The simian immunodeficiency virus, SIV, is a lentivirus with many of the same properties as HIV, including cellular tropism, molecular heterogeneity, and induction of an AIDS-like disease in experimentally inoculated macaques. We propose to use the SIV- macaque system to test prototype vaccines for immunogenicity and protective and therapeutic efficacy. The primary goal of this project is to identify a vaccine that protects macaques from infection by SIV as a prototype after which a vaccine against HIV can be designed. Initially, to maximize the possibility for success and minimize the possibility that vaccine failure may be due to antigenic heterogeneity among SIV isolates or to variants in the vaccine challenge virus, the BK28 molecular clone of SIVmac will be used both as the source of vaccine antigens and infectious challenge virus. Proteins encoded by the SIVmac-BK28 env, gag, pol, and nef genes will be produced by recombinant DNA techniques and administered to macaques in the form of ISCOMs, Colloidomes, liposomes, or intact inactivated or non-infectious SIV virions. Humoral and cell-mediated immunity to SIV will be determined before and after intravenous challenge with either cell-free or cell- associated virus. Protection against homologous virus challenge will be assessed by failure to isolate or to detect virus by coculture and PCR techniques. We will also determine whether immunized macaques can be protected from challenge with a pathogenic heterologous strain of SIV (SIV/SMM, isolated from mangabey monkeys). To understand the pathogenesis of attenuated versus virulent SIV infection in macaques, the tissue tropism and lesions produced by molecularly cloned pathogenic strains will be established using immunocytochemical and.in situ hybridization analysis of tissues from animals infected with BK28 and a prototype pathogenic SIV. If protection against heterologous challenge with virulent SIV/SMM can not be demonstrated, experiments will be performed to determine whether immunization alters virus disease pathogenesis. Finally, we will evaluate the ability of vaccine administration to enhance SIV-specific immune responses or to alter progression to AIDS following immunization of macaques in various stages in the course of SIV infection. The proposed research will provide data pertinent to strategies for vaccination against HIV infection or disease.