This U19 research grant application responds to the Hepatitis C Cooperative Research Center (HC CRC) RFA to establish the Center for the Study of Innate Immunity to Hepatitis C virus (HCV) Infection. The Center is comprised of three projects, an Administrative Core, and a Clinical Core, integrated into a Program of study aimed at defining the innate immune mechanisms that control hepatitis C virus infection and the response to antiviral therapy. HCV is a major public health problem, infecting nearly 200 million people worldwide. Most people exposed to HCV go on to develop a chronic infection that often associates with liver disease or liver failure, and can result in death. Infection with HCV is treated with alpha interferon (IFN)- based therapy but only 50% of patients respond to treatment. Thus, there is a great need to understand the basis of HCV persistence and IFN actions in order to improve HCV Infection and treatment outcome. Our studies have defined specific virus and host processes that control the hepatic innate immune response against HCV as major determinants directing the outcome of HCV infection and treatment. The studies in this U19 Program are therefore focused on the common theme of understanding hepatic innate immune programs that control HCV infection, and will investigate the overarching hypothesis that virus and host control of innate hepatic immune defenses define the outcome of HCV infection and IFN therapy. To investigate this hypothesis our Program will include studies to: Project 1) Define the viral and host genetic determinants that confer pathogen recognition of HCV, regulate hepatic innate immune triggering, and that mediate effector and evasion responses during infection; Project 2) Define the HCV/host interactions that drive hepatic IFN production and response between hepatocytes and liver dendritic cells to control HCV infection; Project 3) Determine the role of hepatic microRNA effectors in regulating hepatic innate immunity and the response to IFN therapy in HCV patients. The management for the U19 Program will be conducted though an Administrative Core. The research materials support and clinical data support for this Program will be facilitated through a Clinical Core. Overall, the proposed projects are unique to focus on understanding the virus/host interface that controls hepatic innate immunity to govern the outcome of HCV infection. Results from these studies will provide novel insights to guide the design of improved therapeutic strategies and vaccine approaches aimed at modulating HCV infection. RELEVANCE: Hepatitis C virus (HCV) infects the liver and causes liver disease and death. There are nearly 200 million people with HCV infection in the world but the molecular mechanisms that support infection are not understood. Our studies have now linked HCV infection with virus and host processes that control innate immunity of the liver. We propose to investigate these processes of innate immunity in order to understand how innate immune programs of the liver can control HCV infection and the outcome of antiviral therapy. Results from these studies will provide novel insights to guide the design of improved therapeutic strategies and vaccine approaches aimed at controlling HCV infection and associated liver disease. PROJECT 1: Title: Mechanisms of Pathogen Recognition and Innate Immune Control of Hepatitis C Virus Project Leader: GALE, M. PROJECT 1 DESCRIPTION (provided by applicant): Project 1 comprises a component of our Hepatitis C virus Cooperative Research Center (HC CRC) U19 application. The focus of Project 1 is to understand the molecular mechanisms by which HCV is recognized by the host cell as a foreign pathogen to trigger immunity against infection, and to learn how HCV evades these processes to mediate infection outcome among clinical cases of HCV. HCV is a hepatotropic virus that mediates a persistent infection and chronic liver disease in millions of people worldwide. HCV persistence is associated with viral strategies to evade innate immune defenses and a interferon (IFN) immune actions that normally limit Infection. We have identified HCV genome RNA and the cellular RIG-I protein as the viral pathogen-associated molecular pattern (PAMP) and host pathogen recognition receptor that interact to trigger the expression of RIG-l-responsive genes that serve as immune effectors to control innate immunity and HCV infection. We have found that HCV can disrupt innate immune signaling via the actions of the viral NS3/4A protease, thus providing an evasion strategy that allows HCV to persist. We hypothesize that viral PAMP signaling and gene expression mediated through the RIG-I pathway are critical determinants controlling hepatic immunity and the outcome of HCV infection. Our studies are therefore deigned 1) Define the structure-function relationship of viral PAMP recognition by RIG-I among clinical isolates of HCV, 2) Identify the RIG-l-responsive genes of the liver that regulate HCV infection, and 3) Determine the function of NS3/4A to regulate the RIG-I pathway among clinical cases of HCV infected with different viral genotypes. Our studies are linked with the U19 Clinical Core, and Projects 2 and 3 to feature translational approaches aimed at defining the virus-host interface that controls hepatic innate immunity and HCV infection.