Defining the roles of PP2A B56 isoforms in HTLV-1 infection.

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，因为它们是严重的，致残的，有时是致命的疾病的原因。全世界有1000万到2000万人感染了HTLV-1。在这些人中，约有10%会生病。最严重的HTLV-1诱导的疾病是成人T细胞白血病（ATL）和神经系统疾病HTLV诱导的脊髓病/热带痉挛性下肢轻瘫（HAM/TSP）。到目前为止，HTLV-1感染患者的治疗被证明是非常低效的。被诊断为ATL的患者通常在出现后两年内死亡。HTLV-1与其他逆转录病毒一样，是将其RNA基因组逆转录为DNA的RNA病毒。逆转录病毒生命周期中的关键步骤是将该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。病毒在宿主基因组中整合其DNA拷贝的位置不是随机的，我们知道基因组某些区域的整合可能使患者易于患病。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。我们已经鉴定了一种重要的宿主蛋白复合物，蛋白磷酸酶2A（PP 2A），其特异性结合HTLV-1整合酶并强烈刺激整合酶活性。我们还表明，当我们使用突变的病毒失去与PP 2A的相互作用时，感染被严重抑制。我们现在想了解PP 2A如何调节HTLV-1感染的机制。PP 2A不结合DNA，但具有与人DNA相关的广泛的底物和结合伴侣。我们假设整合体使用PP 2A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PP 2A底物的位置。PP 2A由三个亚基组成;核心由支架和催化亚基组成，可以与四种不同调节亚基中的任何一种结合。HTLV-1整合酶与具有B56型调节亚基的PP 2A特异性结合。细胞中有五种不同的B56亚型。虽然整合酶可以结合所有五个，我们不知道是否都在建立HTLV-1感染中发挥作用。在这项工作中，我们的目标是研究B56亚型如何影响HTLV-1感染，以及它们如何将HTLV-1整合机制带到其整合位点。了解这一过程不仅会增加我们对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向前发展，因为已知PP 2A及其一些底物在肿瘤发生中发挥作用。最后，确定哪些B56亚型有助于HTLV-1感染，哪些不有助于设计和开发可以特异性阻止整合酶与其宿主之间相互作用的药物。

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. We now want to understand the mechanism of how PP2A modulates HTLV-1 infection. 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. PP2A is composed of three subunits; the core is made up of a scaffold and catalytic subunit which can bind to any one type of four different regulatory subunits. HTLV-1 integrase specifically associates with PP2A that has a B56 type of regulatory subunit. There are five different isoforms of B56 in the cell. Although integrase can bind to all five of them, we don't know whether all play a role in establishing HTLV-1 infection. In this work we aim to characterise how each of the B56 isoforms influence HTLV-1 infection and how they bring the HTLV-1 integration machinery to its site of integration. 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 some of its substrates are known to play a role in oncogenesis. Finally, identifying which of the B56 isoforms contribute to HTLV-1 infection and which don't will also aid in the design and development of drugs that can specifically prevent the interaction between integrase and its host.