Development of a safe and effective HIV-0vaccine remains a critically important but elusive goal. Progress towards an effective HIV vaccine will likely require a better understanding of the determinants of the magnitude and duration of immune responses to HIV antigens, and the derivation of immunization strategies that are significantly more potent than those available currently. Recent application of newly available, high-resolution immunologic methods to characterize immune responses to virus infections suggest that a major determinant of CD8 and CD4 T cell memory responses to viral antigens is the magnitude of the primary immune response to the infection. We hypothesize that similar new methods to augment the immunogenicity of HIV antigens and thereby increase their ability to elicit high-level, long-term memory T cell responses must be developed. Furthermore, any such methods defined in animal models must be able to translate into affordable, safe and practicable vaccines to protect the millions of persons at high for HIV infection worldwide. To address these theoretical and practical needs, we propose to develop recombinant vectors that express HIV and SIV antigens based on the Modified Vaccinia Ankara (MVA) virus, and to evaluate the immunogenicity of these candidate vaccines in HLA-A2 transgenic mice and rhesus macaques. These vectors will provide valuable experimental tools to test alternative strategies to increase the magnitude of memory responses to HIV antigens, and will hopefully provide promising HIV vaccine candidates for use in humans. In hopes of generating new candidate vaccines that elicit more effective and longer- lasting antiviral immune responses, the following specific aims will be pursued: (1) evaluate the extent to which targeting of HIV antigens for proteasome degradation increases the magnitude and duration of immune responses they elicit, (2) evaluate methods to increase the immunogenicity of MVA-HIV vectors by inclusions of genes encoding co-stimulatory molecules and cytokines that augment antigen presenting and T cell function, (3) define the most effective combinations of MVA- based strategies for induction of high-level, balanced CD8 and CD4 T cell responses to multiple HIV antigens, and based on these results (4) construct MVA vectors with enhanced immunogenicity for immunization and challenge studies in rhesus macaques.
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