title: A G1-like state allows HIV-1 to bypass SAMHD1 restriction in macrophages.
abstract: An unresolved question is how HIV-1 achieves efficient replication in terminally differentiated macrophages despite the restriction factor SAMHD1. We reveal inducible changes in expression of cell cycle-associated proteins including MCM2 and cyclins A, E, D1/D3 in macrophages, without evidence for DNA synthesis or mitosis. These changes are induced by activation of the Raf/MEK/ERK kinase cascade, culminating in upregulation of CDK1 with subsequent SAMHD1 T592 phosphorylation and deactivation of its antiviral activity. HIV infection is limited to these G1-like phase macrophages at the single-cell level. Depletion of SAMHD1 in macrophages decouples the association between infection and expression of cell cycle-associated proteins, with terminally differentiated macrophages becoming highly susceptible to HIV-1. We observe both embryo-derived and monocyte-derived tissue-resident macrophages in a G1-like phase at frequencies approaching 20%, suggesting how macrophages sustain HIV-1 replicationin vivoFinally, we reveal a SAMHD1-dependent antiretroviral activity of histone deacetylase inhibitors acting via p53 activation. These data provide a basis for host-directed therapeutic approaches aimed at limiting HIV-1 burden in macrophages that may contribute to curative interventions.
authors.affiliation: Division of Infection and Immunity, University College London, London, UK.
authors.forename: Petra
authors.initials: P
authors.lastname: Mlcochova
authors.affiliation: Division of Infection and Immunity, University College London, London, UK.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Sutherland
authors.affiliation: Division of Infection and Immunity, University College London, London, UK.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Watters
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London, UK.
authors.forename: Cosetta
authors.initials: C
authors.lastname: Bertoli
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London, UK.
authors.forename: Rob Am
authors.initials: RA
authors.lastname: de Bruin
authors.affiliation: Medical Research Council Human Immunology Unit, Radcliffe Department of Medicine, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Jan
authors.initials: J
authors.lastname: Rehwinkel
authors.affiliation: Division of Immunology, Infection and Inflammatory Disease, King's College, London, UK.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Neil
authors.affiliation: Department of Pediatrics, Center for Drug Discovery, Emory School of Medicine, Atlanta, GA, USA.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Lenzi
authors.affiliation: Department of Pediatrics, Center for Drug Discovery, Emory School of Medicine, Atlanta, GA, USA.
authors.forename: Baek
authors.initials: B
authors.lastname: Kim
authors.affiliation: Research Department of Haematology, UCL, London, UK.
authors.forename: Asim
authors.initials: A
authors.lastname: Khwaja
authors.affiliation: Division of Medicine, University College London, London, UK.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Gage
authors.affiliation: Division of Medicine, University College London, London, UK.
authors.forename: Christiana
authors.initials: C
authors.lastname: Georgiou
authors.affiliation: Division of Medicine, University College London, London, UK.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Chittka
authors.affiliation: Division of Medicine, University College London, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Yona
authors.affiliation: Division of Infection and Immunity, University College London, London, UK.
authors.forename: Mahdad
authors.initials: M
authors.lastname: Noursadeghi
authors.affiliation: Division of Infection and Immunity, University College London, London, UK.
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Towers
authors.affiliation: Division of Infection and Immunity, University College London, London, UK ravindra.gupta@ucl.ac.uk.|Africa Health Research Institute, KwaZulu Natal, South Africa.
authors.forename: Ravindra K
authors.identifier: 0000-0001-9751-1808
authors.initials: RK
authors.lastname: Gupta
mesh_terms: D002478:Cells, Cultured; D016193:G1 Phase; D015497:HIV-1 / Q000276:immunology / Q000502:physiology*; D006801:Humans; D057131:Immune Evasion; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology* / Q000821:virology*; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D000076106:SAM Domain and HD Domain-Containing Protein 1
chemical_list: D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins
keywords: 
  HIV
  ; SAMHD1; cell cycle; histone deacetylase; macrophage