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Dissecting the initial events of human cytomegalovirus cell entry

Murray, Matthew James; (2019) Dissecting the initial events of human cytomegalovirus cell entry. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Human cytomegalovirus (HCMV), a member of the herpesvirus family, is a highly prevalent virus that establishes a lifelong infection within the host. It is associated with severe morbidity in immunocompromised patient groups such as transplant recipients or neonates. Whilst first line treatment is generally successful, therapeutic options are limited and associated with resistance. To identify host factors involved in the virus lifecycle, a screen of ion channel inhibitors was performed to assess their impact on HCMV replication. 4,4,-diisothiocyano-2,2’-stilbenedisulfonic acid (DIDS) was found to be a potent inhibitor of virus replication. Further investigations revealed that DIDS functioned by blocking the ability of HCMV to engage with the cell surface during the earliest steps of its entry pathway, and that DIDS achieved this by directly binding to the virion, likely through a cystine-reactive pathway. Passage of HCMV in the presence of DIDS identified two mutations as putatively being associated with resistance to DIDS; one in glycoprotein M, and another in RL13. Whilst the gM mutation did not confer a benefit to the virus when introduced in isolation, the RL13 mutation did, arguing for a role of the relatively unstudied RL13 protein in viral entry. Analysis of several well-established HCMV strains also identified a mutation in glycoprotein B associated with resistance to DIDS. The consequence of DIDS-resistance was an increased sensitivity to neutralising antibodies, observed in the passaged DIDS-resistant virus. This suggests that a key reason behind the complexity of HCMV entry may be to hide antibody epitopes from the immune system, and thus a greater understanding of how the virus achieves this may inform the development of a key therapeutic goal: a highly effective HCMV vaccine.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Dissecting the initial events of human cytomegalovirus cell entry
Event: UCL
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 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/10079453
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