A G1‐like state allows HIV‐1 to bypass SAMHD1 restriction in macrophages. (25th January 2017)

• Record Type: Journal Article
• Authors: Mlcochova, Petra; Sutherland, Katherine A; Watters, Sarah A; Bertoli, Cosetta; de 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
• Is Part Of: EMBO journal. Volume 36:Number 5(2017)
• Page Start: 604
• Page End: 616
• Publication Date: 2017-01-25
• Subjects: cell cycle -- histone deacetylase -- HIV -- macrophage -- SAMHD1; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201696025
• Languages: English
• ISSNs: 0261-4189

Abstract

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. Synopsis: Here, we show that macrophages are found in both G0‐ and G1‐like phases, and the latter are permissive to HIV‐1 due to the canonical Raf/MEK/ERK pathway which deactivates SAMHD1 by CDK1‐mediated phosphorylation at T592. Therefore, HIV‐1 does not need to encode a SAMHD1 antagonist. Macrophages transition between a classical G0 quiescent state and a G1‐like state, with the latter representing up to 20% of tissue macrophages. G0–G1 transition is regulated by the Raf/MEK/ERK pathway, associated with increased CDK1 protein, SAMHD1 T592 phosphorylation and a permissivity window to HIV‐1 infection. Histone deacetylase inhibitors possess SAMHD1‐dependent antiretroviral activity acting via p53 activation. Abstract : Terminally differentiated macrophages displaying a Raf/MEK/ERK pathway‐dependent G1‐like cell cycle expression profile are permissive to HIV‐1 infection due to deactivation of the host HIV‐1 restriction factor SAMHD1.