Heidari, Farshad (2017) In Vitro modulation of host immune response by the Varicella Zoster Virus ORF1 gene product. (PhD thesis), Kingston University, .
Abstract
Varicella-zoster virus causes chicken pox (Varicella) primary infection, which becomes latent in the dorsal root ganglia and trigeminal ganglia, and may reactivate to cause shingles, the most serious complication of which is post-herpetic neuralgia occurring in 50% of individuals over 60 years. Severity of lesions depends on host's immune response. Like many viruses, varicella-zoster virus appears to have evolved escape mechanisms from host immune surveillance by downregulating cell surface major histocompatibility complex class 1 expression and may delay of resolution of infection. Major histocompatibility complex class 1 is processed and transported to the cell surface through the Golgi apparatus. Varicella-zoster virus genome encodes a membrane gene, open reading frame type 1, which is localised in the enoplasmic reticulum and Golgi apparatus. Given the cellular localisation of open reading frame type 1 in the Golgi apparatus, this study investigated the expression of major histocompatability complex class 1 in human immortalised keratinocytes transfected with only empty vector. As a control, the expression of major histocompatability complex class 1 human immortalised keratinocytes parental cells were also examined using current molecular biology techniques. The results of this thesis demonstrate that the expression of varicella-zoster virus-open reading frame type 1 prevents the transport of major histocompatibility complex class 1 complexes to the cell surface and causes its retention in the Golgi apparatus, which is compensated by treatment with IFN-[alpha]. Varicella-zoster virus (VZV)-open reading frame type 1 does not affect the synthesis of human leukocyte antigen class 1 heavy chains or the expression of the transporter associated with antigen processing. Additionally, we determined that varicella-zoster virus-open reading frame type 1 impedes the surface expression of human leukocyte antigen class-A and human leukocyte antigen class-B, which present viral peptides to major histocompatibility complex class I-restricted cytotoxic T lymphocytes, but not the natural killer cell inhibitory ligands human leukocyte antigen class-C and non-classical human leukocyte antigen class-E. This selective downregulation of cell surface human leukocyte antigen class 1 molecules may allow the virus to establish infection by avoiding immune clearance of virus-infected cells by both cytotoxic T lymphocytes and natural killer cells. However, it remains to be seen if open reading frame type 1 expressing cells evade cytotoxic T lymphocytes killing, through downregulation of classical major histocompatibility complex class I, and natural killer killing, through lack of downregulation of non-classical major histocompatibility complex class I. The study outcome will be a valuable attempt to elucidate factors involved in varicella-zoster virus-related lesion progression, contribute to existing knowledge, and importantly allude to further investigations on the pathogenesis of this virus on human disease. The data obtained may also offer novel means of therapeutic intervention.
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