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We reveal inducible changes in expression of cell cycle\u2010associated 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\u2010like phase macrophages at the single\u2010cell level. Depletion of SAMHD1 in macrophages decouples the association between infection and expression of cell cycle\u2010associated proteins, with terminally differentiated macrophages becoming highly susceptible to HIV\u20101. We observe both embryo\u2010derived and monocyte\u2010derived tissue\u2010resident macrophages in a G1\u2010like phase at frequencies approaching 20%, suggesting how macrophages sustain HIV\u20101 replication\n                    <jats:italic>in\u00a0vivo<\/jats:italic>\n                    . Finally, we reveal a SAMHD1\u2010dependent antiretroviral activity of histone deacetylase inhibitors acting via p53 activation. These data provide a basis for host\u2010directed therapeutic approaches aimed at limiting HIV\u20101 burden in macrophages that may contribute to curative interventions.\n                  <\/jats:p>","DOI":"10.15252\/embj.201696025","type":"journal-article","created":{"date-parts":[[2017,1,25]],"date-time":"2017-01-25T20:40:39Z","timestamp":1485376839000},"page":"604-616","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":101,"title":["A G1\u2010like state allows HIV\u20101 to bypass SAMHD1 restriction in macrophages"],"prefix":"10.1038","volume":"36","author":[{"given":"Petra","family":"Mlcochova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A","family":"Sutherland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah A","family":"Watters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cosetta","family":"Bertoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob AM","family":"de Bruin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Rehwinkel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart J","family":"Neil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gina M","family":"Lenzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baek","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asim","family":"Khwaja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew C","family":"Gage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiana","family":"Georgiou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Chittka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Yona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahdad","family":"Noursadeghi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greg J","family":"Towers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9751-1808","authenticated-orcid":false,"given":"Ravindra K","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,1,25]]},"reference":[{"key":"BFEMBJ201696025_CR1","doi-asserted-by":"crossref","first-page":"e1005194","DOI":"10.1371\/journal.ppat.1005194","volume":"11","author":"LH Arnold","year":"2015","unstructured":"Arnold LH, Groom HC, Kunzelmann S, Schwefel D, Caswell SJ, Ordonez P, Mann MC, Rueschenbaum S, Goldstone DC, Pennell S, Howell SA, Stoye JP, Webb M, Taylor IA, Bishop KN (2015) Phospho\u2010dependent regulation of SAMHD1 oligomerisation couples catalysis and restriction. 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