Herpes simplex virus (HSV) infections in humans are responsible for a variety of syndromes ranging from fever blisters to viral encephalitis. HSV infections are frequent in cancer patients and in patients undergoing immunosuppression. Efforts to control HSV infections by immunological intervention have only been partially successful i the experimental host due to the ability to the virus to establish latent infection in the ganglia and to subsequently reactivate under a variety of conditions. Convincing evidence exists for a role of the immune response in virus clearance and elimination of virus infected cells. Both CD8+ and CD4+ T lymphocytes contribute to the immunological defense against HSV infections. The overall goal of this proposal is to predict and to localize the CTL recognition epitopes on proteins encoded by the HSV genome and to determine their ability to both function as target site for HSV-specific CTL and to induce immunological responses in vivo. The proposed studies are based on our understanding of MCH restriction, antigen processing involving protein degradation into peptides, and the presentation of peptides by MHC class I molecules to the T cell receptor. Using a mouse model, we will achieve our goal by predicting and localizing CTL epitopes coded for by the HSV genome and by identifying the dominant HSV CTL epitopes and determine the ability of these epitopes to confer protection against HSV primary infection and establishment of latent infection. In addition, we will express these synthetic peptides and HSV-specific CTL epitopes in heterologous proteins and in vaccinia virus recombinants as immunogens in which attempts will be made to enhance their immunogenicity in vivo by increasing the efficiency of antigen processing and presentation. Ultimately, these epitope-specific CTL will be examined for their ability to suppress viral pathogenicity and establishment of latency. The stability of HSV CTL epitopes under CTL selective pressure will also be determined. Together, these approaches will allow us to develop effective vaccine candidates for immune defense against HSV infection.
