Ward Jeffrey, Davis Zachary, DeHart Jason, Zimmerman Erik, Bosque Alberto, Brunetta Enrico, Mavilio Domenico, Planelles Vicente, Barker Edward
Department of Microbiology and Immunology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.
PLoS Pathog. 2009 Oct;5(10):e1000613. doi: 10.1371/journal.ppat.1000613. Epub 2009 Oct 2.
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.
自然杀伤（NK）细胞受到病毒感染细胞上配体的刺激。我们最近证明，NK细胞对人类免疫缺陷病毒1型（HIV-1）感染的自体T细胞有反应，部分原因是通过识别感染细胞表面NK细胞活化受体NKG2D的配体。未感染的原代CD4⁺ T细胞母细胞即使有表达，也很少表达NKG2D配体。在本研究中，我们确定了HIV-1感染细胞上诱导NKG2D配体的机制。我们的研究表明，在HIV-1感染的情况下，Vpr的表达对于引发NKG2D配体的表达是必要且充分的。Vpr特异性诱导独特长16结合蛋白（ULBP）-1和ULBP-2的表面表达，但不诱导ULBP-3、MHC I类相关链分子（MIC）-A或MIC-B的表达。在这些研究中，我们还证明Vpr增加了原代CD4⁺ T细胞母细胞中ULBP-1和ULBP-2 mRNA的水平。HIV-1感染细胞上ULBP-1和ULBP-2的存在取决于Vpr与一种称为Cullin 4a（Cul4a）/损伤DNA结合蛋白1（DDB1）和Cul4a相关因子-1（DCAF-1）E3泛素连接酶（Cul4a（DCAF-1））的蛋白复合物结合的能力。Vpr对ULBP-1和-2的表达也取决于DNA损伤传感器共济失调毛细血管扩张症和rad-3相关激酶（ATR）的激活。当T细胞母细胞感染vpr缺陷型HIV-1时，NK细胞杀伤感染细胞的能力受损。因此，HIV-1 Vpr积极触发NK细胞活化受体配体的表达。
