Skasko, M. & Kim, B. Compensatory role of human immunodeficiency virus central polypurine tract sequence in kinetically disrupted reverse transcription. J. Virol. 82, 7716–7720 (2008).

    CAS  Article  Google Scholar 

  44. 44

    Mangeot, P.E. et al. High levels of transduction of human dendritic cells with optimized SIV vectors. Mol. Ther. 5, 283–290 (2002).

    CAS  Article  Google Scholar 

  45. 45

    Naldini, L. et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272, 263–267 (1996).

    CAS  Article  Google Scholar 

  46. 46

    Berger, G. et al. A simple, versatile and efficient method to genetically modify human monocyte-derived dendritic cells with HIV-1-derived lentiviral vectors. Nat. Protoc. 6, 806–816 (2011).

    CAS  Article  Google Scholar 

  47. 47

    Goujon, C. et al. SIVSM/HIV-2 Vpx proteins promote retroviral escape from a proteasome-dependent restriction pathway present in human dendritic cells. Retrovirology 4, 2 (2007).

    Article  Google Scholar 

  48. 48

    Gramberg, T., Sunseri, N. & Landau, N.R. Evidence for an activation domain at the amino terminus of simian immunodeficiency virus Vpx. J. Virol. 84, 1387–1396 (2010).

    CAS  Article  Google Scholar 

  49. 49

    Connor, R.I., Chen, B.K., Choe, S. & Landau, N.R. Vpr is required for efficient replication of human immunodeficiency virus type-1 in mononuclear phagocytes. Virology 206, 935–944 (1995).

    CAS  Article  Google Scholar 

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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




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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The authors declare no competing financial interests.

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Supplementary Figures 1–7 and Table 1 (PDF 294 kb)

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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).

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