title: Modulation of NKG2D-mediated cytotoxic functions of natural killer cells by viral protein R from HIV-1 primary isolates.
abstract: HIV-1 viral protein R (Vpr) from laboratory-adapted virus strains activates the DNA damage/stress sensor ATR kinase and induces cell cycle arrest at the G(2)/M phase through a process that requires Vpr to engage the DDB1-CUL4A (VprBP/DCAF-1) E3 ligase complex. Activation of this DNA damage/stress checkpoint in G(2) by Vpr was shown to modulate NKG2D-dependent NK cell effector functions via enhancing expression of NKG2D ligands, notably ULBP2. However, it is unknown whether Vpr from HIV-1 primary isolates (groups M, N, O, and P) could modulate NKG2D-mediated cytotoxic functions of NK cells. Here, we report that Vpr from most HIV-1 primary isolates can upregulate ULBP2 expression and induce NKG2D-dependent NK cell killing. Importantly, these activities were always accompanied by an active G(2) cell cycle arrest function. Interestingly, Vpr variants from group P and a clade D isolate of group M were defective at enhancing NKG2D-mediated NK cell lysis owing to their inability to augment ULBP2 expression. However, distinct mechanisms were responsible for their failure to do so. While Vpr from group P was deficient in its ability to engage the DDB1-CUL4A (VprBP/DCAF-1) E3 ligase complex, the Vpr variant from group D was unable to properly localize to the nucleus, underlining the importance of these biological properties in Vpr function. In conclusion, the ability of Vpr from HIV-1 primary isolates to regulate NK cell effector function underscores the importance of this HIV-1 accessory protein in the modulation of the host's innate immune responses.
authors.affiliation: Institut de recherches cliniques de Montréal, 110, Avenue des Pins Ouest, Montreal, Quebec, Canada H2W 1R7.
authors.forename: Tram N Q
authors.initials: TN
authors.lastname: Pham
authors.forename: Jonathan
authors.initials: J
authors.lastname: Richard
authors.forename: Francine C A
authors.initials: FC
authors.lastname: Gerard
authors.forename: Christopher
authors.initials: C
authors.lastname: Power
authors.forename: Éric A
authors.initials: ÉA
authors.lastname: Cohen
mesh_terms: D000595:Amino Acid Sequence; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D004249:DNA Damage; D005455:Fluorescent Antibody Technique; D016195:G2 Phase; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000302:isolation & purification* / Q000472:pathogenicity*; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism* / Q000473:pathology*; D008969:Molecular Sequence Data; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D017386:Sequence Homology, Amino Acid; D014779:Virus Replication; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; C423230:ULBP2 protein, human; D054325:vpr Gene Products, Human Immunodeficiency Virus; D046988:Proteasome Endopeptidase Complex