We have developed two methods to genetically engineer virulence- attenuated yellow fever virus. Through this novel method, it is possible to create replication-competent recombinant viruses that stably carry and express genetic sequences derived from other pathogenic agents. The objective of this proposal is to evaluate the potential of recombinant yellow fever virus expressing proteins derived from simian immunodeficiency virus (SIV) to serve as safe and effective vaccines for the prevention of infection by immunosuppressive lentiviruses. Important advantages of the live-attenuated yellow fever vaccine include its ability to induce long-lasting immunity, its safety, affordability and documented efficacy in both developed and developing nations. In these studies, recombinant live-attenuated (strain 17D) YFV will be constructed to express HIV 89.6 envelope, and SIV Gag, Pol and Nef. The expression of HIV/SIV proteins will be studied. Yellow fever recombinants will be optimized for replication competence and genetic stability. YFV recombinants will be used to inoculate mice and their ability to elicit humoral and cellular immunity directed against HIV/SIV antigens will be evaluated. Because monkeys are natural host of YFV we will also examine the ability of recombinant YFV viruses to elicit a strong and long-lasting immunity in rhesus macaques. We will determine whether vaccination with SHIV/YFV recombinants induce production of antibodies and cellular immunity directed against HIV/SIV proteins. If strong immunity is generated by the vaccination, vaccinated animal will be challenged by inoculation of virulent HIV/SIV chimeric virus (SHIV).