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HLA-mediated control and CD8+ T cell response mechanisms in persistent viral infections

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Title: HLA-mediated control and CD8+ T cell response mechanisms in persistent viral infections
Authors: Seich al Basatena, Nafisa-Katrin
Item Type: Thesis or dissertation
Abstract: Background: There are many viruses that result in persistent infections affecting millions of people worldwide. Although our immune system deploys different strategies to eliminate them, many times they prove unsuccessful and call for a better understanding of the host-virus interplay. One important weapon of the immune system is CD8+ T cells which identify infected cells and limit the spread of infection using different effector mechanisms. Aim: The aim of this study is two-fold; the investigation of 1) the impact of immunogenetic factors such as HLA class I molecules and Killer cell immunoglobulin-like receptors (KIRs) on CD8+ T cell responses and 2) the efficiency of lytic and non-lytic CD8+ T cell responses and how they shape viral escape dynamics. Methods: The methods used to address the aims include statistical models, high-throughput sequence analysis, ordinary differential equation models and agent-based models. Results: We find that HLA class I molecules explain a small percentage of the heterogeneity observed in the outcome of HCV, HTLV-1 and HIV infections. However, we show that an inhibitory KIR, namely KIR2DL2, can enhance both protective and detrimental HLA class I-restricted anti-viral immunity, for both HCV and HTLV-1 infections and in a manner compatible with the modulation of CD8+ T cell downstream responses. Furthermore, for HIV/SIV infection, we show that the CD8+ T cell control of the infection can be consistent with a non-lytic mechanism. Additionally, we find that lytic CD8+ T cell responses are more efficient than non-lytic responses which can lead to slower and less frequent viral escape explained by spatial factors. Conclusions: We conclude that KIRs can play an important role in shaping HLA class-I mediated immunity and suggest that this occurs in synergy with CD8+ T cells whose lytic and non-lytic effector functions can differ in efficiency and lead to variable viral escape rates.
Issue Date: Sep-2012
Date Awarded: Jan-2013
URI: http://hdl.handle.net/10044/1/10753
DOI: https://doi.org/10.25560/10753
Supervisor: Asquith, Becca
Bangham, Charles
Sponsor/Funder: Wellcome Trust (London, England)
Department: Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses



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