The immune system is capable of controlling and/or clearing most viral pathogens from infected hosts. Effective immune system-mediated control of this type of pathogen typically requires both antibodies and cellular immune response. In HIV-1 infected individuals and the immune system can control the virus for only a short period of time and ultimately AIDS develops. Vaccine studies using the SIV- rhesus macaque model have demonstrated that vaccination can sometimes protect animals from infection but usually protection is in the form of increased survival time. Based on these findings, we have developed the hypothesis that genetic immunization given as a therapy can augment immune responses and thereby control viral replication and disease pathogenesis. The research goals of Project 1 will focus on the characterization of safety, immunogencicity and ultimately efficacy of the genetic vaccine approach when used as an active immunotherapeutic in SIV-infected rhesus macaques. In the first set of animals studies rhesus macaques will be infected with SIV-mac 239 and then immunized with vaccine plasmids containing the SIV-mac 239 gag + pol genes, the env genes or a mixture of the two plasmids. The immune responses that are induced in these infected animals will be evaluated and thoroughly characterized by their comparison to immune responses induced by similar vaccination of noninfected animals and to the immune responses produced by infected but control vaccinated animals. The focus will be on the induction of immune responses that are different from those induced by infection, immune responses that may contribute to a therapeutic effect. The effects of this treatment on viral burden will also be evaluated, primarily to exclude the possibility that such a treatment will increase SIV-induced disease pathogenesis. Once the plasmid formulation and dose regime that is required to induce immune responses in these animals is identified, two additional genetic immunotherapy vaccine studies will be done to document the effects of this type of therapy on heterologous infections using SIV-mac251 and Delta-B670 variants and on established SIV-mac239 infections. The results of these studies will be used to determine the safety and potential benefit of this approach for use in human AIDS patients.