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)
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Special Emphasis Panel (ZAI1-LAR-I (J1))
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Massachusetts General Hospital
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