Reske, A.; (2009) The innate immune response to HSV-1: glycoprotein mediated activation of dendritic cells. Doctoral thesis , UCL (University College London).

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Abstract

Herpes Simplex Virus (HSV) – 1 also known as Human Herpes Virus (HHV) – 1 is a common infectious agent of humans which can cause a wide variety of clinical outcomes, ranging from mild mucocutaneous lesions to long term morbidity and possible mortality. Viral entry into cells requires the co-ordinated action of at least four HSV-1 envelope glycoproteins: gB, gD and the heterodimer gHgL. Dendritic cells (DC) are the most potent antigen presenting cells and are likely to encounter the virus early after entry into the host. HSV-1 readily infects DC leading to a series of both morphological and functional changes, and yet the pathway induced by HSV-1 that leads to DC maturation has not been elucidated. This thesis aims to understand the role of the viral entry glycoproteins in the activation of DC and the consequent initiation of an immune response. Defining this role has important implications not only in understanding immunopathogenesis, but also in the study of HSV-1 as an immunotherapeutic vector, and in the design of an efficient HSV-1 vaccine. Monocyte-derived DCs (MDDC) were found to recognise and respond to the complex of four essential viral glycoproteins, independent of other viral proteins or nucleic acids. MDDC recognition of these four glycoproteins leads to the upregulation of a maturation phenotype and the production of type I interferon (IFN) as well as the induction of a strongly polarised TH1, IFN-γ dominated allogeneic T cell response. In contrast, monocyte-derived Langerhans cells (MDLC), display only partial maturation phenotype and do not produce type I IFN. Plasmacytoid DC (pDC) induce a strong type I IFN response to a viral infection, but not to the viral surface glycoproteins. In the context of natural HSV-1 infection, these results suggest a model in which at the site of HSV-1 infection, different DC sub-populations respond differently to a viral infection and to glycoproteins expressed on the surface of infected cells in order to provide an effective immune response.

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