Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Blood. 2013 May 16;121(20):4090-100. doi: 10.1182/blood-2012-10-461566. Epub 2013 Mar 27.
As a result of its interaction with transcription factors, HIV type 1 (HIV-1) Tat can modulate the expression of both HIV and cellular genes. In antigen-presenting cells Tat induces the expression of a subset of interferon (IFN)-stimulated genes (ISGs) in the absence of IFNs. We investigated the genome-wide Tat association with promoters in immature dendritic cells and in monocyte-derived macrophages. Among others, Tat associated with the MAP2K6, MAP2K3, and IRF7 promoters that are functionally part of IL-1 and p38 mitogen-activated protein kinase (MAPK) signaling pathways. The association correlated with their increased gene expression, increased activation of p38 MAPK and of phosphorylated signal transducer and activator of transcription 1 (STAT1), and consequent induction of ISGs. Probing these pathways with RNA interference, pharmacological p38 MAPK inhibition, and in cell lines lacking STAT1s or the type I IFN receptor chain confirmed the role of MAPKKs and IRF7 in Tat-mediated modulation of ISGs and excluded the involvement of IFNs in this modulation. Tat interaction with the 2 MAPKK and IRF7 promoters in HIV-1-infected cells and the resulting persistent activation of ISGs, which include inflammatory cytokines and chemokines, can contribute to the increased immune activation that characterizes HIV infection.
由于其与转录因子的相互作用，HIV 型 1（HIV-1）Tat 可以调节 HIV 和细胞基因的表达。在抗原呈递细胞中，Tat 在没有 IFNs 的情况下诱导一组干扰素（IFN）刺激基因（ISGs）的表达。我们研究了 HIV-1 在未成熟树突状细胞和单核细胞衍生的巨噬细胞中与启动子的全基因组关联。除此之外，Tat 与 MAP2K6、MAP2K3 和 IRF7 启动子相关，这些启动子在功能上是 IL-1 和 p38 丝裂原活化蛋白激酶（MAPK）信号通路的一部分。这种关联与它们的基因表达增加、p38 MAPK 和磷酸化信号转导和转录激活因子 1（STAT1）的激活增加以及随后的 ISGs 诱导相关。用 RNA 干扰、药理学 p38 MAPK 抑制以及缺乏 STAT1 或 I 型 IFN 受体链的细胞系探测这些途径证实了 MAPKKs 和 IRF7 在 Tat 介导的 ISGs 调节中的作用，并排除了 IFNs 在这种调节中的作用。Tat 与 HIV-1 感染细胞中 2 个 MAPKK 和 IRF7 启动子的相互作用以及由此产生的持续激活的 ISGs，包括炎症细胞因子和趋化因子，可能有助于 HIV 感染特征性的免疫激活增加。
