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.
|Bengsch, Bertram; Ohtani, Takuya; Herati, Ramin Sedaghat et al. (2017) Deep immune profiling by mass cytometry links human T and NK cell differentiation and cytotoxic molecule expression patterns. J Immunol Methods :|
|Herati, Ramin Sedaghat; Muselman, Alexander; Vella, Laura et al. (2017) Successive annual influenza vaccination induces a recurrent oligoclonotypic memory response in circulating T follicular helper cells. Sci Immunol 2:|
|Stelma, Femke; van der Ree, Meike H; Sinnige, Marjan J et al. (2017) Immune phenotype and function of natural killer and T cells in chronic hepatitis C patients who received a single dose of anti-MicroRNA-122, RG-101. Hepatology 66:57-68|
|Huang, Alexander C; Postow, Michael A; Orlowski, Robert J et al. (2017) T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545:60-65|
|Wolski, David; Foote, Peter K; Chen, Diana Y et al. (2017) Early Transcriptional Divergence Marks Virus-Specific Primary Human CD8+ T Cells in Chronic versus Acute Infection. Immunity 47:648-663.e8|
|Chen, Zeyu; Stelekati, Erietta; Kurachi, Makoto et al. (2017) miR-150 Regulates Memory CD8 T Cell Differentiation via c-Myb. Cell Rep 20:2584-2597|
|Hedegaard, Ditte L; Tully, Damien C; Rowe, Ian A et al. (2017) High resolution sequencing of hepatitis C virus reveals limited intra-hepatic compartmentalization in end-stage liver disease. J Hepatol 66:28-38|
|Sise, Meghan E; Backman, Elke; Ortiz, Guillermo A et al. (2017) Effect of Sofosbuvir-Based Hepatitis C Virus Therapy on Kidney Function in Patients with CKD. Clin J Am Soc Nephrol 12:1615-1623|
|Kurioka, Ayako; Jahun, Aminu S; Hannaway, Rachel F et al. (2017) Shared and Distinct Phenotypes and Functions of Human CD161++ V?7.2+ T Cell Subsets. Front Immunol 8:1031|
|Vergara, C; Thio, C; Latanich, R et al. (2017) Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections. Genes Immun 18:82-87|
Showing the most recent 10 out of 150 publications