Munis, Altar Mert;
(2018)
Envelope glycoproteins of vesiculoviruses: characteristics of antibody interactions and immunogenicity.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Vesicular stomatitis virus Indiana strain is the prototype envelope glycoprotein for the genus Vesiculovirus. While the wild-type virus, VSVind, has developed into a potent and versatile oncolytic virotherapy and vaccine vector delivery platform, the G protein (VSVind.G) is ubiquitously used to pseudotype lentiviral vectors (LVs) for experimental and clinical applications. Recently, G proteins derived from other vesiculoviruses (VesG), for example, Cocal, Piry, and Chandipura viruses have been proposed as alternative LV envelopes with possible advantages compared to VSVind.G. However, vesiculovirus research has not developed extensively, and there is a gap in knowledge regarding the antigenic and immunogenic characteristic of VesG. In this work, I investigated two anti-VSVind.G monoclonal antibodies for their ability to cross-react with other VesG, identified the epitopes they recognise, and explored the mechanisms behind their neutralisation activity. Furthermore, these G proteins were characterised for their sensitivity to inactivation by fresh mammalian sera. Using some mix-and-match constructs, I identified that the hypervariable PH domain of VSVind.G confers sensitivity to otherwise serum resistant Cocal G. I further examined VesG regarding their immunogenicity, explored the humoral immune response triggered by systemic administration of LVs and investigated the inhibitory effects of the induced anti-G neutralising response on subsequent LV administrations. However, this could be alleviated using a heterogeneous panel of envelopes sequentially. Taken together, this work will broaden the use of VesG pseudotyped lentiviral vectors in clinical gene therapy by providing the proof-of-concept to circumvent anti-envelope immunity where repeated systemic vector administration is necessary and the opportunity to modify the VesG and improve G protein-containing advanced therapy medicinal products and vaccine vectors.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Envelope glycoproteins of vesiculoviruses: characteristics of antibody interactions and immunogenicity |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2018. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10060753 |
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