A G1‐like state allows HIV‐1 to bypass SAMHD1 restriction in macrophages
書誌事項
- 公開日
- 2017-01-25
- 権利情報
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- https://creativecommons.org/licenses/by/4.0/
- https://creativecommons.org/licenses/by/4.0/
- DOI
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- 10.15252/embj.201696025
- 公開者
- Springer Science and Business Media LLC
この論文をさがす
説明
<jats:title>Abstract</jats:title> <jats:p> 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 <jats:italic>in vivo</jats:italic> . 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. </jats:p>
収録刊行物
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- The EMBO Journal
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The EMBO Journal 36 (5), 604-616, 2017-01-25
Springer Science and Business Media LLC