Since its isolation in 1983 as a causative agent of AIDS, HIV-1 has remained an exceptional challenge. The human immune system usually ultimately fails at controlling infection by the virus. In contrast, most individuals infected with the related and poorly studied lentivirus HIV-2 do not develop AIDS. The immune response is clearly implicated in this protection, but the mechanisms are not well understood. DCs are a unique type of immune cell that sense pathogens and couple this sensing to the activation of innate and adaptive immunity. We have recently discovered that unlike HIV-1, HIV-2 is sensed in dendritic cells (DCs), a finding that is strikingly parallel to the in vivo situation. We found that sensing of the virus in DCs in vitro induces an antiviral innate response and activation of CD4+ and CD8+ T cells. Whether this adaptive response contributes to the lack of AIDS pathology in HIV-2 infected patients is unknown. Therefore, while the vast majorities of studies have focused on HIV-1, we believe that the HIV-2 represents a unique opportunity to discover how HIV-sensing in DCs translates into protective immune responses. To address this question, we propose an approach at the interface of immunology and virology. We propose to:1) Unravel the type of CD4+ and CD8+ T cell responses induced by DCs that sense HIV-2. We will examine how naïve T cells respond to HIV-2 in vitro and how this compares with the response of memory T cells isolated from HIV-2 infected patients who control their virus.2) Determine what is sensed by DCs in HIV-2.3) Identify cellular regulators of HIV sensing in DCs.Altogether, this study will integrate molecular sensing of the virus and adaptive immunity to provide an understanding of how the immune response against HIV-2 operates. We believe that this may lead to novel approaches based on the manipulation of innate immunity against HIV-1 and HIV-2 infections and in other types of infection.