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

• Petra Mlcochova ^[1] ; Katherine A Sutherland ^[1] ; Sarah A Watters ^[1] ; Cosetta Bertoli ^[1] ; Rob AM de Bruin ^[1] ; Jan Rehwinkel ^[2] ; Stuart J Neil ^[3] ; Gina M Lenzi ^[4] ; Baek Kim ^[4] ; Asim Khwaja ^[5] ; Matthew C Gage ^[1] ; Christiana Georgiou ^[1] ; Alexandra Chittka ^[1] ; Simon Yona ^[1] ; Mahdad Noursadeghi ^[1] ; Greg J Towers ^[1] ; Ravindra K Gupta ^[6]
  1. [1] University College London

     University College London

     Reino Unido

     
  2. [2] Weatherall Institute of Molecular Medicine

     Weatherall Institute of Molecular Medicine

     Oxford District, Reino Unido

     
  3. [3] King's College London

     King's College London

     Reino Unido

     
  4. [4] 5 Department of Pediatrics Center for Drug Discovery Emory School of Medicine Atlanta GA USA
  5. [5] 6 Research Department of Haematology UCL London UK
  6. [6] 1 Division of Infection and Immunity University College London London UK; 8 Africa Health Research Institute KwaZulu Natal South Africa

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 36, Nº. 5, 2017, págs. 604-616
• Idioma: inglés
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• Resumen

  • 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.