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A G1-like state allows HIV-1 to bypass SAMHD1 restriction in macrophages

Mlcochova, P; Sutherland, KA; Watters, SA; Bertoli, C; de Bruin, RAM; Rehwinkel, J; Neil, SJ; ... Gupta, RK; + view all (2017) A G1-like state allows HIV-1 to bypass SAMHD1 restriction in macrophages. The EMBO Journal , 36 (5) pp. 604-616. 10.15252/embj.201696025. Green open access

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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 replication in vivo. Finally, 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.

Type: Article
Title: A G1-like state allows HIV-1 to bypass SAMHD1 restriction in macrophages
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/embj.201696025
Publisher version: http://doi.org/10.15252/embj.201696025
Language: English
Additional information: © 2017 The Authors. This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, cell cycle, histone deacetylase, HIV, macrophage, SAMHD1, SIMIAN IMMUNODEFICIENCY VIRUS, DNA-REPLICATION, CELL-CYCLE, ANTIRETROVIRAL ACTIVITY, HDAC INHIBITORS, MYELOID CELLS, T-CELLS, PROTEIN, PHOSPHORYLATION, VPX
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Metabolism and Experi Therapeutics
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health
URI: http://discovery.ucl.ac.uk/id/eprint/1538518
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