Journal Article

SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx

Yatim, Ahmad, Ringeard, Mathieu, Emiliani, Stéphane, Chable-Bessia, Christine, Sobhian, Bijan, Benkirane, Monsef, Schwartz, Olivier, Ségéral, Emmanuel, Laguette, Nadine, Casartelli, Nicoletta

2011

Overview

How macrophages avoid HIV-1 infection HIV-1 is unable to replicate efficiently in dendritic cells, the antigen-presenting tissue cells that function in both innate and adaptive immunity. Other primate lentiviruses, including HIV-2 and some simian immunodeficiency viruses, express a protein called Vpx that is able to overcome the block to replication. Two groups now report the identification of the restriction factor in dendritic cells and macrophages that is overcome by Vpx. Vpx is found to induce degradation of the protein SAMHD1. Mutations in SAMHD1 cause Aicardi–Goutières syndrome, a disorder characterized by inappropriate activation of the immune system. Knockdown of SAMHD1 increases HIV-1 replication in dendritic cells, which could be important for generating appropriate immune responses to the virus. The primate lentivirus auxiliary protein Vpx counteracts an unknown restriction factor that renders human dendritic and myeloid cells largely refractory to HIV-1 infection 1 , 2 , 3 , 4 , 5 , 6 . Here we identify SAMHD1 as this restriction factor. SAMHD1 is a protein involved in Aicardi–Goutières syndrome, a genetic encephalopathy with symptoms mimicking congenital viral infection, that has been proposed to act as a negative regulator of the interferon response 7 . We show that Vpx induces proteasomal degradation of SAMHD1. Silencing of SAMHD1 in non-permissive cell lines alleviates HIV-1 restriction and is associated with a significant accumulation of viral DNA in infected cells. Concurrently, overexpression of SAMHD1 in sensitive cells inhibits HIV-1 infection. The putative phosphohydrolase activity of SAMHD1 is probably required for HIV-1 restriction. Vpx-mediated relief of restriction is abolished in SAMHD1-negative cells. Finally, silencing of SAMHD1 markedly increases the susceptibility of monocytic-derived dendritic cells to infection. Our results demonstrate that SAMHD1 is an antiretroviral protein expressed in cells of the myeloid lineage that inhibits an early step of the viral life cycle.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/2504/133/2505 / 631/326/596 / 692/699/255/1901 / Acquired immune deficiency syndrome / AIDS / Antiretroviral agents / Biological and medical sciences / Cell Line / Dendritic Cells / Dendritic Cells - metabolism / Dendritic Cells - virology / Diagnosis / DNA, Viral / DNA, Viral - metabolism / Fundamental and applied biological sciences. Psychology / Gene Silencing / Genetics / HeLa Cells / HIV infection / HIV Infections / HIV Infections - metabolism / HIV-1 / HIV-1 - physiology / Humanities and Social Sciences / Humans / Infections / letter / Life Sciences / Mass spectrometry / Microbiology / Monomeric GTP-Binding Proteins / Monomeric GTP-Binding Proteins - genetics / Monomeric GTP-Binding Proteins - metabolism / multidisciplinary / Myeloid Cells / Myeloid Cells - metabolism / Myeloid Cells - virology / Physiological aspects / Proteasome Endopeptidase Complex / Proteasome Endopeptidase Complex - metabolism / Proteins / Replicative cycle, interference, host-virus relations, pathogenicity, miscellaneous strains / SAM Domain and HD Domain-Containing Protein 1 / Science / Science (multidisciplinary) / U937 Cells / Viral infections / Viral Regulatory and Accessory Proteins / Viral Regulatory and Accessory Proteins - metabolism / Virology / Virus Replication