Modulating the immune response to control virus infection

Cwyfan Hughes, Nia 2024. Modulating the immune response to control virus infection. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Human Cytomegalovirus (HCMV) is the most common viral cause of congenital malformation. Antivirals exist, but have issues regarding toxicity, resistance and/or efficacy. The development of novel therapeutics is paramount. One therapeutic avenue is small molecule inhibitors (SMIs) targeting key viral proteins, inhibiting the ability of the virus to grow or evade the immune response. Utilising a novel computational screening workflow I identified 6 interfaces and 5 pockets across 3 proteins that a SMI could target. A computational screen identified compounds that could interact with these pockets, I refined the hit-lists by ranking interactions and compound structures, and a visual screen. The top 8-10 compounds for each pocket (44 total) were assessed in vitro, identifying 20 that impacted target protein function in isolation and/or in the context viral infection. 18 of these compounds underwent a computational analogue study. This validated the computational workflow and identifies 20 SMIs that could be developed into antiHCMV inhibitors. The SMI pipeline depends on identifying therapeutic targets. The function of most HCMV proteins has been identified in fibroblasts, but the virus also infects dendritic cells (DCs) in vivo. The laboratory previously identified viral proteins that have important effects in DCs. To determine whether these could be future therapeutic targets I examined the impact of ICOSL modulation on the ability of DCs to stimulate T-cells. Activation was measured via proliferation (CD4+) and CD107a expression (CD8+). I developed a model where CD4+ T-cells were dependent upon DC presence, and found that HCMV inhibits CD4+ T-cell proliferation, and that this was partially dependent on ICOSL modulation. I also examined the impact of ICOSL modulation on CD8+ T-cell activation. Overall, this identifies novel candidate SMIs, and has identified a viral function which can be used as the basis design of future therapeutics in multiple cell types.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	4 April 2025
Last Modified:	04 Apr 2025 14:28
URI:	https://orca.cardiff.ac.uk/id/eprint/177389

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