After the failure of the Merck STEP trial that appears to have enhanced the rate of infection in vaccinees, the need for new vectors for HIV vaccine development has become urgent. We believe a solution might be found in the live-attenuated yellow fever vaccine. This vaccine has proven to be one of the most successful and safe vaccines ever created. It has been used in more than 400 million people worldwide. Moreover several aspects of the biology of the yellow fever vaccine 17D (YF-17D) make it an outstanding candidate vector for delivering HIV genes. Recent attempts to elucidate the mechanism of action of the YF-17D vaccine have found that immunization induces a vast network of antiviral genes involved in virus innate sensing and polyfunctional immune responses. Neutralizing antibodies develop rapidly and can be detected as early as one week after inoculation. YF-17D vaccination also elicits robust CD8+ T cell responses that peak at around day 15 after immunization, when roughly 10% of all circulating CD8+ T cells exhibit an activated phenotype. Studies of virus-specific CD4+ T cells have shown that this vaccine induces a mixed T helper 1 (THI) and TH2 profile that persists for at least one year after immunization. Additionally, YF-17D triggers several innate immune pathways, which are likely to contribute to its well-documented immunogenicity and YF-17D replication activates several dendritic cell subsets via Toll-like receptors (TLRs). Taken together, these data demonstrate that the yellow fever vaccine YF-17D induces broad and robust adaptive immune responses, including the generation of effector CD8+ T cells and mixed TH1/TH2 CD4+ T cell responses. Thus, given all of the outstanding qualities of YF-17D listed above, we now hypothesize that recombinant yellow fever can be an efficacious priming agent in a vaccine regimen designed to control replication of the AIDS virus. We plan to test the efficacy of a recombinant yellow fever prime/boost regimen in a monkey model of AIDS. We will improve yellow fever vaccine vector and insert stability. Finally, we will synthesize rYF-17D constructs encoding multiple SIVmac239 inserts for a prime/boost and SIVmac251 and SIVsmE660 repeated low dose challenge study.