Considerable evidence indicates that CD8+ cells play a critical role in controlling HIV/SIV disease progression, but neither the quantity nor breadth of the HIV-specific CD8+ T cell response as measured using standard approaches (MHC class I tetramer and single function analysis) conclusively correlate with control of replication or disease progression. Recently, using a novel polyfunctional analytical approach, we have identified patterns of CD8+ T cell function that appear to provide discriminate HIV disease progression status. HIV-infected subjects during chronic uncontrolled infection possess functionally limited HIV-specific CD8+ T cell responses, whereas long-term nonprogressors maintain polyfunctional responses. We believe that these polyfunctional patterns may enable us to identify correlates of natural immune protection and, furthermore, that they may have implications for vaccine development strategies. It is pertinent to define HIV-specific CD8+ T cell responses during acute infection, as the events during this period define future disease progression. Furthermore, an effective HIV vaccine will need to stimulate responses protective during this particular phase of infection. Our goals are to define the polyfunctional and phenotypic characteristics of HIV-specific CD8+ T cells that arise during primary infection, determine how they are modulated, and define their relationship to viral control and disease course. We will also determine if these responses can be altered by vaccination, using as a model a DNA/Adenovirus approach and exploiting the unique resource of a small number of vaccinated individuals who became HIV infected. Together, these studies will provide critical information regarding immune correlates of protection against which HIV vaccine candidates can be measured for potential protective effects. Lay Description: Development of a vaccine against HIV requires the understanding of the natural immune responses against HIV after infection occurs. In this proposal, we will determine how the immune system fights HIV during early infection and apply this knowledge to the development and testing of HIV vaccines.