Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada.
Virology. 2013 Sep 1;443(2):248-56. doi: 10.1016/j.virol.2013.04.037. Epub 2013 May 31.
HIV-1 Vpr triggers NK cell-mediated lysis of infected cells by upregulating ULBP2, a ligand of the NKG2D receptor, through activation of the ATR-mediated DNA damage response. Herein, we demonstrate that Vpr augments ULBP2 expression on both infected and uninfected bystander cells during HIV-1 infection of primary CD4+ T lymphocytes. Indeed, the frequency of uninfected bystander cells expressing high levels of ULBP2 was elevated in a Vpr-dependent manner. Nevertheless, the same does not hold true for a Vpr mutant that is not packaged into virions, suggesting the involvement of virion-associated Vpr in this process. Additionally, we show that soluble Vpr has the ability to induce a DNA damage response and to augment cell-surface ULBP2 upon transducing target cells, including T cells, conditions known to promote NK cell-mediated killing. Overall, these findings suggest that Vpr could contribute to CD4+ T cell loss by rendering uninfected bystander cells susceptible to NK cell-mediated killing.
HIV-1 Vpr 通过激活 ATR 介导的 DNA 损伤反应，上调 NKG2D 受体配体 ULBP2，从而触发 NK 细胞介导的感染细胞裂解。在此，我们证明在 HIV-1 感染原代 CD4+T 淋巴细胞过程中，Vpr 可增加感染和未感染旁观者细胞上的 ULBP2 表达。事实上，高水平 ULBP2 表达的未感染旁观者细胞的频率以 Vpr 依赖的方式增加。然而，对于不能包装到病毒颗粒中的 Vpr 突变体来说，情况并非如此，这表明病毒颗粒相关的 Vpr 参与了这一过程。此外，我们还表明，可溶性 Vpr 具有诱导 DNA 损伤反应和在转导靶细胞（包括 T 细胞）时增加细胞表面 ULBP2 的能力，这些条件已知可促进 NK 细胞介导的杀伤。总的来说，这些发现表明，Vpr 通过使未感染的旁观者细胞易受 NK 细胞介导的杀伤，可能导致 CD4+T 细胞的丧失。
