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

Citation:

Mlcochova, P. et al., 2017. A G1-like state allows HIV-1 to bypass SAMHD1 restriction in macrophages. EMBO J, 36, pp.604-616.

Date Published:

Mar 1

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.

Notes:

Mlcochova, PetraSutherland, Katherine AWatters, Sarah ABertoli, Cosettade Bruin, Rob AmRehwinkel, JanNeil, Stuart JLenzi, Gina MKim, BaekKhwaja, AsimGage, Matthew CGeorgiou, ChristianaChittka, AlexandraYona, SimonNoursadeghi, MahdadTowers, Greg JGupta, Ravindra KengG0801172/Medical Research Council/United KingdomG9721629/Medical Research Council/United KingdomT32 GM008602/GM/NIGMS NIH HHS/R01 AI049781/AI/NIAID NIH HHS/R01 GM104198/GM/NIGMS NIH HHS/MC_UU_12010/8/Medical Research Council/United KingdomR56 AI049781/AI/NIAID NIH HHS/Wellcome Trust/United KingdomWT108082AIA/Wellcome Trust/United Kingdom339223/European Research Council/InternationalResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tEnglandEMBO J. 2017 Mar 1;36(5):604-616. doi: 10.15252/embj.201696025. Epub 2017 Jan 25.