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

EMBO J. 2017 Mar 1;36(5):604-616. doi: 10.15252/embj.201696025. Epub 2017 Jan 25.


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.

Keywords: HIV; SAMHD1; cell cycle; histone deacetylase; macrophage.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • G1 Phase*
  • HIV-1 / immunology
  • HIV-1 / physiology*
  • Humans
  • Immune Evasion*
  • Immunity, Innate
  • Macrophages / immunology*
  • Macrophages / virology*
  • Monomeric GTP-Binding Proteins / metabolism*
  • Phosphorylation
  • Protein Processing, Post-Translational*
  • SAM Domain and HD Domain-Containing Protein 1


  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human
  • Monomeric GTP-Binding Proteins