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Title: Mathematical modelling of the host-virus interaction in chronic HTLV-I infection and its impact on our understanding of viral persistence and pathogenesis
Author: Lim, Aaron Guanliang
ISNI:       0000 0004 6346 4363
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Human T-cell lymphotropic virus type I (HTLV-I) is a persistent human retrovirus characterised by life-long infection and risk of developing one of two major, clinically independent diseases: adult T-cell leukaemia/lymphoma (ATL), an aggressive blood cancer, and HAM/TSP, a progressive neurological and inflammatory disease. Infected individuals typically mount a large, chronically activated CD8+ cytotoxic T-lymphocyte (CTL) response against HTLV-I-infected cells, but ultimately fail to effectively eliminate the virus. Moreover, the identification of determinants to disease manifestation has thus far been elusive. A central issue in current HTLV-I research is how the virus is able to persist despite strong immune pressure. To explore this issue, we adopt a mathematical modelling approach. Mathematical modelling can help us break apart the complex mechanisms of HTLV-I persistence and identify the underlying principles that govern successful viral propagation in the presence of host immunity. Understanding these interactions is a crucial step on the road to developing effective ways to disrupt the virus life-cycle and may help identify promising new treatment strategies to reduce the severity of HTLV-I infection and minimise the detriment due to associated disease. The objective of this thesis is to develop a consistent theoretical framework that can help shed light on specific, biologically relevant questions that are of interest to experimentalists and theoretical immunologists trying to understand the complicated host-pathogen dynamics of chronic infection by HTLV-I. In this thesis, we construct a series of mathematical models, each incorporating an increasing level of immunological detail, designed to explore the impact of three biologically significant features that have not been fully considered in previous mathematical models of HTLV-I: (I) the trade-off between proviral latency and activation, (II) the simultaneous expression of viral proteins, and (III) the role of antigenic variability. The results from investigation of these features in the various models help contribute to our understanding of the dynamics of persistent HTLV-I infection alongside virus-specific host immunity. Although our approach is primarily theoretical in nature, our research is principally driven by a desire to elucidate biologically and clinically relevant phenomena observed in HTLV-I and, for each of the models, we link our results to what is known from experimental observations and discuss their significance in a biologically meaningful context.
Supervisor: Maini, Philip K. ; Gupta, Sunetra Sponsor: Natural Sciences and Engineering Research Council of Canada ; Alberta Heritage Scholarship Fund ; Canadian Centennial Scholarship Fund ; Vice-Chancellors' Fund
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available