HIV-1 Vpr triggers natural killer cell-mediated lysis of infected cells through activation of the ATR-mediated DNA damage response

PLoS Pathog. 2009 Oct;5(10):e1000613. doi: 10.1371/journal.ppat.1000613. Epub 2009 Oct 2.

Abstract

Natural killer (NK) cells are stimulated by ligands on virus-infected cells. We have recently demonstrated that NK cells respond to human immunodeficiency virus type-1 (HIV-1)-infected autologous T-cells, in part, through the recognition of ligands for the NK cell activating receptor NKG2D on the surface of the infected cells. Uninfected primary CD4(pos) T-cell blasts express little, if any, NKG2D ligands. In the present study we determined the mechanism through which ligands for NKG2D are induced on HIV-1-infected cells. Our studies reveal that expression of vpr is necessary and sufficient to elicit the expression of NKG2D ligands in the context of HIV-1 infection. Vpr specifically induces surface expression of the unique-long 16 binding proteins (ULBP)-1 and ULBP-2, but not ULBP-3, MHC class I-related chain molecules (MIC)-A or MIC-B. In these studies we also demonstrated that Vpr increases the level of ULBP-1 and ULBP-2 mRNA in primary CD4(pos) T-cell blasts. The presence of ULBP-1 and ULBP-2 on HIV-1 infected cells is dependent on the ability of Vpr to associate with a protein complex know as Cullin 4a (Cul4a)/damaged DNA binding protein 1 (DDB1) and Cul4a-associated factor-1(DCAF-1) E3 ubiquitin ligase (Cul4a(DCAF-1)). ULBP-1 and -2 expression by Vpr is also dependent on activation of the DNA damage sensor, ataxia telangiectasia and rad-3-related kinase (ATR). When T-cell blasts are infected with a vpr-deficient HIV-1, NK cells are impaired in killing the infected cells. Thus, HIV-1 Vpr actively triggers the expression of the ligands to the NK cell activation receptor.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins
  • CD4-Positive T-Lymphocytes / virology
  • Cell Cycle Proteins / metabolism*
  • Cullin Proteins / biosynthesis
  • DNA Damage
  • Flow Cytometry
  • GPI-Linked Proteins
  • Gene Expression
  • Gene Expression Regulation, Viral
  • Gene Products, vpr / genetics
  • Gene Products, vpr / metabolism*
  • HIV Infections / genetics
  • HIV Infections / immunology*
  • HIV Infections / metabolism
  • HIV-1 / immunology
  • Humans
  • Intercellular Signaling Peptides and Proteins / biosynthesis
  • Intracellular Signaling Peptides and Proteins
  • Killer Cells, Natural / immunology*
  • Membrane Proteins / biosynthesis
  • NK Cell Lectin-Like Receptor Subfamily K / biosynthesis
  • Protein-Serine-Threonine Kinases / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stem Cells / virology
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • CUL4A protein, human
  • Cell Cycle Proteins
  • Cullin Proteins
  • GPI-Linked Proteins
  • Gene Products, vpr
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • KLRK1 protein, human
  • Membrane Proteins
  • NK Cell Lectin-Like Receptor Subfamily K
  • ULBP1 protein, human
  • ULBP2 protein, human
  • ULBP3 protein, human
  • Ubiquitin-Protein Ligases
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases