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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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.).
The authors declare no competing financial interests.
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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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