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

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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.