Significant practical and technical advances have been achieved during the first five years of the vaccine development program. Many novel vaccine vectors have been constructed and tested for immunogenicity in both human volunteers and experimental primates, and potentially protective responses have been detected. Improved knowledge of the underlying basic immunologic principles, including insights in to the antigen processing machinery and requirements for stimulation of CD8+ CTL responses, the adjuvenicity of immunogens necessary for inducing strong responses, and the requirements for maintenance of immunologic memory, have provided rational direction for vaccine design. Challenge studies with SIV in primates have demonstrated that a variety of vaccine preparations can induce protective immunity. However, despite these encouraging results, no currently tested vaccine regimen, if applied to a large at-risk population, would likely provide long-term protection. Consequently, it is essential to more closely examine the requirements for providing such protection, and to design vaccine strategies to accomplish these goals. In this project, we will evaluate the role of specific components of vaccine-induced CD4+ and CD8+ T cell responses in protective immunity, and determine the immunologic and virologic reasons why potentially protective immune responses successfully or unsuccessfully eliminate a viral challenge. The goals are to: 1. Evaluate the immunogenicity of SIV subunit vaccines. Studies will be performed to determine the effect(s) of priming and boosting with vaccines selected for distinctive immunologic properties on the magnitude, specificity and durability and durability of T cell responses. 2. Analyze the outcome of challenge of vaccinated macaques with SIV. Studies will determine if the presence or magnitude of particular responses prior to challenge predicts for host resistance, and if protective immunity must prevent infection or can eliminate virus despite replication in the host after challenge. 3. Evaluated vaccinated macaques developing infection following challenge to determine the reasons the induced immunity failed to protect. Studies will determine if the host can resist challenge with defined mixtures of cloned homologous and heterologous virus, if the host selects antigen-loss mutants in vivo even if challenged with homologous virus, and if increasing the diversity of induced immunity significantly impacts on resistance. 4. Evaluated the immunogenicity and efficacy of HIV-1 vaccines in the macaque HIV-1 infection model. Studies analogous to those performed with SIV will determine the immune responses elicited by candidate HIV vaccines, and the relationship of those responses with protective immunity. 5. Analyze the contribution of selectively augmented CD4+ and CD8+T cell responses in providing protection from challenge with SIV. CD4+ and CD8+T cell clones will be isolated from animals shortly after protection from challenge with SIV. CD4+ and CD8+T cell clones will be isolated from animals shortly after vaccination, expanded to large number, and administered after host immunity has declined and just prior to challenge. The goal is to define which T cell responses must be augmented to maintain protective immunity.