Herpes simplex virus 1 and 2 (HSV-1 and HSV-2) infections are among the most common encountered by humans. Usually associated with nuisance infections of the lip or genital tract, excretion of HSV from infected individuals can lead to person to person transmission, including from mother to baby and among sexual partners. Following mother to baby transmission, neonatal HSV infection can assume life-threatening proportions even in the presence of antiviral therapy. To date, there is no licensed vaccine for either the prevention or, possibly, the treatment of HSV infections, although two vaccines are in clinical trials. It is the purpose of this Program Project to extend knowledge generated from our studies of latency and virulence (AI 24,009) as well as other recent discoveries in molecular biology to rationally engineer HSV in order to be safe and efficacious immunogens for human vaccination. This multidisciplinary group of investigators brings many years of experience in molecular biology, biology, animal models and immunology to the task of developing an ideal HSV vaccine. Our goal is to engineer a HSV vaccine which: (i) does not replicate in the central nervous system (CNS), (ii) replicates to high titer in cells suitable for vaccine production, (iii) replicates at peripheral sites in animal models but does not spread to distant sites, (iv) does not reactivate from the latent state through mutations which disable the ability of the viral DNA to be amplified in sensory neurons, (v) provides significant protection from HSV disease and can serve as a vector for the delivery of genes that express antigenic determinants of other infectious agents. In addition, we will investigate the relative contribution of mucosal versus systemic immunity in the protection of the host. This Program Project application includes plans to test the feasibility of experimental augmentation of the immune response by careful use of interleukins such as IL-6 in conjunction with vaccination. The current application projects studies in mice and guinea pigs only. It is expected that this Program Project will accomplish two objectives. First it will generate the knowledge and reagents that will permit the development and testing of an HSV vaccine in humans. Second, it will provide additional and valuable information on the molecular biology of HSV in lytic and latent infections and on the role of mucosal immunity in preventing transmission of the virus.