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A G1-like state allows HIV-1 to bypass SAMHD1 restriction in macrophages.
- Source :
-
EMBO Journal . 3/1/2017, Vol. 36 Issue 5, p604-616. 13p. 2 Color Photographs, 3 Graphs. - Publication Year :
- 2017
-
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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *MACROPHAGES
*ANTIGEN presenting cells
*DNA synthesis
*MITOSIS
*CELL division
Subjects
Details
- Language :
- English
- ISSN :
- 02614189
- Volume :
- 36
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- EMBO Journal
- Publication Type :
- Academic Journal
- Accession number :
- 121502046
- Full Text :
- https://doi.org/10.15252/embj.201696025