SALMONELLA HIV VACCINES WITH DIRECTED CELLULAR TROPISM

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DESCRIPTION (Adapted from applicant's abstract): Attenuated strains of Salmonella have been used as carriers of heterologous antigens for human and animal vaccination. In mice, S. typhimurium is thought to infect macrophages in the Peyer's patches of the gut and also cells of the liver and the spleen. The investigators will examine the effect on elicited immune responses of mice orally inoculated with HIV p24 expressed in two differently engineered S. typhimurium strain backgrounds: (1) A Salmonella strain engineered to specifically target dendritic cells (DC) of the mouse, and (2) a Salmonella strain that will translocate antigen directly to the cytoplasmic compartment of an antigen-presenting cell (APC). In the first case, the Salmonella strain will present on its surface a single-chain antibody specific for the known murine DC marker, CD11c. Enhancing the association of Salmonella and DC will result in more efficient processing and presentation by these specialized APCs, thus resulting in better class I responses toward Salmonella antigens as well as carried antigens. In the second case, the Salmonella strain will express the p24 antigen fused to a type III secreted protein, SipC, which is known to be translocated directly to the cytoplasm of the host cell. This approach will permit more efficient class I presentation of p24 epitopes that otherwise would be diluted out by Salmonella antigens when p24 is delivered as a soluble intracellular antigen. Finally, the investigators will use a Salmonella vaccine strain that combines these two new approaches to evaluate CTL induction in a double-transgenic mouse line that expresses HLA-A2.1 and human CD8, to test the potential efficacy of these vaccines to elicit appropriate immune responses in humans. The results from these studies may have direct application to the production of effective vaccines that could specifically modulate the immune system to develop a protective response against HIV.