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Title: Viral Factors Controlling HTLV-1 Proviral Load and Proviral Expression
Author: Meekings, Kiran Nicola
ISNI:       0000 0001 3391 646X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2008
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A high level of provirus expression and a high proviral load during persistent Human T Lymphotropic Virus Type 1 (HTLV-1) infection are associated with an increased risk of the inflammatory disease HTLV-1 associated myelopathy (HAMITSP). However, the factors that control HTLV-1 proviral expression and proviral load in vivo are not known. In this study, we investigate the. influences of epigenetics and the distribution of proviral integration sites on the control of these factors. Using inhibitors of histone deacetylases (HDACi) and methyl-transferases (MTi), we determined that acetylation controls proviral expression in vivo but epigenetic differences between individuals do not cause proviral load and disease-risk variation. • By analysing proviral integration sites derived from individuals persistently infected with HTLV-1, we identified that the distribution' of integration sites is associated with the probability of provirus expression and thG risk of HAMITSP. As an independent verification of this observation, analysis of integration sites found in provirus-expressing and provirus-non-expre~sing infected cells wit~in an individual found that provirus expression is associated with integration into genes. By comparing the distribution of integration sites from HTLV-1-infected individuals with a set of integration sites derived from a co-culture system in vitro, we infer that the distribution of integration sites in persistent infection is subject to in vivo selection. We identified positive selection for cells containing proviral integrations within transcriptionally active regions of the genome but negative selection against cells containing proviral integration sites in transcription units (Le. genes) in vivo. An investigation into alternative markers of transcriptional activity identified a previously uncharacterised transcriptionally active region of the HTLV-1 genome. Preliminary identification and characterization of a novel non-coding anti-sense transcript (AST2) was carried out. In summary, we have demonstrated that the cellular epigenetic status and the distribution of proviral integration sites are associated with provirus ex'pression in vivo. The interplay of these factors with previously defined parameters, such as the efficiency of the CTL response, determines an individual's provirus expression, proviral load and consequent disease risk during persistent infection by HTLV-1.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available