The principal goal of this project is to enhance antibody and T cell responses to HIV-1 mucosal subunit vaccines. To achieve this goal, we are using the Escherichia coil heat-labile enterotoxin (LT) to target chimeric HIV-1 proteins to mucosal surfaces. Because there is no single accepted correlate of protective immunity, our studies will pursue both cellular and humoral responses that follow from mucosal immunization. To augment T cell responses, we have developed systems to replace segments of LT with epitopes of HIV-1 proteins in order to selectively deliver these determinants to the cytoplasmic compartment that intersects with the Class I MHC antigen processing pathway. The abilities of these chimeric proteins to induce and elicit responses in this pathway will be evaluated in murine and monkey models, with special emphasis being placed on responses that call up T cells that secrete beta-chemokines. In addition, we have developed a novel eukaryotic expression system that allows the proper folding of LT-Env chimeras that are expected to elicit potent neutralizing antibody responses after mucosal immunization. These chimeras will be evaluated in murine and monkey models with emphasis on the induction of antibodies that neutralize primary isolates of HIV-1.
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