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.
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.
|Honegger, Jonathan R; Zhou, Yan; Walker, Christopher M (2014) Will there be a vaccine to prevent HCV infection? Semin Liver Dis 34:79-88|
|Callendret, Benoit; Eccleston, Heather B; Hall, Shelby et al. (2014) T-cell immunity and hepatitis C virus reinfection after cure of chronic hepatitis C with an interferon-free antiviral regimen in a chimpanzee. Hepatology 60:1531-40|
|Honegger, Jonathan R; Kim, Seungtaek; Price, Aryn A et al. (2013) Loss of immune escape mutations during persistent HCV infection in pregnancy enhances replication of vertically transmitted viruses. Nat Med 19:1529-33|
|Fuller, Michael J; Callendret, Benoit; Zhu, Baogong et al. (2013) Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1). Proc Natl Acad Sci U S A 110:15001-6|
|Callendret, Benoît; Bukh, Jens; Eccleston, Heather B et al. (2011) Transmission of clonal hepatitis C virus genomes reveals the dominant but transitory role of CD8? T cells in early viral evolution. J Virol 85:11833-45|
|Gottwein, Judith M; Scheel, Troels K H; Callendret, Benoit et al. (2010) Novel infectious cDNA clones of hepatitis C virus genotype 3a (strain S52) and 4a (strain ED43): genetic analyses and in vivo pathogenesis studies. J Virol 84:5277-93|
|Uebelhoer, Luke; Han, Jin-Hwan; Callendret, Benoit et al. (2008) Stable cytotoxic T cell escape mutation in hepatitis C virus is linked to maintenance of viral fitness. PLoS Pathog 4:e1000143|
|Erickson, A L; Kimura, Y; Igarashi, S et al. (2001) The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes. Immunity 15:883-95|