In response to the Innovation Grant Program for AIDS Vaccine Research (PA-03-082), we propose to use a functional genomics approach to identify biologically relevant changes in cellular gene expression in response to alternative AIDS vaccine strategies. These analyses will be performed using blood samples obtained from rhesus macaques (Macaca mulatta) in an ongoing vaccine study being conducted by Dr. Marjorie Robert-Guroff at the Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute. This vaccine study is using macaques to evaluate the contribution of HIV envelope subunit boosts to the immunogenicity of a replicating adenovirus (Ad)-HIV/SIV recombinant vaccine. Our collaboration with Dr. Robert-Guroff has the important advantage of expanding the types of data collected for this study without the need for additional animal experimentation. With the recent sequencing of the rhesus macaque genome, and our development of macaque-specific genomic reagents, we have for the first time at our disposal the species-specific tools needed to successfully carry out these studies. We will use the newly developed macaque genomic resources to perform global gene expression analyses on blood samples obtained from animals prior to immunization, at week 14 (after the second immunization with the Ad-HIV/SIV recombinants), immediately prior to challenge at week 44 (after protein boosting of Groups 2 and 3), and at time points corresponding to acute-phase and set-point viral burdens. A total of five time points will be analyzed, with samples obtained from all 6 animals from each immunization or control group, resulting in 120 samples. For the vaccine test groups, expression profiles will be analyzed for patterns that correlate with acquired immunity (e.g., specific cytotoxic T-lymphocytes or antibodies), as well as for expression differences that are associated with the attenuation of disease. Longitudinal studies over vaccination stages will show the temporal evolution of features associated with each immunization strategy and may furnish mechanistic insights into the process. Analysis of the infected, non-immunized control animals will furnish a detailed view of those genes and pathways altered in the course of disease progression, consequently giving a more comprehensive view of viral pathogenesis in these models. It is our hypothesis that genomic profiling of the blood will reveal gene expression changes that are indicative of the host response to vaccination. These profiles may reveal genomic markers of protective immunity or gene expression changes that are indicative of a predisposition to a particular response to immunization and subsequent challenge. Ultimately, these studies may also suggest mechanisms to enhance current AIDS vaccine strategies. ? ? ?
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