<p> Oncolytic viruses are able to selectively replicate in tumour cells and are an attractive new avenue of cancer therapy that lacks the toxic side effects of current treatment modalities. HSV-1 mutants lacking ICPO are promising oncolytic vectors, however, the mechanisms behind viral oncolysis remain unclear. Since PML contributes to the repression of HSV-1 and also is downregulated in various types of cancer, but particularly in prostate cancer, PML has been implicated as a factor influencing the permissiveness of tumour cells to I CPO-null HSV-1 oncolysis. By screening a series of immortalized patient matched normal and tumour prostate epithelial cells for sensitivity to ICPO-null HSV-1 oncolysis and evaluating the levels of PML in each cell line, we were unable to establish a link between PML status and permissiveness to ICPO-null HSV-1 oncolytic vectors. Also, since a large proportion of the population possesses pre-existing immunity to HSV -1, which may hinder systemic administration of HSV-1 vectors, we sought to determine if BHV-1 could be an alternative oncolytic herpesvirus. BHV-1 was cytotoxic to various human immortalized and transformed cell lines in vitro, but was generally more restricted from normal human cells, suggesting that BHV -1 may have potential as an oncolytic virus. However, the sensitivity of human cells to BHV -1 infection did not correlate with type I IFN signaling, as has been demonstrated for other oncolytic viruses. Furthermore, neutralizing antibodies against HSV-1 were unable to cross-react with BHV -1 in vitro suggesting that pre-existing immunity to HSV -1 in humans may not hinder BHV -1 infection. It is hoped that these results will contribute to the understanding of viral mediated oncolysis and also provide some evidence that BHV-1 may be a new alternative oncolytic herpesvirus, however, in vivo studies are necessary to evaluate the oncolytic efficacy of BHV -1. </p> / Thesis / Master of Science (MSc)

Varicella zoster virus (VZV) is an alpha herpes virus that causes primary infection with varicella (chicken pox), establishes latency in ganglia and may later reactivate as herpes zoster (shingles). Innate immune effectors are thought to control initial viral replication, but it is the adaptive immune system, involving T cells that mediates eventual control of viraemia and the associated clinical disease. Although both CD4⁺ and CD8⁺ T cells mediate viral clearance during acute illness, memory responses are dominated by CD4⁺ T cells. We tested the hypothesis that the paucity in memory CD8⁺ T cell effectors is partly attributed to immune evasion mechanisms that are mounted by VZV. We confirmed that VZV readily down regulates cell surface HLA-A and HLA-C but spares HLA-B onVZV infected keratinocytes and VZV infected Mewo cells. Analysis of intracellular HLA protein expression and gene transcription showed global down regulation of all HLA subtypes. Further analysis showed that VZV inhibits IFN-γ mediated up regulation of HLA expression and augments IFN-γ mediated up regulation of HLA-E and CD71 expression. Furthermore, we show that acute VZV infection lowers the frequency of circulating peripheral blood myeloid dendritic cells (mDC), reduces the expression of the DC activation marker HLA-DR and impairs inflammatory cytokine secretion in blood DC populations. Inhibition of DC cytokine secretion was found to be dependent on viral replication as irradiated virus resulted only in mild inhibition of IFN-α and TNF-α secretion. Lastly, we observed that VZV infection results in increased expression of host peptides, including MHC derived leader sequences that potentially bind to HLA-E. Cell surface HLA-E is known to be a ligand for the natural killer (NK) cell inhibitory receptor CD94/ NKG2A identifying a novel mechanism of viral immune escape from NK cell surveillance. In conclusion, our data reiterates the fact that VZV targets different aspects of antigen presentation to evade the immune system with implications for pathogenesis and approaches to improved vaccination and treatment.

Thesis (M.S.)--University of Wyoming, 2008. / Title from PDF title page (viewed on Mar. 4, 2010). Includes bibliographical references (p. 65-72).

Thesis (Ph. D.)--University OF MICHIGAN.

Thesis (Ph. D.)--University of Southern California, 1999. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (M.S.)--University of Southern California, 1999. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D.)--University OF MICHIGAN. / eContent provider-neutral record in process. Description based on print version record.

Thesis (Ph. D.)--University of Southern California, 1999. / Includes bibliographical references.

Thesis (M.S.)--University of Southern California, 1999. / Includes bibliographical references.

Thesis (Ph. D.)--University OF MICHIGAN.