We are developing a oral Salmonella typhimurium-based vaccine to elicit mucosal immunity against sexually-transmitted SIV infection in the rhesus monkey. The vector system is designed to express viral gene products at specified locations within the host mucosal immune system. The current project seeks to investigate the adjuvant mechanisms of S. typhimurium for host responses to these co-delivered SIV antigens. Murine and nonhuman primate (rhesus monkey) models are used to evaluate immune responses to recombinant Salmonella expressing SIV gene products and to investigate the mechanisms responsible for the adjuvant effects seen in these bacterial- based vaccines. The essential interplay between murine and primate experimental systems is fundamental to understanding the role that Salmonella adjuvants play in enhancing host immune responses. Our experimental approaches concentrate on three main properties of the Salmonella-based vaccine system that might explain the dramatic effects observed in many oral vaccination experiments. Firstly, we will characterize the tissue distribution and local host immune response to novel, attenuated strains of Salmonella typhimurium. Individual mutant strains vary in their capacity to invade and replicate in organs of the immune system including Peyer's patches, mesenteric lymph nodes and spleen. The particular properties of each attenuated strain will be characterized in detail to understand the nature of the attenuating mutation and its effects on the adjuvant effect for bacterial and co-delivered antigens. Secondly, we will examine the patterns of immunological reactivity to vaccine strains with particular emphasis on the stimulation of cytotoxic T cell subpopulations bearing the gammadelta T-cell receptor for antigen. Our recent studies indicate a significant role for gammadelta T cells in the host immune response to SIV or HIV-infected cells and this same cell population (bearing the Vgamma9/Vdelta2 receptor) recognizes the Salmonella proteins produced in high levels when the bacterium invades host macrophages. We will determine whether responding gammadelta T cells enhance or inhibit host immune responses to bacterial-based vaccines. Lastly, we will evaluate the duration of immunological memory in mice and monkeys vaccinated with recombinant, attenuated Salmonella-based vaccines. Our ultimate goals are to understand the variety of immunological mechanisms that mediate adjuvant effects of Salmonella and to learn how best to manipulate these features in order to achieve effective vaccination against sexually-transmitted HIV-1 infection in man.
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