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Title: Characterisation of the induction of autophagy by hepatitis C virus
Author: Mohl, Bjorn-Patrick
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2012
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Hepatitis C virus (HCV) is a major public health burden. It is thought to currently infect 2-3% of the world population. Treatment options are limited, a situation which is compounded by the abandonment of regimens due to adverse effects as a resuit of the treatment. Furthermore there are genotype dependent outcomes, some genotypes responding better than others. Consequently, a better understanding of virus-host interactions and the virus life-cycle may provide new insights for developing new treatment strategies. HCV induces autophagy. Autophagy ('self-eating') is a homeostatic process in eukaryotic cells in which regions of cytoplasm, damaged or redundant organelles, insoluble protein aggregates, or invading pathogens are engulfed and sequestered by a double membrane. These double membranes form vesicles and are termed autophagosomes. Autophagosomes then fuse with lysosomes to degrade their contents. The replicative success of HCV and the establishment of an infection has been shown to be dependent upon this cellular process. It has been suggested that HCVinduced endoplasmic reticulum (ER)-stress is the induction mechanism. To understand in more detail the mechanisms that HCV might employ to mediate this crucial process, experiments were conducted with infectious virus and subgenomic repliains to elucidate these processes. During the course of these experiments it was found that Hut' could mediate the induction of autophagy in the absence of ER-stress. ER-stress was mediated by the viral glycoproteins, but their absence did not impede autophagy induction. Furthermore, the viral replicase alone was necessary and sufficient for the induction of autophagy. Autophagosomes and viral replication complexes were found not to colocalize. Furthermore, non-replicative, exogenous viral RNA was found to be a potent inducer of autophagy. A number of pathways leading to autophagy were investigated in order to determine how HCV might induce this process. The host cellular signalling pathways mediated by 5'-AMP-activated protein kinase (AMPK) and class I Ptdlns3K-protein kinase B (AKT), modulated by HCV, were found not to play a role in HCV-mediated autophagy induction. The role of B-cell leukaemia/lymphoma 2 (Bcl-2) in HCV-mediated autophagy remained inconclusive, whilst GTPase Rab5 interference did not prevent ongoing HCV-mediated autophagy. With the importance of autophagy to HCV noted, it was attempted to develop a compound screening assay for autophagy inhibition in collaboration with our industrial partners GlaxoSmithKline. Presented here is the work carried out to understand HCV-mediated autophagy induction along with the insights gained during this study.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available