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

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.

Source: EMBO Journal - February 28, 2017 Category: Molecular Biology Authors: Mlcochova, P., Sutherland, K. A., Watters, S. A., Bertoli, C., de Bruin, R. A., Rehwinkel, J., Neil, S. J., Lenzi, G. M., Kim, B., Khwaja, A., Gage, M. C., Georgiou, C., Chittka, A., Yona, S., Noursadeghi, M., Towers, G. J., Gupta, R. K. Tags: Microbiology, Virology & Host Pathogen Interaction Articles Source Type: research