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Title: The regulation of HTLV-1 integration by a host co-factor
Author: McCallin, Amy Joanna
ISNI:       0000 0004 7657 0915
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Retroviruses must integrate a DNA copy of their genome into host cell chromatin to establish infection. The pre-integration complex of the retroviruses, HIV-1 and murine leukemia virus interact with a host co-factor through their integrase enzyme to preferentially integrate into particular sites of host cell chromatin. This results in a unique pattern of integration site distribution in the host genome for each retroviral genus. HTLV-1, a delta-retrovirus, has a well-defined preferential integration pattern that is important for supporting viral gene expression during chronic infection. So far, a deltaretroviral integrase host co-factor has not yet been identified, however, biochemical evidence suggested that the protein phosphatase 2A (PP2A) complex could fulfil this function. Here, I report the results of a Y2H screen which independently confirms that PP2A B' regulatory subunits interact directly with HTLV-1 IN. Second, I show, using three different experimental approaches, that HTLV-1 integration is redistributed in cells that lack functional PP2A. This is the first evidence that a loss of PP2A activity in live cells leads to an altered integration site preference and strongly suggests that PP2A acts as an HTLV-1 IN co-factor. ShRNA-mediated knockdown of either of the two B' isoforms most highly expressed in Jurkat T cells, B' γ and B' δ, indicates that B' γ mediates the majority of IN co-factor function, since B' γ depletion resulted in the most extensive redistribution of integration sites compared to cells treated with control shRNA. However, it is likely that other PP2A holoenzymes can also act as co-factors for HTLV-1 IN. PP2A is ubiquitously and highly expressed, making it an attractive target for co-factor function. Future analysis of PP2A's co-factor function should aim to use HTLV-1 IN mutants to specifically disrupt the interaction between PP2A and HTLV-1 IN.
Supervisor: Bangham, Charles R. M. Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral