HIV-1 Vpr up-regulates expression of ligands for the activating NKG2D receptor and promotes NK cell-mediated killing.
HIV up-regulates cell-surface expression of specific ligands for the activating NKG2D receptor, including ULBP-1, -2, and -3, but not MICA or MICB, in infected cells both in vitro and in vivo. However, the viral factor(s) involved in NKG2D ligand expression still remains undefined. HIV-1 Vpr activates the DNA damage/stress-sensing ATR kinase and promotes G(2) cell-cycle arrest, conditions known to up-regulate NKG2D ligands. We report here that HIV-1 selectively induces cell-surface expression of ULBP-2 in primary CD4(+) T lymphocytes by a process that is Vpr dependent. Importantly, Vpr enhanced the susceptibility of HIV-1-infected cells to NK cell-mediated killing. Strikingly, Vpr alone was sufficient to up-regulate expression of all NKG2D ligands and thus promoted efficient NKG2D-dependent NK cell-mediated killing. Delivery of virion-associated Vpr via defective HIV-1 particles induced analogous biologic effects in noninfected target cells, suggesting that Vpr may act similarly beyond infected cells. All these activities relied on Vpr ability to activate the ATR-mediated DNA damage/stress checkpoint. Overall, these results indicate that Vpr is a key determinant responsible for HIV-1-induced up-regulation of NKG2D ligands and further suggest an immunomodulatory role for Vpr that may not only contribute to HIV-1-induced CD4(+) T-lymphocyte depletion but may also take part in HIV-1-induced NK-cell dysfunction.
Richard
Jonathan
J
Institut de Recherches Cliniques de Montréal, QC, Canada.
Sindhu
Sardar
S
Pham
Tram N Q
TN
Belzile
Jean-Philippe
JP
Cohen
Eric A
EA
D064007:Ataxia Telangiectasia Mutated Proteins; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018797:Cell Cycle Proteins / Q000276:immunology / Q000378:metabolism; D016923:Cell Death / Q000276:immunology; D058851:GPI-Linked Proteins; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D007668:Kidney / Q000166:cytology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D016086:Lentivirus / Q000235:genetics; D008024:Ligands; D016297:Mutagenesis, Site-Directed; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology* / Q000378:metabolism; D010957:Plasmids; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism; D013312:Stress, Physiological / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D018797:Cell Cycle Proteins; D058851:GPI-Linked Proteins; D007155:Immunologic Factors; D036341:Intercellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011956:Receptors, Cell Surface; C423230:ULBP2 protein, human; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases