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Vaccinia virus requires heat-shock proteins for genome replication and virion assembly

Mok, Harriet G. W.; (2019) Vaccinia virus requires heat-shock proteins for genome replication and virion assembly. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The large double-stranded DNA virus, vaccinia virus (VACV), is closely related to variola virus, the causative agent of smallpox. While the poxvirus lifecycle has been studied for over 50 years, much is still unknown about the complex multi-step process of genome uncoating. Viral and cellular factors involved in poxvirus uncoating have been identified, including host cell proteasomes, ubiquitin, and heat-shock proteins (HSPs), which play a critical role in protein folding and the prevention of protein aggregation. Although HSPs have been linked to the lifecycle of many viruses including VACV, the role of these proteins in poxvirus infection has not been defined. Using various small compound inhibitors and RNAi, in combination with a battery of virus-specific assays, I show that heat-shock proteins are required for multiple stages of the VACV lifecycle. I demonstrate that Hsp90 is required for two stages of infection: release of the genome from the viral core and assembly of new virions. Following the finding that HSF1, the transcription factor for inducible HSPs, is required for infection, I also identify the Hsp105 as the inducible HSP required for post-replication formation of nascent virions. Given the clinical relevance of HSP inhibitors these results highlight HSPs as potential anti-poxviral drug targets. Collectively, through this work I define new cell factors required for poxvirus infection and demonstrate that subjugation of cellular HSPs during the poxvirus lifecycle is far more complex than previously appreciated.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Vaccinia virus requires heat-shock proteins for genome replication and virion assembly
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. 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
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 Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10085832
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