Down-regulation of MHC class I by papillomavirus E5 proteins

Araibi, El Hadi Saad Mohamed (2006) Down-regulation of MHC class I by papillomavirus E5 proteins. PhD thesis, University of Glasgow.

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Abstract

Like many viruses, papillomaviruses are totally dependent upon host biosynthetic machinery for replicating their genomes and establishing infection. These processes are associated with the production of antigenic proteins that make the virus vulnerable to immune surveillance which ultimately results in elimination of viral infection. However, papillomaviruses have developed mechanisms to escape the cellular immune recognition of the virally-infected cells by encoding proteins that interfere with antigen presentation to immune cells. Papillomavirus E5 are small oncoproteins of 42 to 83 amino acids in BPV-4 and HPV-16 respectively, expressed at low levels mainly in the deep layers of infected epithelia and down-regulate the expression and transport to the cell surface of the major histocompatibility complex class I (MHC I). The BPV-4 E5 protein inhibits transcription of heavy chain, retains MHC class I in the Golgi apparatus and prevents its transport to the cell surface. In this study, we investigated expression of MHC class I in natural infection by BPV-4. We determined that MHC I is not expressed in cells expressing BPV-4E5. We also determined that expression of BPV-4E5 is accompanied by expression of the proliferation marker (Ki67) also in the differentiated cells of upper layers of papillomas. Down-regulation of MHC class I in papilloma cells expressing E5 would allow escaping recognition by cytotoxic T lymphocytes (CTL). Cells lacking MHC I are subjected to NK cells attack, which recognise and destroy cells lacking surface expression of MHC I unless non classical MHC class I molecules are presented on the cell surface. Because of the impossibility to investigate expression of non classical MHC class I in cells expressing classical MHC class I due to the absence of appropriate antibodies, we investigated the effect of BPV-4E5 on expression of bovine classical (N*01301)or non classical (N*50001) MHC class I in transfected mouse mastocytoma cells. We determined that E5 does not retain N*50001 MHC class I complex in the Golgi, and does not inhibit the transport of the complex to the cell surface. We also determined that E5 induces degradation of N*01301 heavy chain but does not affect the stability of N*50001 heavy chain. We also determined that retention of MHC class I in the Golgi and thus prevention of its transport to the cell surface requires the C-terminus domain of E5. We also investigated the relationship between HPV-16E5 and HLA class I. HPV-16E5 down-regulates surface expression of HLA-A, but not of HLA-C/E. Because of a lack of antibodies capable of distinguishing C and E, we introduced either HLA-A2 or HLA-E cDNA in mouse mastocytoma cells expressing HPV-16E5. We confirmed that HPV-16E5 down-regulates HLA-A2 by retaining it in the Golgi and inhibits its transport to the cell surface but it does not affect HLA-E. We extended our observations to investigate the effect of HPV-16E5 on expression of MHC class I in cervical intraepithelial neoplasia grade I (CIN I). We determined that in some CIN cells, expression of E5 and HLA class I was incompatible, while in other cases E5 and HLA class I were co-expressed. Expression of E5 in some cells was accompanied by expression of Ki67. We also determined that down-regulation of HLA class I by E5 is independent of expression of HPV-16E7 in raft cultures of HaCaT cells expressing HPV-16E5 only. E5 does not affect expression of HLA-E. Therefore down-regulation of classical MHC class I by PVE5 proteins on the surface of infected cells would allow escaping recognition by CTL while, undisturbed expression of non-classical MHC I on the cell surface would escape destruction by NK cells. It remains to be determined if E5 expressing cells do avoid being killed by both CTL and NK cells.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Colleges/Schools: College of Medical Veterinary and Life Sciences
Supervisor's Name: Campo, Prof. Saveria
Date of Award: 2006
Depositing User: Mrs Monika Milewska-Fiertek
Unique ID: glathesis:2006-30960
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 26 Oct 2018 09:16
Last Modified: 26 Oct 2018 09:16
URI: http://theses.gla.ac.uk/id/eprint/30960
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