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EMBO J. 2017 Mar 1;36(5):604-616. doi: 10.15252/embj.201696025. Epub 2017 Jan 25.

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

Author information

1
Division of Infection and Immunity, University College London, London, UK.
2
MRC Laboratory for Molecular Cell Biology, University College London, London, UK.
3
Medical Research Council Human Immunology Unit, Radcliffe Department of Medicine, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
4
Division of Immunology, Infection and Inflammatory Disease, King's College, London, UK.
5
Department of Pediatrics, Center for Drug Discovery, Emory School of Medicine, Atlanta, GA, USA.
6
Research Department of Haematology, UCL, London, UK.
7
Division of Medicine, University College London, London, UK.
8
Division of Infection and Immunity, University College London, London, UK ravindra.gupta@ucl.ac.uk.
9
Africa Health Research Institute, KwaZulu Natal, South Africa.

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.

KEYWORDS:

HIV ; SAMHD1; cell cycle; histone deacetylase; macrophage

PMID:
28122869
PMCID:
PMC5331754
DOI:
10.15252/embj.201696025
[Indexed for MEDLINE]
Free PMC Article

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