The goal of this project is to examine the mechanisms of immunity and disease in a murine models and develop methods for optimizing long-lived protective responses. Our preliminary data have demonstrated the potential of using replication-defective herpes simplex virus as a vector for inducing immune responses to heterologous proteins. In particular, this viral vector stimulates preferential Th1 responses, which are postulated to be protective in respiratory syncytial virus (RSV) infection. Based on these findings we propose the following aims: I. Characterize the immune responses to genetically engineered viral vaccines: The nature of the antibody, cytokine, and CTL responses to beta galactosidase (betagal) genetically engineered into a replication defective HSV-1 virus will be analyzed and compared to the same antigen presented as a soluble protein or in a plasmid. The duration of the responses, effects of pre-existing immunity, and effects on responses to concurrently administered antigens will be defined. Antigenic constructs designed to enhance immunogenicity (from Project 1) will be studied. II. Definition of the mechanisms that regulate the nature of the effector T cell response to replication defective virus. The roles of cytokines and co-stimulators in Th1/Th2 responses to purified antigen, HSV-1 vectored antigen and plasmid encoded antigen will be examined. These experiments will establish the mechanisms by which distinct antigen preparation induce distinct patterns of responses. III. Role of T-cell immunity in the mechanism of protection and pulmonary disease enhancement by RSV infection in mice immunized with various RSV vaccines. The mechanisms of protective immunity and immune pathology in a mouse model of RSV will be defined. HSV-1 based vectors will be used to modulate immune responses to RSV, using information generated in aims I and II, with the goal of testing hypotheses generated in Specific Aims I and II manipulations of antigen for their use in vaccines. Thus this project extends to a model of infection data on basic mechanisms of control of T cell responses and immunogenicity.
| London, C A; Lodge, M P; Abbas, A K (2000) Functional responses and costimulator dependence of memory CD4+ T cells. J Immunol 164:265-72 |
| London, C A; Perez, V L; Abbas, A K (1999) Functional characteristics and survival requirements of memory CD4+ T lymphocytes in vivo. J Immunol 162:766-73 |
