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EMBO J ; 36(5): 604-616, 2017 03 01.
Article in English | MEDLINE | ID: mdl-28122869

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.


Subject(s)
G1 Phase , HIV-1/physiology , Immune Evasion , Macrophages/immunology , Macrophages/virology , Monomeric GTP-Binding Proteins/metabolism , Protein Processing, Post-Translational , Cells, Cultured , HIV-1/immunology , Humans , Immunity, Innate , Phosphorylation , SAM Domain and HD Domain-Containing Protein 1
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