Linking the HTLV-1 pre-integration complex to the chromatin

将 HTLV-1 预整合复合物连接至染色质

• 批准号: MR/Y002083/1
• 负责人: Goedele Maertens
• 金额: $ 125.34万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY002083%2F1
• 关键词: Linking; HTLV; pre; integration; complex

Human immunodeficiency virus type 1 (HIV-1) and human T-cell lymphotropic virus type 1 (HTLV-1) are the most notorious retroviruses since they are the cause of severe, disabling and sometimes fatal diseases. Ten to 20 million people worldwide are infected with HTLV-1. Of these individuals, about 10% will become ill. The most severe HTLV-1 induced diseases are adult T-cell leukaemia (ATL) and the neurological disorder HTLV-induced myelopathy/tropical spastic paraparesis (HAM/TSP). So far, treatment of HTLV-1 infected patients was proven to be very inefficient. Patients diagnosed with ATL, typically die within two years of presentation. HTLV-1, like other retroviruses, are RNA viruses that reverse transcribe their RNA genome into DNA. A critical step in the lifecycle of retroviruses is the integration (or insertion) of this DNA copy into the host genome. This reaction is facilitated by the viral enzyme integrase. Where in the host genome the virus will integrate its DNA copy is not random and we know that integration in certain areas of the genome likely predispose the patients to disease. Our aim is to understand the mechanism of how the integration machinery choses where it will insert the viral DNA. We have identified an important host protein complex, protein phosphatase 2A (PP2A), that specifically binds to HTLV-1 integrase and strongly stimulates integrase activity. We have also shown that when we use viruses mutated to lose its interaction with PP2A, infection is severely inhibited. PP2A does not bind DNA but has a wide range of substrates and binding partners that are associated with the human DNA. We hypothesize that the intasome uses PP2A as a bridging factor to bring the integration machinery to its site of integration, i.e. places in the genome that are enriched for substrates of PP2A. We have recently identified a complex of chromatin-associated proteins that modulate chromatin compaction, influence gene expression and organisation of the cellular chromatin which (indirectly) associates with HTLV-1 integrase. We have shown that the structural integrity of the complex is essential to establish HTLV-1 infection. Here we aim to dissect which components are critical for HTLV-1 infection and integration and characterise the mechanism by which this chromatin-associated complex influences HTLV-1 infection. We also aim to solve the 3D structure of the integration machinery in complex with these host proteins.Understanding this process will not only increase our understanding in HTLV-1 biology and possible chance of disease progression but will also propel cancer research forward since both PP2A and this chromatin complex are involved in a wide range of human diseases. Finally, identifying the mechanism by which HTLV-1 establishes infection, and structurally characterising the players involved in this process will also aid in the design and development of drugs that can specifically prevent the interaction between integrase and its host.

人类免疫缺陷病毒 1 型 (HIV-1) 和人类 T 细胞嗜淋巴细胞病毒 1 型 (HTLV-1) 是最臭名昭著的逆转录病毒，因为它们是严重、致残甚至致命疾病的原因。全世界有 10 到 2000 万人感染 HTLV-1。在这些人中，大约 10% 会生病。最严重的 HTLV-1 诱发疾病是成人 T 细胞白血病 (ATL) 和神经系统疾病 HTLV 诱发的脊髓病/热带痉挛性截瘫 (HAM/TSP)。迄今为止，HTLV-1感染患者的治疗被证明是非常低效的。诊断患有 ATL 的患者通常会在发病后两年内死亡。 HTLV-1 与其他逆转录病毒一样，都是 RNA 病毒，可将 RNA 基因组反转录为 DNA。逆转录病毒生命周期中的一个关键步骤是将该 DNA 拷贝整合（或插入）到宿主基因组中。该反应由病毒酶整合酶促进。病毒将其 DNA 副本整合到宿主基因组中的位置并不是随机的，我们知道，在基因组的某些区域进行整合可能会使患者容易患病。我们的目的是了解整合机制如何选择插入病毒 DNA 的位置的机制。我们已经鉴定出一种重要的宿主蛋白复合物，即蛋白磷酸酶 2A (PP2A)，它特异性结合 HTLV-1 整合酶并强烈刺激整合酶活性。我们还表明，当我们使用突变后失去与 PP2A 相互作用的病毒时，感染会受到严重抑制。 PP2A 不结合 DNA，但具有多种与人类 DNA 相关的底物和结合伴侣。我们假设整合体使用 PP2A 作为桥接因子将整合机制带到其整合位点，即基因组中富含 PP2A 底物的位置。我们最近发现了一种染色质相关蛋白复合物，可调节染色质压缩、影响基因表达和细胞染色质的组织，而细胞染色质与 HTLV-1 整合酶（间接）相关。我们已经证明复合物的结构完整性对于建立 HTLV-1 感染至关重要。在这里，我们的目标是剖析哪些成分对于 HTLV-1 感染和整合至关重要，并描述这种染色质相关复合物影响 HTLV-1 感染的机制。我们还旨在解决与这些宿主蛋白复合的整合机制的 3D 结构。了解这一过程不仅将增加我们对 HTLV-1 生物学和疾病进展可能机会的理解，而且还将推动癌症研究的发展，因为 PP2A 和这种染色质复合物与多种人类疾病有关。最后，确定 HTLV-1 建立感染的机制，并对参与这一过程的参与者进行结构表征，也将有助于设计和开发能够特异性阻止整合酶与其宿主之间相互作用的药物。