Our goal is to understand the innate immune response to HIV-1. We have found that a cryptic innate immune response to HIV-1 exists in dendritic cells (DC). This response is normally inactive because HIV-1 is unable to infect DC. We have used the Vpx protein found in other lentiviruses to render DC susceptible to HIV-1 infection. The resulting innate response to HIV-1 requires an interaction between de novo synthesized Capsid and cellular Cyclophilin A. This interaction leads to the IRF-3-dependant production of type-I interferon and the activation of antigen-specific T cells. This study will aim at understanding the molecular mechanisms controlling this response.In Aim 1, we will determine the host and viral factors implicated in the innate response to HIV-1. At the host level, we will evaluate a panel of candidate genes using a novel RNAi strategy using shRNA vectors in DC. At the viral level, we will determine the minimal viral elements required for triggering the response.In Aim 2, we will identify novel regulators of the innate immune response in human DC, including the DC-specific HIV-1 innate sensor. Using a DC cDNA library, we will screen for inducers of type-I interferon in cell lines. This library will also be used to identify the Vpx-sensitive HIV-restriction factor in human DC.The cryptic nature of the innate response to HIV-1 may explain in part the failure of the immune system to control HIV-1 in the vast majority of infected individuals, as well as the failure of current vaccine strategies. This study will provide a novel understanding of the molecular mechanisms responsible for innate immune responses, and may provide new immunological strategies for controlling HIV-1 infection.