SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates.
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.
Inserm, U1016, Institut Cochin, 27 rue du faubourg St Jacques, Bat G. Roussy, 75014 Paris France.|Cnrs, UMR8104, Paris, France.|Univ Paris Descartes, Paris, France.
Hichem
H
Lahouassa
Department of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Waaqo
W
Daddacha
New York University School of Medicine, Microbiology Department, 550 First Ave., New York, NY 10016, USA.
Henning
H
Hofmann
Inserm, U1016, Institut Cochin, 27 rue du faubourg St Jacques, Bat G. Roussy, 75014 Paris France.|Cnrs, UMR8104, Paris, France.|Univ Paris Descartes, Paris, France.
Diana
D
Ayinde
New York University School of Medicine, Microbiology Department, 550 First Ave., New York, NY 10016, USA.
Eric C
EC
Logue
Inserm, U1016, Institut Cochin, 27 rue du faubourg St Jacques, Bat G. Roussy, 75014 Paris France.|Cnrs, UMR8104, Paris, France.|Univ Paris Descartes, Paris, France.
Loïc
L
Dragin
New York University School of Medicine, Microbiology Department, 550 First Ave., New York, NY 10016, USA.
Nicolin
N
Bloch
Inserm, U1016, Institut Cochin, 27 rue du faubourg St Jacques, Bat G. Roussy, 75014 Paris France.|Cnrs, UMR8104, Paris, France.|Univ Paris Descartes, Paris, France.
Claire
C
Maudet
Inserm, U1016, Institut Cochin, 27 rue du faubourg St Jacques, Bat G. Roussy, 75014 Paris France.|Cnrs, UMR8104, Paris, France.|Univ Paris Descartes, Paris, France.
Matthieu
M
Bertrand
Virologisches Institut, Klinische und Molekulare Virologie, Universitat Erlangen-Nurnberg, 91054 Erlangen.
Thomas
T
Gramberg
Institut Pasteur, Unité de Régulation des Infections Rétrovirales, 25 rue du Dr Roux, 75724 Paris Cedex 15, France.
Gianfranco
G
Pancino
Laboratoire d'Architecture et Fonction des Macromolécules Biologiques, UMR6098, CNRS-Universitéd'Aix-Marseille, 13288 Marseille cedex 09, France.
Stéphane
S
Priet
Laboratoire d'Architecture et Fonction des Macromolécules Biologiques, UMR6098, CNRS-Universitéd'Aix-Marseille, 13288 Marseille cedex 09, France.
Bruno
B
Canard
Institut de Génétique Humaine, Laboratoire de Virologie Moléculaire, CNRS UPR1142, Montpellier 34000, France.
Nadine
N
Laguette
Institut de Génétique Humaine, Laboratoire de Virologie Moléculaire, CNRS UPR1142, Montpellier 34000, France.
Monsef
M
Benkirane
Inserm, U1016, Institut Cochin, 27 rue du faubourg St Jacques, Bat G. Roussy, 75014 Paris France.|Cnrs, UMR8104, Paris, France.|Univ Paris Descartes, Paris, France.
Catherine
C
Transy
New York University School of Medicine, Microbiology Department, 550 First Ave., New York, NY 10016, USA.
Nathaniel R
NR
Landau
Department of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Baek
B
Kim
Inserm, U1016, Institut Cochin, 27 rue du faubourg St Jacques, Bat G. Roussy, 75014 Paris France.|Cnrs, UMR8104, Paris, France.|Univ Paris Descartes, Paris, France.
Florence
F
Margottin-Goguet
D000818:Animals; D002460:Cell Line; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008253:Macaca mulatta; D008264:Macrophages / Q000276:immunology; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism*; D000076106:SAM Domain and HD Domain-Containing Protein 1; D014779:Virus Replication
D009711:Nucleotides; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; C484281:Samhd1 protein, mouse; D020559:Monomeric GTP-Binding Proteins