A G1-like state allows HIV-1 to bypass SAMHD1 restriction in macrophages

Petra Mlcochova, Katherine A. Sutherland, Sarah A. Watters, Cosetta Bertoli, Rob A.M. de Bruin, Jan Rehwinkel, Stuart J. Neil, Gina M. Lenzi, Baek Kim, Asim Khwaja, Matthew C. Gage, Christiana Georgiou, Alexandra Chittka, Simon Yona, Mahdad Noursadeghi, Greg J. Towers, Ravindra K. Gupta*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

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.

Original languageAmerican English
Pages (from-to)604-616
Number of pages13
JournalEMBO Journal
Volume36
Issue number5
DOIs
StatePublished - 1 Mar 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 The Authors. Published under the terms of the CC BY 4.0 license

Keywords

  • HIV
  • SAMHD1
  • cell cycle
  • histone deacetylase
  • macrophage

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