Modulation of NKG2D-mediated cytotoxic functions of natural killer cells by viral protein R from HIV-1 primary isolates.
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.
Mesh Terms:
Amino Acid Sequence, Blotting, Western, Cell Cycle Checkpoints, Cell Nucleus, Cell Proliferation, DNA Damage, Fluorescent Antibody Technique, G2 Phase, GPI-Linked Proteins, HIV Infections, HIV-1, HeLa Cells, Humans, Immunoprecipitation, Intercellular Signaling Peptides and Proteins, Killer Cells, Natural, Molecular Sequence Data, NK Cell Lectin-Like Receptor Subfamily K, Proteasome Endopeptidase Complex, Sequence Homology, Amino Acid, Virus Replication, vpr Gene Products, Human Immunodeficiency Virus
Amino Acid Sequence, Blotting, Western, Cell Cycle Checkpoints, Cell Nucleus, Cell Proliferation, DNA Damage, Fluorescent Antibody Technique, G2 Phase, GPI-Linked Proteins, HIV Infections, HIV-1, HeLa Cells, Humans, Immunoprecipitation, Intercellular Signaling Peptides and Proteins, Killer Cells, Natural, Molecular Sequence Data, NK Cell Lectin-Like Receptor Subfamily K, Proteasome Endopeptidase Complex, Sequence Homology, Amino Acid, Virus Replication, vpr Gene Products, Human Immunodeficiency Virus
J. Virol.
Date: Dec. 01, 2011
PubMed ID: 21957298
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