The T cell response to HCV infection is characterized by a range of functional defects collectively termed exhaustion, however the mechanisms that specify this defective state, and the potential for recovery of T cell exhaustion are not known. In this project we will define the global epigenetic state of T cell exhaustion in order to understand the mechanisms that regulate HCV-specific T cell function and the potential for reversibility of exhaustion following elimination of the virus. To achieve this goal, we have optimized assays to generate global histone modification maps from only a few thousand cells, allowing us to study directly the epigenetic state of antigen-specific cells from humans.
AIM 1 : Define the chromatin landscape of CDS T cells specific for chronic vs. acute infection. Our hypothesis is that T cell exhaustion is associated with specific alterations of the profile of chromatin modification in CDS T cells. We will undertake comparative epigenetic analysis of CDS T cells specific for HCV, CMV and influenza virus to determine if chronic infection is associated with global and gene-specific differences in chromatin state. We will identify and experimentally validate candidate regulators of the exhausted CDS T cells We will also use the mouse model of chronic LCMV infection to study the epigenetic state of exhausted CDS T cells over time, validating our findings in humans.
AIM 2. Determine whether the epigenetic state of HCV-specific CDS T cells is altered by cure of infection. Our hypothesis is that cure of HCV with direct acting antiviral (DAA) therapy will be associated with a partial remodeling of the epigenetic landscape of exhaustion. We will compare the epigenetic state of HCV-specific CDS T cells in the same individual before and after DAA therapy. We will use the chronic LCMV model to test whether increasing duration of infection and exposure to Type 1 interferons "cements" the epigenetic and functional state of exhausted CDS T cells. Our proposal is significant because it will determine whether the differentiation state of exhausted CDS T cells is regulated at the epigenetic level. It will identify and validate novel TFs that are differentially active in exhausted CDS T cells. It will determine whether the epigenetic state of exhausted CD8T cells can change following cure of chronic infection.

Public Health Relevance

HCV is associated with profound defects in the function of virus-specific T cells but the mechanisms that regulate exhausted T cells, and the potential for reversibility with antiviral therapy are not fully understood. This project will map the epigenetic regulatory landscape of CDS T cells responding to chronic viral infection and test if this landscape is altered by cure of infection.

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
Lin, Wenyu; Zhu, Chuanlong; Hong, Jian et al. (2015) The spliceosome factor SART1 exerts its anti-HCV action through mRNA splicing. J Hepatol 62:1024-32
Jilg, Nikolaus; Lin, Wenyu; Hong, Jian et al. (2014) Kinetic differences in the induction of interferon stimulated genes by interferon-* and interleukin 28B are altered by infection with hepatitis C virus. Hepatology 59:1250-61
Kroy, Daniela C; Ciuffreda, Donatella; Cooperrider, Jennifer H et al. (2014) Liver environment and HCV replication affect human T-cell phenotype and expression of inhibitory receptors. Gastroenterology 146:550-61
Lee, Mark N; Ye, Chun; Villani, Alexandra-ChloƩ et al. (2014) Common genetic variants modulate pathogen-sensing responses in human dendritic cells. Science 343:1246980
Crawford, Alison; Angelosanto, Jill M; Kao, Charlly et al. (2014) Molecular and transcriptional basis of CD4? T cell dysfunction during chronic infection. Immunity 40:289-302
Feeney, Eoin R; Chung, Raymond T (2014) Antiviral treatment of hepatitis C. BMJ 348:g3308
Fackler, Oliver T; Murooka, Thomas T; Imle, Andrea et al. (2014) Adding new dimensions: towards an integrative understanding of HIV-1 spread. Nat Rev Microbiol 12:563-74
Xiao, Yanping; Yu, Sanhong; Zhu, Baogong et al. (2014) RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance. J Exp Med 211:943-59
Veerapu, Naga Suresh; Park, Su-Hyung; Tully, Damien C et al. (2014) Trace amounts of sporadically reappearing HCV RNA can cause infection. J Clin Invest 124:3469-78
Ussher, James E; Bilton, Matthew; Attwod, Emma et al. (2014) CD161++ CD8+ T cells, including the MAIT cell subset, are specifically activated by IL-12+IL-18 in a TCR-independent manner. Eur J Immunol 44:195-203

Showing the most recent 10 out of 72 publications