期刊
EMBO JOURNAL
卷 36, 期 5, 页码 604-616出版社
WILEY
DOI: 10.15252/embj.201696025
关键词
cell cycle; histone deacetylase; HIV; macrophage; SAMHD1
资金
- Wellcome Trust [WT108082AIA, 108183]
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- European Research Council under the European Union's Seventh Framework Programme (FP7)/ ERC grant [339223]
- Medical Research Council
- USA National Institutes of Health grants [AI049781, GM104198]
- Cancer Research UK [20147] Funding Source: researchfish
- Medical Research Council [MC_UU_12010/8, MC_UU_00008/8] Funding Source: researchfish
- MRC [MC_UU_00008/8, G9721629, MC_UU_12010/8, G0801172] Funding Source: UKRI
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 invivo. 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.
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