title: Inhibition of herpes simplex virus type 1 by the CDK6 inhibitor PD-0332991 (palbociclib) through the control of SAMHD1.
abstract: OBJECTIVE
  Sterile α motif and histidine-aspartate domain-containing protein 1 (SAMHD1) has been shown to restrict retroviruses and DNA viruses by decreasing the pool of intracellular deoxynucleotides. In turn, SAMHD1 is controlled by cyclin-dependent kinases (CDK) that regulate the cell cycle and cell proliferation. Here, we explore the effect of CDK6 inhibitors on the replication of herpes simplex virus type 1 (HSV-1) in primary monocyte-derived macrophages (MDM).
  
  
  METHODS
  MDM were treated with palbociclib, a selective CDK4/6 inhibitor, and then infected with a GFP-expressing HSV-1. Intracellular deoxynucleotide triphosphate (dNTP) content was determined using a polymerase-based method.
  
  
  RESULTS
  CDK6 inhibitor palbociclib blocked SAMHD1 phosphorylation, intracellular dNTP levels and HSV-1 replication in MDM at subtoxic concentrations. Treatment of MDM with palbociclib reduced CDK2 activation, measured as the phosphorylation of the T-loop at Thr160. The antiviral activity of palbociclib was lost when SAMHD1 was degraded by viral protein X. Similarly, palbociclib did not block HSV-1 replication in SAMHD1-negative Vero cells at subtoxic concentrations, providing further evidence for a role of SAMHD1 in mediating the antiviral effect.
  
  
  CONCLUSIONS
  SAMHD1-mediated HSV-1 restriction is controlled by CDK and points to a preferential role for CDK6 and CDK2 as mediators of SAMHD1 activation. Similarly, the restricting activity of SAMHD1 against DNA viruses suggests that control of dNTP availability is the major determinant of its antiviral activity. This is the first study describing the anti-HSV-1 activity of palbociclib.
authors.affiliation: AIDS Research Institute - IrsiCaixa, and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Badia
authors.affiliation: AIDS Research Institute - IrsiCaixa, and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Guillem
authors.initials: G
authors.lastname: Angulo
authors.affiliation: AIDS Research Institute - IrsiCaixa, and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Riveira-Muñoz
authors.affiliation: AIDS Research Institute - IrsiCaixa, and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Pujantell
authors.affiliation: AIDS Research Institute - IrsiCaixa, and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Puig
authors.affiliation: AIDS Research Institute - IrsiCaixa, and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ramirez
authors.affiliation: Research Group on Neuromuscular and Mitochondrial Disorders, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, and Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Torres-Torronteras
authors.affiliation: Research Group on Neuromuscular and Mitochondrial Disorders, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, and Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Martí
authors.affiliation: AIDS Research Institute - IrsiCaixa, and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Pauls
authors.affiliation: AIDS Research Institute - IrsiCaixa, and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.affiliation: AIDS Research Institute - IrsiCaixa, and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Ballana
authors.affiliation: AIDS Research Institute - IrsiCaixa, and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain jaeste@irsicaixa.es.
authors.forename: José A
authors.initials: JA
authors.lastname: Esté
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors*; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000821:virology*; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D000076106:SAM Domain and HD Domain-Containing Protein 1; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D010879:Piperazines; D011725:Pyridines; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins; C500026:palbociclib