The program comprises 7 major subthemes - 4 projects, 2 specific cores and one technical development program. The leader of each team has specific expertise in one area of clinical medicine, immunology, cell biology and/or molecular biology. Each on their own has made a significant contribution to the bigger picture of viral pathogenesis in hepatitis C. The key feature of this consortium is that these have been blended to create a scientific team which is more than the sum of its parts, as will be detailed below. Specifically we propose to:- 1. Define the role of the hepatocyte as a key player in innate and adaptive immune responses (Project 1 Chung) 2. Define the specific qualities of tissue homing T cell populations in relation to hepatitis C infection (Project 2, Klenerman). 3. Define the functional capacity of intrahepatic T cell populations in persistent infection (Project 3, Lauer/Wherry). 4. Define the impact of T cell selection pressure on viral sequence evolution and the fitness landscape (Project 4, Allen/Henn). 5. Create a panel of reagents to modulate the surface signaling platform of T cells and antigen presenting cells (Core C/Freeman). 6. Create a library of tissue and cells from well defined clinical cohorts for experimental use (Core D/Misradji). 7. Develop a platform technology to examine and modulate critical signaling pathways that limit the adaptive immune response (TDP/Haining).
Hepatitis C virus (HCV) is a major global health problem. Nearly 170 million people worldwide are infected and a substantial fraction of these will develop chronic liver disease, leading to cirrhosis, liver failure and liver cancer. Current therapies are imperfect and expensive, and no vaccine exists. However, there is ample evidence that the immune system plays a critical role in protection against chronic infection. Thus in its own right Hepatitis C virus is a critical target for research, with the aim of developing improved understanding of the virus and immunology, leading to improved therapies and interventions.
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