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Structural and functional insights into species D adenovirus receptor usage: Implications for oncolytic virotherapy

Baker, Alexander 2019. Structural and functional insights into species D adenovirus receptor usage: Implications for oncolytic virotherapy. PhD Thesis, Cardiff University.
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Abstract

Adenoviruses are a diverse virus family, infecting a range of animal hosts. The human adenoviruses comprise over 100 types, divided into seven species, A-G. Adenoviruses are clinically important as both engineered therapeutic vectors and pathogens. Adenoviruses are non-membrane bound viruses with double stranded DNA genomes, making them amenable to genetic manipulation and manufacturing at scale. This makes them attractive candidates as therapeutic vectors, currently under development as gene therapy vectors, viral vaccines, and oncolytic viruses. Adenovirus based vectors are in clinical trials for the prevention and treatment of diseases as diverse as Ebola infection and cancer, but are hindered by pre-existing antiviral immunity, leading to neutralisation of the virotherapy before it can have its therapeutic effects, and off-target tissue infections resulting in reduced delivery of therapeutic vector to the site of need. Many natural adenovirus infections do not require medical intervention as they are easily neutralised by the hosts immune system, though they can result in serious disease. Predominantly, this is a concern for immunocompromised patients. However, some types can cause symptoms including gastroenteritis, epidemic keratoconjunctivitis (EKC), and potentially fatal acute respiratory distress syndrome, in healthy adults. Species D adenoviruses are especially diverse, accounting for more than 50% of total adenovirus diversity and many instances of disease, including outbreaks of EKC. They can also be attractive as a basis for therapeutic viruses due to low rates of seroprevelance in the population and favourable immunogenicity profiles. However, little is known about most members of this species or the mechanisms which can make them either pathogenic or therapeutically useful. The work presented herein seeks to better understand how species D adenoviruses infect cells. We therefore investigate their fiber proteins, which mediate primary cell surface receptor binding. We identify previously unknown adenovirus receptor interactions and examine these results in the context of developing new therapeutic adenovirus vectors.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Related URLs:
Last Modified: 11 Nov 2019 10:48
URI: http://orca-mwe.cf.ac.uk/id/eprint/126681

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