Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States.
Elife. 2019 Feb 5;8:e41930. doi: 10.7554/eLife.41930.
Many viral pathogens target innate sensing cascades and/or cellular transcription factors to suppress antiviral immune responses. Here, we show that the accessory viral protein U (Vpu) of HIV-1 exerts broad immunosuppressive effects by inhibiting activation of the transcription factor NF-κB. Global transcriptional profiling of infected CD4 +T cells revealed that -deficient HIV-1 strains induce substantially stronger immune responses than the respective wild type viruses. Gene set enrichment analyses and cytokine arrays showed that Vpu suppresses the expression of NF-κB targets including interferons and restriction factors. Mutational analyses demonstrated that this immunosuppressive activity of Vpu is independent of its ability to counteract the restriction factor and innate sensor tetherin. However, Vpu-mediated inhibition of immune activation required an arginine residue in the cytoplasmic domain that is critical for blocking NF-κB signaling downstream of tetherin. In summary, our findings demonstrate that HIV-1 Vpu potently suppresses NF-κB-elicited antiviral immune responses at the transcriptional level.
许多病毒病原体靶向先天感应级联和/或细胞转录因子，以抑制抗病毒免疫反应。在这里，我们表明 HIV-1 的辅助病毒蛋白 U（Vpu）通过抑制转录因子 NF-κB 的激活来发挥广泛的免疫抑制作用。感染的 CD4+T 细胞的全基因组转录谱分析显示，-缺陷的 HIV-1 株比各自的野生型病毒诱导更强的免疫反应。基因集富集分析和细胞因子阵列显示，Vpu 抑制 NF-κB 靶基因的表达，包括干扰素和限制因子。突变分析表明，Vpu 的这种免疫抑制活性与其拮抗限制因子和先天传感器 tetherin 的能力无关。然而，Vpu 介导的免疫激活抑制需要细胞质结构域中的一个精氨酸残基，该残基对于阻断 tetherin 下游的 NF-κB 信号至关重要。总之，我们的研究结果表明，HIV-1 Vpu 在转录水平上强烈抑制 NF-κB 诱导的抗病毒免疫反应。
