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Title: HTLV-1 clonality in natural infection
Author: Melamed, Anat
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Human T-Lymphotropic virus type 1 (HTLV-1) maintains persistent infection in the host by driving expansion of HTLV-1-infected T cells. However, the wide variation observed in clonal abundance in vivo remains unexplained. We hypothesize that the site of proviral integration in the host cell genome determines the rate of expression of HTLV-1 genes such as the viral transactivator Tax, which in turn determine the level of clonal expansion in vivo. Utilising Molecular biology techniques, High-throughput sequencing and computing tools, we have developed a high-throughput method for the amplification, mapping and quantification of proviral integration sites. We have used this technique, in combination with bioinformatics analysis, to identify factors associated with clonal expansion. Using PBMCs sorted for CD4+ and CD8+ T cell subsets, we observed differences in the form of the clonal distribution between the cell types. In addition, using flow-cytometric sorting of Tax expressing CD4+ cells, we identified genomic patterns associated with the presence or absence of spontaneous Tax expression. We have also identified a correlation between the expression of Tax and the size of the infected clones. Finally, we identified genomic factors associated with HTLV-1 integration in vitro, suggesting a possible role of these factors in targeting of the pre-integration complex to particular sites in the host genome. The thesis will detail and discuss the findings from these analyses, as well as their impact on the current knowledge. These results would play a role in improving our understanding of HTLV-1 persistence in the face of a strong immune response, and may provide excellent basis from a population level to test mechanisms of proviral latency in natural infection.
Supervisor: Bangham, Charles Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available