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Title: Dissecting the initial events of human cytomegalovirus cell entry
Author: Murray, Matthew James
ISNI:       0000 0004 8499 9754
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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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.
Supervisor: Reeves, M. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available