Controlling HIV latency by manipulating CycT1 turnover

摘要 与混合感染和艾滋病相关癌症相关的免疫功能障碍常见于 感染艾滋病毒的人。特别是，免疫系统中的基因表达程序通常是 在这些个体中有异常的调节。我们和其他组织最近发现， 正转录因子b(P-TEFb)，一种生产延伸所需的关键细胞因子 转录，在静止和异常的T细胞中被严重下调。在静息的CD4+T细胞中， 代表主要潜伏的HIV宿主，P-TEFb的细胞周期蛋白T1(CycT1)亚单位的表达为 通过目前未知的机制导致转录后减少，这是艾滋病毒的一个主要原因 肿瘤特异性T细胞对检查点抑制剂和/或CAR-T细胞的潜伏期和缺陷反应 治疗。由于增加CycT1是最佳HIV重新激活的先决条件和强制性步骤 和对其他病原体和肿瘤细胞的适当免疫反应，了解 CycT1下调的机制至关重要。我们最近证明了P-TEFb 由磷酸化调控的组装决定了CycT1的稳定性。此外，我们已经确认了所有 参与CycT1降解的关键分子，包括E3连接酶。因此，我们假设 通过操纵细胞通路增加静息和异常CD4+T细胞中的CycT1蛋白 调节P-TEFb组装将逆转HIV潜伏期并改善HIV感染者的免疫功能 个人。在这项拟议的研究中，我们将操纵调节P-TEFb的细胞通路 组装和CycT1稳定性，以控制HIV潜伏期和改善免疫功能。我们还将 确定以前未表征的“CycT1-降解复合体”，它们将作为新的 治疗靶点。拟议研究的成功完成将产生T细胞的新概念 由主要转录调节因子的蛋白质水平调节的调节。

Abstract Immune dysfunction associated with co-infection and AIDS-related cancers is commonly observed in HIV-infected individuals. In particular, gene expression programs in the immune system are often abnormally regulated in these individuals. We and other groups have recently discovered that the positive transcription factor b (P-TEFb), a critical cellular factor required for productive elongation of transcription, is severely down-regulated in quiescent and aberrant T cells. In resting CD4+ T cells, representing major latent HIV reservoirs, the expression of the cyclin T1 (CycT1) subunit of P-TEFb is diminished post-transcriptionally via currently unknown mechanisms, this being a main cause of HIV latency and tumor-specific T cells' defective response to check-point inhibitors and/or CAR-T cell therapies. Since increasing CycT1 is a prerequisite and mandatory step for optimal HIV reactivation and proper immune response against other pathogens and tumor cells, understanding the mechanism of CycT1 down-regulation is crucial. We have recently demonstrated that P-TEFb assembly regulated by phosphorylation determines the stability of CycT1. Also, we have identified all key players, including E3 ligases, involved in CycT1-degradation. Therefore, we hypothesize that increasing CycT1 proteins in resting and aberrant CD4+ T cells by manipulating cellular pathways to regulate P-TEFb assembly will reverse HIV latency and improve immune functions in HIV-infected individuals. In the proposed study, we will manipulate the cellular pathways regulating P-TEFb assembly and CycT1 stability to control HIV latency and improve immune functions. We will also identify previously uncharacterized "CycT1-degradation complexes", which will serve as new therapeutic targets. Successful completion of the proposed study will result in a new concept of T cell regulation modulated by the protein level of a master transcriptional regulator.