| First Author | Mlcochova P | Year | 2017 |
| Journal | EMBO J | Volume | 36 |
| Issue | 5 | Pages | 604-616 |
| PubMed ID | 28122869 | Mgi Jnum | J:240874 |
| Mgi Id | MGI:5896679 | Doi | 10.15252/embj.201696025 |
| Citation | Mlcochova P, et al. (2017) A G1-like state allows HIV-1 to bypass SAMHD1 restriction in macrophages. EMBO J 36(5):604-616 |
| abstractText | 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. |
