Cannon, M.; (2007) A functional analysis of the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor. Doctoral thesis , University of London.

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Abstract

Human herpesvirus-8, or KSHV, was discovered in 1994 and is the causative agent of all forms of Kaposi's sarcoma (KS). It is also associated with two lymphoproliferative disorders: primary effusion lymphoma (PEL) and multicentric Castleman's disease. The KSHV viral chemokine receptor, vGPCR, is a homologue of the IL8 receptors CXCR1 and CXCR2. vGPCR is considered a viral oncogene: it transforms fibroblasts in vitro and enhances growth and longevity of primary endothelial cells. vGPCR signals promiscuously via several heterotrimeric G-protein subtypes and activates the MAP and SAP kinases, the Src family kinases, and PI3 kinase. However, little is known about vGPCR in the context of KSHV-infected haematopoietic cells. In this thesis, a tetracycline-inducible vGPCR-expressing PEL line is used to show that vGPCR causes a G0/G1 arrest in PEL cells via inhibition of Cdk2. This lack of Cdk2 function inhibits the chemically mediated KSHV latent-to- lytic switch. We hypothesize that expression of vGPCR outside of the normal lytic phase could inhibit virion production and resultant cell death this would allow the many vGPCR-induced cytokines to have a more prolonged effect on the tumour microenvironment. These effects would result in enhanced angiogenesis, a hallmark of KS, as well as the recruitment of new infectable KSHV cells. The vGPCR is among the most promising targets for rationally designed anti-KSHV therapy. However, a better understanding of vGPCR signalling events is required. This thesis also examines how vGPCR affects the function of the protein tyrosine phosphatases (PTPs), a family of enzymes that regulates many extracellular signalling events. PTPs are an exciting new potential target in anti-infective and anti-tumour therapeutics. Lastly, we examine the inhibition of TGFp signalling by KSHV in PEL cells. PEL cells secrete TGFp but are resistant to its effects due to downregulation of TGFp Rll. This suggests a KSHV-mediated anti-immune strategy that requires further exploration.

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