The ongoing objective of this Project is to better understand why HCV-specific CD4+ helper and CD8+ cytotoxic T cells fail to control persistent HCV replication and the how they might contribute to liver pathogenesis.
Specific Aims of this application have been refined to answer several key questions. The major objective remains to determine the function of helper and cytotoxic T lymphocytes in the chronically infected liver. The 5 Specific Aims of this extended project have remained the same with some refinements described in the Progress Report and Research Plan sections. The revised Aims are:
Specific Aim 1. Map MHC class Tepitopes that stimulate production of inflammatory or fibrogenic mediators by virus-specific CD8+ T cells and compare their susceptibility to immune selection pressure.
Specific Aim 2. Determine if intrahepatic CD8+ T cells express inhibitory molecules with the potentialto alter effector functions and assess how they are maintainedin the persistently infected liver.
Specific Aim 3. Compare the repertoire and frequency of intrahepatic HCV-specific CD4+ T cells in chronic and resolved infections, and determine if they function to suppress immunity or drive liver disease.
Specific Aim 4. Superinfect persistently viremic chimpanzees with wild-type HCV to test directly the in situ responsiveness of CD4+ and CD8+ T cells. Assess the potential to rescue HCV-specific T cells inchronic hepatitis C by immunotherapeutic intervention.
Specific Aim 5. Determine protective immunity mechanismsin HBV vaccinated and infected chimpanzees.

Public Health Relevance

Chronic hepatitis C is characterized by life-long replication of the hepatitis C virus in liver and increased risk for serious diseases like cirrohsis and even cancer. The goal of this research is explore why the immune system fails to control this virus and strategies to reverse defects that lead to serious progressive liver disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Koshy, Rajen
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Nationwide Children's Hospital
United States
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Mitchell, Jonathan K; Midkiff, Bentley R; Israelow, Benjamin et al. (2017) Hepatitis C Virus Indirectly Disrupts DNA Damage-Induced p53 Responses by Activating Protein Kinase R. MBio 8:
Lanford, Robert E; Walker, Christopher M; Lemon, Stanley M (2017) The Chimpanzee Model of Viral Hepatitis: Advances in Understanding the Immune Response and Treatment of Viral Hepatitis. ILAR J 58:172-189
Walker, Christopher M (2017) Designing an HCV vaccine: a unique convergence of prevention and therapy? Curr Opin Virol 23:113-119
Walker, Christopher M; Lemon, Stanley M (2016) Getting the Skinny on CD4(+) T Cell Survival in Fatty Livers. Immunity 44:725-7
Honegger, Jonathan R; Tedesco, Dana; Kohout, Jennifer A et al. (2016) Influence of IFNL3 and HLA-DPB1 genotype on postpartum control of hepatitis C virus replication and T-cell recovery. Proc Natl Acad Sci U S A 113:10684-9
Rybczynska, Jolanta; Campbell, Katherine; Kamili, Saleem et al. (2016) CD4+ T Cells Are Not Required for Suppression of Hepatitis B Virus Replication in the Liver of Vaccinated Chimpanzees. J Infect Dis 213:49-56
Callendret, Benoit; Eccleston, Heather B; Satterfield, William et al. (2016) Persistent hepatitis C viral replication despite priming of functional CD8+ T cells by combined therapy with a vaccine and a direct-acting antiviral. Hepatology 63:1442-54
Ploss, Alexander; Walker, Christopher (2015) Editorial overview: Progress and challenges in modeling human viral diseases in vivo. Curr Opin Virol 13:v-vii
Walker, Christopher M; Grakoui, Arash (2015) Hepatitis C virus: why do we need a vaccine to prevent a curable persistent infection? Curr Opin Immunol 35:137-43
Honegger, Jonathan R; Zhou, Yan; Walker, Christopher M (2014) Will there be a vaccine to prevent HCV infection? Semin Liver Dis 34:79-88

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