The overall goal of this project is the development and testing of a multi- epitope HIV vaccine, composed of the defined set of conserved CTL and HTL epitopes, which are described in the overview section. Our vaccine will be designed to allow for significant, non-ethnically biased population coverage, and will focus on epitopes conserved Amongst different viral isolates. The vaccines will be optimized with regard to the magnitude and breadth of responses, and to allow for the simplest epitope configuration. To accomplish these goals, we plan to build small, multi-epitope minigenes, each encompassing up to 12 different CTL and HTL epitopes. Next, we plan to demonstrate simultaneous induction of responses against these epitopes by the use of single promoter minigenes, either injected into normal and HLA transgenic mice (immunogenicity assays), or transfected into human APC's, and utilized to stimulate specific HTL or CTL lives (antigenicity assays). We plan to further optimize these minigene constructs based on analysis of the influence sequences on optimal anti-genicity and immunogenicity. Finally, the simplest plasmid configuration capable of effective delivery of the selected sets of epitopes, in the context of a plasmid backbone acceptable for manufacturing and clinical use will be determined. In the later stages of the project, we will move our focus to the establishment of strategies to assess the vaccine's potential in the treatment and prevention of HIV infection. Finally, CD8+ lymphocyte responses induced in HIV-1 infected, HAART-treatment and HIV-1 normal, non-infected subjects by our HIV minigene will be evaluate, in parallel with similar analyses regarding CD4+ responses conducted a UCHS by C. Wilson's group.
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