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Characterising the intra-host spread of clinical human cytomegalovirus

Kerr, Lauren 2021. Characterising the intra-host spread of clinical human cytomegalovirus. PhD Thesis, Cardiff University.
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In vivo, Human Cytomegalovirus (HCMV) spreads predominantly via direct cell-cell contact, as do recent clinical isolates. In vitro, HCMV mutants are selected that produce higher levels of cell-free infectivity. Hence, laboratory strains predominantly spread via cell-free virions, and cell-cell spread has been less well characterised. The Merlin strain accurately recapitulates this mode of spread, enabling us to characterise it in more detail. I found that cell-cell transfer is equivalent to an extremely high MOI infection, potentially providing an explanation for the ‘immune-evasive’ properties of this method of viral infection. Furthermore, infectious virions accumulated at cell-cell contacts between cells – potentially forming a virological synapse that protect virions from neutralising antibodies. As HCMV is able to superinfect individuals and recombine within the host, we investigated whether the higher number of genomes delivered by cell-cell spread affected recombination rates. However recombination was barely detectable following co-infection, even by the cell-cell route. The interactions between HCMV and primary immature dendritic cells (DCs) were able to be explored as the Merlin strain enables efficient cell-cell infection of DCs with a virus expressing the full repertoire of viral genes. Proteomic analysis of DCs infected via the cell-cell route revealed modulation of proteins involved in the antiviral immune response, therefore providing novel insight into how HCMV manipulates the immune response to infection. Finally, we also discovered that DCs mount two distinct responses to interfere with the Merlin strain’s ability to undergo a full lytic cycle. One leading to caspasemediated death, and a second which halted the replication cycle at the stage of genome replication. These may represent previously unrecognised routes that the host uses to limit virus spread.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 12 January 2022
Last Modified: 12 Jan 2022 12:42

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