SAMHD1 Is the Dendritic- And Myeloid-Cell-Specific HIV-1 Restriction Factor Counteracted by Vpx

Nature. 2011 May 25;474(7353):654-7. doi: 10.1038/nature10117.

Abstract

The primate lentivirus auxiliary protein Vpx counteracts an unknown restriction factor that renders human dendritic and myeloid cells largely refractory to HIV-1 infection. 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. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • DNA, Viral / metabolism
  • Dendritic Cells / metabolism*
  • Dendritic Cells / virology
  • Gene Silencing
  • HIV Infections / metabolism
  • HIV-1 / physiology*
  • HeLa Cells
  • Humans
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism*
  • Myeloid Cells / metabolism*
  • Myeloid Cells / virology
  • Proteasome Endopeptidase Complex / metabolism
  • SAM Domain and HD Domain-Containing Protein 1
  • U937 Cells
  • Viral Regulatory and Accessory Proteins / metabolism*
  • Virus Replication

Substances

  • DNA, Viral
  • VPX protein, Simian immunodeficiency virus
  • Viral Regulatory and Accessory Proteins
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human
  • Proteasome Endopeptidase Complex
  • Monomeric GTP-Binding Proteins