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).

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI082630-04
Application #
8277265
Study Section
Special Emphasis Panel (ZAI1-KS-I (J4))
Program Officer
Quill, Helen R
Project Start
2009-06-08
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$2,902,971
Indirect Cost
$921,752
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Rowe, Ian A; Tully, Damien C; Armstrong, Matthew J et al. (2016) Effect of scavenger receptor class B type I antagonist ITX5061 in patients with hepatitis C virus infection undergoing liver transplantation. Liver Transpl 22:287-97
Fergusson, J R; Hühn, M H; Swadling, L et al. (2016) CD161(int)CD8+ T cells: a novel population of highly functional, memory CD8+ T cells enriched within the gut. Mucosal Immunol 9:401-13
Attanasio, John; Wherry, E John (2016) Costimulatory and Coinhibitory Receptor Pathways in Infectious Disease. Immunity 44:1052-68
Llibre, Alba; López-Macías, Constantino; Marafioti, Teresa et al. (2016) LLT1 and CD161 Expression in Human Germinal Centers Promotes B Cell Activation and CXCR4 Downregulation. J Immunol 196:2085-94
Kurioka, Ayako; Walker, Lucy J; Klenerman, Paul et al. (2016) MAIT cells: new guardians of the liver. Clin Transl Immunology 5:e98
van Wilgenburg, Bonnie; Scherwitzl, Iris; Hutchinson, Edward C et al. (2016) MAIT cells are activated during human viral infections. Nat Commun 7:11653
Jeffery, Hannah C; van Wilgenburg, Bonnie; Kurioka, Ayako et al. (2016) Biliary epithelium and liver B cells exposed to bacteria activate intrahepatic MAIT cells through MR1. J Hepatol 64:1118-27
Kelly, Christabel; Swadling, Leo; Capone, Stefania et al. (2016) Chronic hepatitis C viral infection subverts vaccine-induced T-cell immunity in humans. Hepatology 63:1455-70
Chusri, Pattranuch; Kumthip, Kattareeya; Hong, Jian et al. (2016) HCV induces transforming growth factor β1 through activation of endoplasmic reticulum stress and the unfolded protein response. Sci Rep 6:22487
Swadling, Leo; Halliday, John; Kelly, Christabel et al. (2016) Highly-Immunogenic Virally-Vectored T-cell Vaccines Cannot Overcome Subversion of the T-cell Response by HCV during Chronic Infection. Vaccines (Basel) 4:

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