Role of lncRNAs in cell activation, actin remodeling and HIV latency in CD4 T lymphocytes

lncRNA在CD4 T淋巴细胞的细胞激活、肌动蛋白重塑和HIV潜伏期中的作用

• 批准号: 508136175
• 负责人: Professor Dr. Oliver T. Fackler, Ph.D.
• 金额: --
• 依托单位: Sektion Integrative Virologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/508136175?language=en
• 关键词: Role; lncRNAs; cell; activation; actin

Therapeutic reversal of HIV latency (i.e. transcriptional silence) and elimination of the latent reservoir is the final frontier towards a cure of HIV infection. However, current “shock-and kill” or “shock-and-lock” strategies unfortunately fail in clinical settings as they do not reach all anatomical sites of the reservoir and not all proviral HIV genome copies are sensitive to transcriptional activation by current regimens. Since the underlying mechanisms of this insensitivity to latency reversal are unknown, the inability to design effective therapeutic options that control HIV expression reflects gaps in our understanding of how HIV gene expression and viral latency are regulated. The understanding of how Pol II, the host transcription machinery and epigenetic modifications regulate steps of HIV gene expression is as advanced as that for cellular genes. However, the emerging role of lncRNAs as regulators of cellular gene expression has not yet been carefully studied in the context of T cell activation and HIV gene expression, and may be the key gap to a comprehensive understanding of steps that establish viral latency. Our preliminary results suggest that Cytor (lincRNA00152) is a novel activator of HIV gene expression that suppresses viral latency establishment and facilitates latency reversal as well as actin dynamics in CD4 T cells lines. Building on these findings, we now aim at (i) dissecting the mechanisms by which Cytor regulates HIV gene activation and host cell actin dynamics, (ii) exploring potential mechanistic links between these activities and (iii) defining the physiological relevance of Cytor functions in primary cells including cells from HIV patients. In the long-term these efforts aim at achieving a comprehensive understanding of the role of cellular lncRNAs in CD4 T cell activation as well as HIV gene expression and latency establishment and at evaluating host cell lncRNAs as therapeutic target in latency reversal approaches.

治疗逆转HIV潜伏期（即转录沉默）和消除潜伏库是治愈HIV感染的最后前沿。然而，目前的“休克和杀死”或“休克和锁定”策略不幸地在临床环境中失败，因为它们不能到达储库的所有解剖学位点，并且不是所有前病毒HIV基因组拷贝都对当前方案的转录激活敏感。由于这种对潜伏期逆转不敏感的潜在机制尚不清楚，因此无法设计控制HIV表达的有效治疗方案反映了我们对HIV基因表达和病毒潜伏期如何调节的理解存在差距。对Pol II、宿主转录机制和表观遗传修饰如何调节HIV基因表达步骤的理解与对细胞基因的理解一样先进。然而，lncRNA作为细胞基因表达调节因子的新兴作用尚未在T细胞活化和HIV基因表达的背景下仔细研究，并且可能是全面理解建立病毒潜伏期的步骤的关键差距。我们的初步结果表明，Cytor（lincRNA00152）是HIV基因表达的一种新型激活剂，可抑制病毒潜伏期建立并促进CD 4 T细胞系中的潜伏期逆转以及肌动蛋白动力学。在这些发现的基础上，我们现在的目标是（i）解剖Cytor调节HIV基因激活和宿主细胞肌动蛋白动力学的机制，（ii）探索这些活动之间的潜在机制联系，（iii）定义原代细胞（包括HIV患者细胞）中Cytor功能的生理相关性。从长远来看，这些努力旨在全面了解细胞lncRNA在CD4 T细胞活化以及HIV基因表达和潜伏期建立中的作用，并评估宿主细胞lncRNA作为潜伏期逆转方法中的治疗靶点。