title: Cell cycle control and HIV-1 susceptibility are linked by CDK6-dependent CDK2 phosphorylation of SAMHD1 in myeloid and lymphoid cells.
abstract: Proliferating cells are preferentially susceptible to infection by retroviruses. Sterile α motif and HD domain-containing protein-1 (SAMHD1) is a recently described deoxynucleotide phosphohydrolase controlling the size of the intracellular deoxynucleotide triphosphate (dNTP) pool, a limiting factor for retroviral reverse transcription in noncycling cells. Proliferating (Ki67(+)) primary CD4(+) T cells or macrophages express a phosphorylated form of SAMHD1 that corresponds with susceptibility to infection in cell culture. We identified cyclin-dependent kinase (CDK) 6 as an upstream regulator of CDK2 controlling SAMHD1 phosphorylation in primary T cells and macrophages susceptible to infection by HIV-1. In turn, CDK2 was strongly linked to cell cycle progression and coordinated SAMHD1 phosphorylation and inactivation. CDK inhibitors specifically blocked HIV-1 infection at the reverse transcription step in a SAMHD1-dependent manner, reducing the intracellular dNTP pool. Our findings identify a direct relationship between control of the cell cycle by CDK6 and SAMHD1 activity, which is important for replication of lentiviruses, as well as other viruses whose replication may be regulated by intracellular dNTP availability.
authors.affiliation: AIDS Research Institute-IrsiCaixa and AIDS Unit, Hospital Germans Trias i Pujol, Autonomous University of Barcelona, 08916 Badalona, Spain;
authors.forename: Eduardo
authors.initials: E
authors.lastname: Pauls
authors.affiliation: AIDS Research Institute-IrsiCaixa and AIDS Unit, Hospital Germans Trias i Pujol, Autonomous University of Barcelona, 08916 Badalona, Spain;
authors.forename: Alba
authors.initials: A
authors.lastname: Ruiz
authors.affiliation: AIDS Research Institute-IrsiCaixa and AIDS Unit, Hospital Germans Trias i Pujol, Autonomous University of Barcelona, 08916 Badalona, Spain;
authors.forename: Roger
authors.initials: R
authors.lastname: Badia
authors.affiliation: AIDS Research Institute-IrsiCaixa and AIDS Unit, Hospital Germans Trias i Pujol, Autonomous University of Barcelona, 08916 Badalona, Spain;
authors.forename: Marc
authors.initials: M
authors.lastname: Permanyer
authors.affiliation: Cell Signaling Unit, Department of Experimental Science and Health, Pompeu Fabra University, Barcelona Biomedicine Research Park, 08003 Barcelona, Spain;
authors.forename: Albert
authors.initials: A
authors.lastname: Gubern
authors.affiliation: AIDS Research Institute-IrsiCaixa and AIDS Unit, Hospital Germans Trias i Pujol, Autonomous University of Barcelona, 08916 Badalona, Spain;
authors.forename: Eva
authors.initials: E
authors.lastname: Riveira-Muñoz
authors.affiliation: Vall d'Hebron Research Institute, Autonomous University of Barcelona and Biomedical Research Centre on Rare Diseases, Health Institute Carlos III, Spain;
authors.forename: Javier
authors.initials: J
authors.lastname: Torres-Torronteras
authors.affiliation: Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), 28049 Madrid, Spain;
authors.forename: Mar
authors.initials: M
authors.lastname: Alvarez
authors.affiliation: AIDS Research Institute-IrsiCaixa and AIDS Unit, Hospital Germans Trias i Pujol, Autonomous University of Barcelona, 08916 Badalona, Spain;
authors.forename: Beatriz
authors.initials: B
authors.lastname: Mothe
authors.affiliation: AIDS Research Institute-IrsiCaixa and AIDS Unit, Hospital Germans Trias i Pujol, Autonomous University of Barcelona, 08916 Badalona, Spain; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain;
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.affiliation: Infectious Diseases Department, Vall d'Hebron University Hospital, 08035 Barcelona, Spain; and.
authors.forename: Manel
authors.initials: M
authors.lastname: Crespo
authors.affiliation: Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), 28049 Madrid, Spain;
authors.forename: Luis
authors.initials: L
authors.lastname: Menéndez-Arias
authors.affiliation: AIDS Research Institute-IrsiCaixa and AIDS Unit, Hospital Germans Trias i Pujol, Autonomous University of Barcelona, 08916 Badalona, Spain;
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.affiliation: Institute of Medical Virology, University of Frankfurt, 60596 Frankfurt, Germany.
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Keppler
authors.affiliation: Vall d'Hebron Research Institute, Autonomous University of Barcelona and Biomedical Research Centre on Rare Diseases, Health Institute Carlos III, Spain;
authors.forename: Ramon
authors.initials: R
authors.lastname: Martí
authors.affiliation: Cell Signaling Unit, Department of Experimental Science and Health, Pompeu Fabra University, Barcelona Biomedicine Research Park, 08003 Barcelona, Spain;
authors.forename: Francesc
authors.initials: F
authors.lastname: Posas
authors.affiliation: AIDS Research Institute-IrsiCaixa and AIDS Unit, Hospital Germans Trias i Pujol, Autonomous University of Barcelona, 08916 Badalona, Spain;
authors.forename: Ester
authors.initials: E
authors.lastname: Ballana
authors.affiliation: AIDS Research Institute-IrsiCaixa and AIDS Unit, Hospital Germans Trias i Pujol, Autonomous University of Barcelona, 08916 Badalona, Spain; jaeste@irsicaixa.es.
authors.forename: José A
authors.initials: JA
authors.lastname: Esté
mesh_terms: D001596:Benzylamines; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002453:Cell Cycle / Q000276:immunology; D059447:Cell Cycle Checkpoints / Q000276:immunology*; D002478:Cells, Cultured; D000080027:Cyclams; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D022423:Myeloid Cells / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D000076106:SAM Domain and HD Domain-Containing Protein 1
chemical_list: D001596:Benzylamines; C527276:CXCR4 protein, human; D000080027:Cyclams; D006571:Heterocyclic Compounds; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; C495894:CDK2 protein, human; C495911:CDK6 protein, human; D051357:Cyclin-Dependent Kinase 2; D051361:Cyclin-Dependent Kinase 6; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins; C088327:plerixafor