This project aims to understand the mechanisms underlying key immune defects occurring during chronic virus infection and the ability ofthe relevant cell populations to recover after effective virologic cure. The focus of this study is Hepatitis C Virus (HCV) a pathogen infecting 170 million people globally and a major cause of liver disease and liver cancer. HCV is highly suitable for analysis of human infection because of the robust outcomes of persistent vs naturally cleared infection, and the demonstrated role of T cell subsets in this outcome.The project harnesses advances in 3 areas to allow for experimental in vivo and ex vivo study of these responses. A) The development of effective directly acting antiviral agents (DAAs) such that DAA-mediated cure may be achieved without interferon. B) The ability to induce robust antiviral T cell populations in vivo using combinations of virally vectored vaccine constructs. This protocol - using material already available - allows for controlled analysis of CD4+ and CD8+ T cell responses to vaccine and non-vaccine HCV antigens, antigens within the vector (adenovirus), and unrelated antigens. C) The definition of novel, dominant intrahepatic CD8+ T cell populations during the last U19 period - notably the CDl61++ subset, which represent up to 50% of the CD8+ T cell liver infiltrate and are dysregulated during chronic infection. The relevant populations will be studied using mulfiparametric flow cytometry and Cytof, analysis of gene expression and regulation after tetramer-sorting, and analysis of TCR usage to explore their function, phenotype and regulation. Two major aims will be addressed:
AIM 1 : To test whether HCV-specific memory CD4+ and CD8+ T cell pools induced in the presence or absence of HCV infection share common pathways of regulation and differentiation and assess the impact of DAA-mediated cure.
AIM 2 : To test whether common molecular and cellular mechanisms exist for negative regulation of distinct HCV-specific and non HCV-specific T cells, including liver-homing T cell populations and whether DAA-mediated cure can reverse this regulation.

Public Health Relevance

Hepatitis C virus is a major global health problem, causing liver failure and cancer. Resistance to infection is mediated in part through effective T cell responses, which are severely dyregulated during chronic infection. With advent of novel antiviral drugs mediating cure, we can examine immunologic recovery, defining the protective capacity of such cured populations and the mechanisms underpinning their dysfunction.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-LAR-I (J1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
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:

Showing the most recent 10 out of 128 publications