Evidence for the key role of cellular immune responses in protection from HIV has emerged from subjects who are exposed and uninfected with HIV, from studies of the importance of T helper cell (Th) proliferative responses in the control of HIV viremia, and from studies of the role of CTL in controlling viral load levels in acute HIV infection. This study combines expertise in mucosal immunogen delivery, HIV immunogen design, and expertise in understanding and study of rhesus monkey and human immune systems to design and study novel vaccine candidates for preventing HIV infection. The first project will study novel ways of mucosal immunization to induce both systemic and local CTL and antibody responses to HIV. The second project combines epitope-based HIV immunogen design with incorporation of Th and CTL immunogenic regions of HIV proteins into modified vaccinia Ankara (MVA) in order to maximize HIV vaccine immunogenicity. These projects will collaborative to develop an optimal adjuvant formulation for the HIV immunogens, by incorporating and testing cytokines, chemokines, ligands for dendritic cell CD40 and angiogenic factors in vaccine formulations. The third project will use rhesus monkey model and SHIV challenge viruses to test the novel immunogens and adjuvant formulations from the first and second projects as well as to study issues of CTL recognition of HIV and SIV variants, and define cytokine profiles of CD4+ T cells following HIV and SIV infection and vaccination. Taken together,, this is a highly interactive project comprised of investigators who have been working together on HIV vaccine development in a sustained effort to develop practical HIV vaccine candidates. By using an iterative process of experimental design and testing in animals and then performing incisive human clinical trials, the studies should provide key information for development of a practical HIV vaccine for humans.
