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Title: Down-regulation of MHC class I by human papillomavirus type 16 E5 protein
Author: Haghshenas, Mohammad Reza
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2006
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Like many viruses, papillomaviruses appear to have evolved mechanisms resulting in escape from host immune surveillance and delay of resolution of infection. The E5 protein is expressed early in papillomavirus infection in the deep layers of the infected epithelium. Human papillomavirus type 16 (HPV-16) E5 is a small protein, 83 amino acids long, and has three hydrophobic domains connected by less hydrophobic regions. It is located mainly at the endosomal membranes, Golgi apparatus (GA) and, to a lesser extent, the plasma membrane. The E5 protein of bovine papillomavirus (BPV) impairs the synthesis and stability of major histocompatibility (MHC) class I complex and prevents their transport to the cell surface due to retention in the GA. The results in this thesis demonstrated that HPV-16 E5 wild type down-regulates surface expression of MHC class I, retains MHC class I complexes in the GA and impedes their transport to the cell surface, which is rescued by treatment with interferon. Unlike BPV E5, HPV-16 E5 does not affect the synthesis of MHC class I heavy chains, and the morphology of the GA. HPV-16 E5 physically interacts with MHC heavy chain in the GA and this interaction is associated with the down-regulation of surface MHC class I. Moreover, we determined that HPV-16 E5 down-regulates selectively HLA-A and B but does not inhibit HLA-C and non-classical HLA-E thus potentially escaping both cytotoxic T lymphocyte (CTL) and natural killer (NK) cells. Deletion mutants of HPV-16 E5 lacking each one of the hydrophobic domains were generated to define its functional domains. HaCaT cells expressing either HPV-16 E5 wild type or its mutants were analysed for their ability to down-regulate surface MHC class I and determine the localization in the cells. All deletion mutants were expressed and localised in the GA. The deletion mutants containing the first hydrophobic domain were all able to down-regulate surface MHC class I, to retain the complex in the GA and interact with MHC heavy chain to extent as HPV-16 E5 wild type. Only the deletion mutant which lacks the first hydrophobic domain was unable to down-regulate surface MHC class I, to retain the complex in the GA and to interact with MHC heavy chain. This study demonstrated that the separate domains of HPV-16 E5 did not have the same function. We found that the first hydrophobic domain of HPV-16 E5 is important for down-regulation of surface MHC class I. Lack of surface MHC class I in infected epithelial cells expressing E5 would allow evasion of CTL killing and thus establishment of viral infection. However, MHC class I down-regulation by E5 is selective, as E5 does not down-regulate HLA-C and non-classical HLA-E. It remains to be seen if E5 expressing cells evade CTL killing, through down-regulation of classical MHC I, and NK killing, through lack of down-regulation of non-classical MHC I.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral