Mason, Rebecca;
(2024)
The Role of Alternative Promoters in the Regulation of Human
Cytomegalovirus Immediate Early Gene Expression.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Human cytomegalovirus (HCMV), a member of the herpesvirus family, is a highly prevalent virus that establishes a lifelong latent infection within the host. Following primary infection, HCMV establishes latent infection in CD34+ progenitor cells in the bone marrow. HCMV reactivates in vivo in terminally differentiated myeloid cells, which typically form upon the migration of monocytes to peripheral tissues, whereupon immediate early (IE) gene expression is a crucial determinant of reactivation. The prevailing hypothesis for HCMV has long been that cell-type-specific differential MIEP regulation dictates the switch between latency and reactivation. However, identification of an alternative promoter (termed iP2), which drives IE gene expression and was shown to be inessential to lytic infection, led to the consideration that it may play a role in HCMV reactivation. Consistent with this, deletion of iP2 was reported to produce a reactivation defect in THP1 and CD34+ models of latency. Overall, our data support the pervading view that the MIEP regulates HCMV IE gene expression. As such, our studies of reactivation show that the IE transcriptional phenotype correlates directly with MIEP activity irrespective of conditional iP2-derived transcription and, while iP2-derived UTR70 is expressed in specific contexts, significant quantities of MIEP-derived IE RNA were also detected. The conditional activity of iP2 posed questions regarding the necessity for multiple promoters during HCMV replication. We postulate that HCMV has evolved to be able to undergo rapid reactivation in monocytes during differentiation or inflammation or as a result of physiological stress. From an evolutionary standpoint, it would be beneficial for HCMV to be able to rapidly reactivate, replicate and disseminate – particularly in contexts in which latent monocytes are at potential risk of death.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The Role of Alternative Promoters in the Regulation of Human Cytomegalovirus Immediate Early Gene Expression |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2024. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/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 > 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/10195751 |
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