Effective vaccines are not currently available for many agents including herpes simplex virus (HSV). One of the challenges of modern vaccinology is to design strategies that will sculpt the immune system to expand components which subserve a protective role and diminish activities which are potentially counterprotective. For optimal defence against HSV, it is probably necessary to maximize the CD8+ T cell and CD4+ Th1 cell subtype response since these components are crucial for prompt and effective viral clearance. Using in vitro systems optimal means of inducing HSV specific cytotoxic T lymphocyte (CTL) and CD4+ Th1 cell mediated response will be developed. As antigens, glycoprotein B and ICP27 proteins and some of their component peptides as well as DNA preparations encoding the protein and peptides, will be used. Culture conditions will be manipulated mainly with respect to the cytokine environment to achieve induction of immune responses dominated by different components of immunity. Optimal means of inducing protective immune responses in vivo against HSV with DNA vaccines will also be sought, and the nature of the immune response induced measured. The achievement of optical protective responses is hypothesized to require the delivery of candidate immunogens maximally to dendritic cells. It may also be necessary for the immunogen to have additional costimulator activity, such as IG-12 production, that will condition the local environment of the antigen presenting and responder T cells to generate mainly the Th1 subtype of CD4+ T cells. Several strategies for maximally inducing CD8+ and CD4+ Th1 HSV specific response will be evaluated and experiments will also be done to demonstrate the relative role of CD8+, CD4+ Th1 and CD4+ Th2 T cells in controlling HSV pathogenesis in mouse model systems. The findings should be relevant to the future development of vaccines that will successfully control HSV infections.
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