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A G1‐like state allows HIV ‐1 to bypass SAMHD 1 restriction in macrophages
Author(s) -
Mlcochova Petra,
Sutherland Katherine A,
Watters Sarah A,
Bertoli Cosetta,
Bruin Rob AM,
Rehwinkel Jan,
Neil Stuart J,
Lenzi Gina M,
Kim Baek,
Khwaja Asim,
Gage Matthew C,
Georgiou Christiana,
Chittka Alexandra,
Yona Simon,
Noursadeghi Mahdad,
Towers Greg J,
Gupta Ravindra K
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201696025
Subject(s) - atlanta , human immunodeficiency virus (hiv) , library science , medicine , family medicine , computer science , metropolitan area , pathology
An unresolved question is how HIV ‐1 achieves efficient replication in terminally differentiated macrophages despite the restriction factor SAMHD 1. We reveal inducible changes in expression of cell cycle‐associated proteins including MCM 2 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 CDK 1 with subsequent SAMHD 1 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 SAMHD 1 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 SAMHD 1‐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.