PDF(Pubmed)
Abstract：
The aryl hydrocarbon receptor (AhR) regulates Th17-polarized CD4+ T cell functions, but its role in HIV-1 replication/outgrowth remains unknown. Genetic (CRISPR-Cas9) and pharmacological inhibition reveal AhR as a barrier to HIV-1 replication in T cell receptor (TCR)-activated CD4+ T cells in vitro. In single-round vesicular stomatitis virus (VSV)-G-pseudotyped HIV-1 infection, AhR blockade increases the efficacy of early/late reverse transcription and subsequently facilitated integration/translation. Moreover, AhR blockade boosts viral outgrowth in CD4+ T cells of people living with HIV-1 (PLWH) receiving antiretroviral therapy (ART). Finally, RNA sequencing reveals genes/pathways downregulated by AhR blockade in CD4+ T cells of ART-treated PLWH, including HIV-1 interactors and gut-homing molecules with AhR-responsive elements in their promoters. Among them, HIC1, a repressor of Tat-mediated HIV-1 transcription and a tissue-residency master regulator, is identified by chromatin immunoprecipitation as a direct AhR target. Thus, AhR governs a T cell transcriptional program controlling viral replication/outgrowth and tissue residency/recirculation, supporting the use of AhR inhibitors in \"shock and kill\" HIV-1 remission/cure strategies.
摘要：
芳香烃受体（AhR）调节Th17极化的CD4+T细胞功能，但其在HIV-1复制/生长中的作用仍然未知。遗传(CRISPR-Cas9)和药理学抑制揭示AhR在体外作为HIV-1在T细胞受体(TCR)激活的CD4+T细胞中复制的屏障。在单轮水疱性口炎病毒（VSV）-G假型HIV-1感染中，AhR阻断增加早期/晚期逆转录和随后促进整合/翻译的功效。此外，AhR阻断促进接受抗逆转录病毒治疗（ART）的HIV-1（PLWH）感染者的CD4+T细胞中的病毒生长。最后,RNA测序揭示了在ART治疗的PLWH的CD4+T细胞中AhR阻断下调的基因/途径，包括HIV-1相互作用者和在其启动子中具有AhR响应元件的肠归巢分子。其中,HIC1，Tat介导的HIV-1转录的阻遏物和组织驻留主调节因子，通过染色质免疫沉淀鉴定为直接的AhR靶标。因此，AhR管理T细胞转录程序，控制病毒复制/生长和组织驻留/再循环，支持在“休克和杀死”HIV-1缓解/治愈策略中使用AhR抑制剂。
