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，因为它们是导致严重、致残甚至有时致命疾病的原因。全世界有1000万到2000万人感染了HTLV-1。在这些人中，大约有10%会患病。HTLV-1诱导的最严重的疾病是成人t细胞白血病（ATL）和htlv诱导的脊髓病/热带痉挛性截瘫（HAM/TSP）神经系统疾病。到目前为止，对HTLV-1感染患者的治疗被证明是非常低效的。被诊断为ATL的患者通常在两年内死亡。HTLV-1，像其他逆转录病毒一样，是RNA病毒，将其RNA基因组逆转录成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。这个反应是由病毒酶整合酶促进的。病毒会在宿主基因组的哪个位置整合它的DNA拷贝不是随机的我们知道基因组某些区域的整合很可能使病人容易患病。我们的目标是了解整合机制如何选择将病毒DNA插入的位置。我们已经确定了一个重要的宿主蛋白复合物，蛋白磷酸酶2A (PP2A)，它特异性地结合HTLV-1整合酶并强烈刺激整合酶的活性。我们还表明，当我们使用失去与PP2A相互作用的突变病毒时，感染受到严重抑制。PP2A不结合DNA，但具有与人类DNA相关的广泛底物和结合伙伴。我们假设，溶入体使用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，它调节染色质压实，影响基因表达和细胞染色质的组织，（间接）与HTLV-1整合酶相关。我们已经证明复合体的结构完整性对于HTLV-1感染的建立至关重要。在这里，我们的目标是剖析哪些成分对HTLV-1感染和整合至关重要，并描述这种染色质相关复合体影响HTLV-1感染的机制。我们还致力于解决与这些宿主蛋白复杂的整合机制的三维结构。了解这一过程不仅将增加我们对HTLV-1生物学和疾病进展的可能机会的理解，而且还将推动癌症研究向前发展，因为PP2A和这种染色质复合体都与广泛的人类疾病有关。最后，确定HTLV-1建立感染的机制，以及在这一过程中所涉及的参与者的结构特征，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。