The proposed studies will explore novel strategies for enhancing the presentation of viral antigens (Ag) to B and T lymphocytes. A basic theme of the application is that the induction of immune responses by vaccines can be greatly enhanced using strategies that bypass low affinity, nonspecific steps in Ag processing and presentation. By incorporation of appropriate sequence elements, Ag will be targeted directly into cellular uptake systems and de degradative compartments. Another basic theme is that with appropriately designed vaccines, presentation of Ag to B and T lymphocytes by the relevant antigen presenting cells (APC) should occur under conditions that promote optimal costimulatory interactions, cytokine effects, and induction of immunologic memory. All five projects utilize influenza virus Ag so that distinct vaccine strategies can be compared directly in a murine vaccine/challenge model in which both antibody and cytolytic T lymphocyte (CTL) responses are important. This model will be used to determining how effective each strategy is in conferring protection against lethal infection by a virus that is also a major human pathogen. In addition, synergy between these novel approaches will be explored. projects 1 and 2 describe novel techniques for promoting high affinity uptake of antigens by specialized APC, including follicular dendritic cells (FTC) that present intact Ag to B cells and the blood-derived dendritic cells (DC) that present processed Ag to T cells. In Project 1, sequence elements from C3 will be used to target Ag to FDC through complement receptor type 2. Project 2 involves targeting Ag to DC via cytokine receptors. Ag-GMCSF fusion proteins will be used to direct Ag to DC while simultaneously inducing differentiation and activation of DC. Projects 3 and 4 will test the hypothesis that induciton of T cell responses can be enhanced by targeting Ag directly into degradative compartments associated with Ag processing. Project 3 involves the expression of viral genes modified to introduce lysosomal targeting sequence that divert Ag into the class II-restricted Ag processing pathway while Project 4 will explore novel methods for enhancing the induction of CD8+ CTL by targeting viral proteins for rapid degradation in the cytosol through the use of transferable degradation signal sequences. Project 5 deals with a critical late step, the generation of memory T cells. Based on preliminary data indicating an important role for class Ib MHC molecules in T-dependent antibody responses and in the generation of memory, Project 5 will examine how class Ib molecules contribute to these critical aspects of immunogenicity.
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