SAMHD1-deficient CD14+ Cells From Individuals With Aicardi-Goutières Syndrome Are Highly Susceptible to HIV-1 Infection

PLoS Pathog. 2011 Dec;7(12):e1002425. doi: 10.1371/journal.ppat.1002425. Epub 2011 Dec 8.

Abstract

Myeloid blood cells are largely resistant to infection with human immunodeficiency virus type 1 (HIV-1). Recently, it was reported that Vpx from HIV-2/SIVsm facilitates infection of these cells by counteracting the host restriction factor SAMHD1. Here, we independently confirmed that Vpx interacts with SAMHD1 and targets it for ubiquitin-mediated degradation. We found that Vpx-mediated SAMHD1 degradation rendered primary monocytes highly susceptible to HIV-1 infection; Vpx with a T17A mutation, defective for SAMHD1 binding and degradation, did not show this activity. Several single nucleotide polymorphisms in the SAMHD1 gene have been associated with Aicardi-Goutières syndrome (AGS), a very rare and severe autoimmune disease. Primary peripheral blood mononuclear cells (PBMC) from AGS patients homozygous for a nonsense mutation in SAMHD1 (R164X) lacked endogenous SAMHD1 expression and support HIV-1 replication in the absence of exogenous activation. Our results indicate that within PBMC from AGS patients, CD14+ cells were the subpopulation susceptible to HIV-1 infection, whereas cells from healthy donors did not support infection. The monocytic lineage of the infected SAMHD1 -/- cells, in conjunction with mostly undetectable levels of cytokines, chemokines and type I interferon measured prior to infection, indicate that aberrant cellular activation is not the cause for the observed phenotype. Taken together, we propose that SAMHD1 protects primary CD14+ monocytes from HIV-1 infection confirming SAMHD1 as a potent lentiviral restriction factor.

Publication types

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

MeSH terms

  • Autoimmune Diseases of the Nervous System / genetics*
  • Autoimmune Diseases of the Nervous System / metabolism
  • Autoimmune Diseases of the Nervous System / virology
  • Cell Separation
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Genetic Predisposition to Disease / genetics*
  • HIV Infections / genetics*
  • HIV-1 / metabolism
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Lipopolysaccharide Receptors / metabolism
  • Microscopy, Confocal
  • Monomeric GTP-Binding Proteins / deficiency*
  • Monomeric GTP-Binding Proteins / genetics*
  • Mutation, Missense
  • Myeloid Cells / metabolism
  • Myeloid Cells / virology*
  • Nervous System Malformations / genetics*
  • Nervous System Malformations / metabolism
  • Nervous System Malformations / virology
  • Reverse Transcriptase Polymerase Chain Reaction
  • SAM Domain and HD Domain-Containing Protein 1
  • Tandem Mass Spectrometry
  • Transfection

Substances

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

Supplementary concepts

  • Aicardi-Goutieres syndrome