Graham-Clarke, Cairistine Naomi Elinor; (2002) The role of herpesviruses in atherosclerosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Atherosclerosis is a series of inflammatory processes within the arterial wall that results in the formation of atherosclerotic plaques, or atheroma. It is the leading cause of death in the Western world and chronic infection is increasingly being cited as a hitherto unconsidered risk factor for the disease. Herpesviruses are one group of potentially pro-atherogenic organisms, and members of the beta- and gamma-herpesvirus families exhibit certain biological properties which make them especially good candidates for being involved in the pathogenesis of atherosclerosis. However sero-epidemiological studies in man have been far from conclusive in demonstrating such a possible link. Animal models have therefore acquired a pivotal role in examining the involvement of herpesviruses in atherogenesis. This thesis addresses the role of herpesvirus infection in atherosclerosis, firstly through the use of two novel animal models, and secondly through two human studies on patients potentially predisposed to atheroma formation - HIV infected and diabetic patients. The Apolipoprotein E-deficient mouse and the C57Bl-diet-induced mouse are models of atherogenesis that have been further developed for this thesis by infection with murine gammaherpesvirus-68 (MHV-68). This has made possible the establishment of a direct aetiological link between herpesvirus infection and accelerated atherogenesis. Further work also explored the underlying mechanisms involved in these models, with enhanced vasoconstriction being strongly implicated. The results from these murine models influenced the approach in the human studies. One study looked at Human herpesvirus-8 (HHV-8), a human virus that is closely related to MHV-68 and that causes the distinctive clinical condition of Kaposi's sarcoma. In a retrospective survey of post-mortem reports on HIV positive individuals, Kaposi's sarcoma was found to be strongly associated with the presence of atheroma. Finally, in a further study in Type 1 diabetic subjects, a potential atherogenic role of human cytomegalovirus (HCMV) was addressed. HCMV infection was found to be strongly and significantly associated with impaired vascular responses (an early marker of atherogenesis); there was also a weaker, non-significant association with coronary artery calcification (a means of quantifying atheroma). This thesis thus summarizes a range of work, both in animal models and in the context of human disease, that has been undertaken in order to explore the role of herpesviruses in the genesis of atherosclerosis.

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