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

Jeffrey Ward, Zachary Davis, Jason DeHart, Erik Zimmerman, Alberto Bosque, Enrico Brunetta, Domenico Mavilio, Vicente Planelles, Edward Barker

Research output: Contribution to journalArticle

88 Citations (Scopus)

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.

Original languageEnglish
JournalPLoS Pathogens
Volume5
Issue number10
Publication statusPublished - Oct 2009

Fingerprint

Natural Killer Cells
DNA Damage
HIV-1
Carrier Proteins
Ligands
Cullin Proteins
Natural Killer Cell Receptors
T-Lymphocytes
Ataxia Telangiectasia
Ubiquitin-Protein Ligases
DNA-Binding Proteins
Virus Diseases
Phosphotransferases
Viruses
Messenger RNA
Proteins

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

HIV-1 Vpr triggers natural killer cell-mediated lysis of infected cells through activation of the ATR-mediated DNA damage response. / Ward, Jeffrey; Davis, Zachary; DeHart, Jason; Zimmerman, Erik; Bosque, Alberto; Brunetta, Enrico; Mavilio, Domenico; Planelles, Vicente; Barker, Edward.

In: PLoS Pathogens, Vol. 5, No. 10, 10.2009.

Research output: Contribution to journalArticle

Ward, Jeffrey ; Davis, Zachary ; DeHart, Jason ; Zimmerman, Erik ; Bosque, Alberto ; Brunetta, Enrico ; Mavilio, Domenico ; Planelles, Vicente ; Barker, Edward. / HIV-1 Vpr triggers natural killer cell-mediated lysis of infected cells through activation of the ATR-mediated DNA damage response. In: PLoS Pathogens. 2009 ; Vol. 5, No. 10.
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