Doctoral Dissertations

Zhiya Yu

Date of Award

12-1997

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Barry T. Rouse

Committee Members

Robert N. Moore, Albert Ichiki, Joyce Merryman

Abstract

The goal of this dissertation is to understand the immune responses generated against cutaneous herpes simplex virus (HSV) infection, with an emphasis on the role of gamma-interferon (IFN-γ) in mediating protection against HSV. Further, novel approaches to achieve optimal immune responses by DNA vaccination in the murine HSV model is explored.

A T-cell mediated inflammatory response dominated by BFN-γ appears to play the essential role in viral clearance during cutaneous HSV infection. In accordance with this hypothesis, this dissertation shows that following infection, IFN-γ gene knock-out (GKO) mice are more susceptible to the development of skin lesions than are wild-type mice. However, following HSV immunization, GKO mice become solidly immune to viral challenge. In addition, transferring T cells from immune GKO mice to nude mice recipients renders them resistant to zosteriform lesions. These results indicate that compensatory mechanisms are available to the body to effect immunity against viral infections.

To test the principle that genetically engineered epitopes in a plasmid DNA can efficiently induce specific immunity, a study on HSV-specific immune responses induced by vaccinating mice with a plasmid DNA (pcMini) encoding cytotoxic T lymphocyte (CTL), helper T and B cell epitopes from HSV is described in this dissertation. Following immunizations with pcMini, mice developed epitope-specific CTLs comparable to the responses induced by live HSV. Antibody, lymphoproliferative responses, and T cell cytokine release were also detected. The protection provided by minigene vaccination was significant; however, not as efficient as live virus immunization. The DNA minigene approach may prove useful to define and induce immune responses against minimal antigenic determinants.

To address the question of whether immune responses to a vector-encoded antigen can be enhanced by the activation of antigen-presenting cells in the local environment, the effects of co-inoculation of an HSV glycoprotein (gB)-expressing plasmid with a plasmid encoding mouse granulocyte-macrophage colony-stimulatory factor (GM-CSF) on modulation of gB-specific immune responses are evaluated in this dissertation. The results show that co-administration of GM-CSF DNA provided increased resistance to HSV infection and this protective response could be related to the enhanced immune induction of CD4-t- T cells and B cells responses.

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