HIV-1 Vpr triggers natural killer cell-mediated lysis of infected cells through activation of the ATR-mediated DNA damage response.
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.
Ward
Jeffrey
J
Department of Microbiology and Immunology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.
Davis
Zachary
Z
DeHart
Jason
J
Zimmerman
Erik
E
Bosque
Alberto
A
Brunetta
Enrico
E
Mavilio
Domenico
D
Planelles
Vicente
V
Barker
Edward
E
D064007:Ataxia Telangiectasia Mutated Proteins; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D044842:Cullin Proteins / Q000096:biosynthesis; D004249:DNA Damage; D005434:Flow Cytometry; D058851:GPI-Linked Proteins; D015870:Gene Expression; D015967:Gene Expression Regulation, Viral; D016336:Gene Products, vpr / Q000235:genetics / Q000378:metabolism*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000276:immunology*; D008565:Membrane Proteins / Q000096:biosynthesis; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000821:virology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
C114234:CUL4A protein, human; D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D058851:GPI-Linked Proteins; D016336:Gene Products, vpr; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; C423231:ULBP1 protein, human; C423230:ULBP2 protein, human; C423229:ULBP3 protein, human; D044767:Ubiquitin-Protein Ligases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases