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Gene delivery to peripheral blood mononuclear cells using herpes simplex virus type 1

Papageorgiou, Konstantina; (2004) Gene delivery to peripheral blood mononuclear cells using herpes simplex virus type 1. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Peripheral Blood Mononuclear Cells (PBMCs), composed mainly of B-lymphocytes, T-lymphocytes and monocytes, are cells vital to the immune system. Many conditions, especially autoimmune diseases, exhibit abnormal behaviour of PBMCs due to the disruption of normal gene expression. We aimed to demonstrate that over-expression of both naturally occurring wild type genes and their inhibitors in PBMCs can alter their behaviour and provide information about the cells' function; as well as providing insights for future therapies and especially gene therapy. Herpes Simplex Virus Type-1 (HSV-I) based viral vectors were used, as vehicles for gene delivery, because HSV-1 is a large double stranded DNA virus that can accommodate large inserts of up to 30kb in size. HSV-1 based viral vectors have also been shown to be relatively benign in respect to cytotoxicity, in most types of cells, and they have the ability to remain in a latent state in non-dividing cells. Furthermore, previously in our laboratory, HSV-1 strain 17+ had been disabled to four different levels providing us with the opportunity to test which virus would strike the perfect balance between effective gene delivery and low cytotoxicity. In this study we have demonstrated that HSV-1 based vectors are suitable for gene delivery to PBMCs, exhibiting relatively high levels of infection in combination with minimal toxicity towards the cells. We have identified the optimal vector for gene delivery to PBMCs in addition to showing that genes delivered to PBMCs are expressed for at least five days after infection. In addition, the genes delivered exhibited active biological function, namely Heat Shock Proteins (hsps) delivered via HSV-1 vectors protected PBMCs from two different types of stress. Finally, we tested HSV-1 vectors for gene delivery to Acute Myeloid Leukaemia (AML) cells and we have demonstrated that gene delivery to these cells is also feasible without exhibiting major cytotoxicity.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Gene delivery to peripheral blood mononuclear cells using herpes simplex virus type 1
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Herpesvirus
URI: https://discovery.ucl.ac.uk/id/eprint/10101380
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