This proposal is focused on the dynamic host-virus relationship very early following hepatitis C virus (HCV) infection in humans. Because of the lack of recognition of acute HCV infection, little is understood about how the immune responses, particularly innate responses, evolve over time and how such activity shapes the kinetics of HCV replication in humans and determines the course of disease, i.e., spontaneous recovery versus chronicity. Early stages of viral infection are associated with the recruitment and local activation of natural killer (NK) and dendritic (DC) cells, cell types capable of exchanging bidirectional activating signals. NK cells are likely important not only for the early virus elimination, but also for the development of Ag-specific memory, since NK cell deficiencies have been associated with recurrent infections both in humans and in mice. The recent development of immunologic techniques that directly enumerate and functionally characterize NK cells, DCs, and regulatory T cells will enable us to study the interactive mechanisms among virus, host immune responses and clinical disease from the incubation phase of HCV infection. The unifying hypothesis is that defects in the innate immune response (including diminished NK cell and DC function) and/or enhanced suppressive activity of the regulatory T cell response early after acute HCV infection in humans correlate with the risk of developing persistent viremia. Experiments characterizing the coordination of various components of the immune response will be carried out using a unique repository of prospectively stored specimens from a network of acutely HCV-infected patients (current n = 54), which was initiated 3 years ago and continues to expand. The individual specific aims are: 1) To prospectively evaluate how NK cell responses contribute to the control of HCV in patients with acute HCV infection. 2): To precisely examine how the frequency and function of myeloid (mDC) and plasmacytoid dendritic cells (pDC) correlate with outcome following acute HCV infection. 3). To define the role of CD4+CD25+ regulatory T cells in viral persistence. These analyses will enhance our understanding of the pathogenesis of HCV, provide biomarkers for identifying patients early in their course who are more likely to develop chronic viremia, and, hopefully, lead to development of novel immunotherapeutic approaches.