application) Up to 3% of the world population is infected with hepatitis C virus (HCV), a hepatotropic RNA virus that causes acute and chronic hepatitis as well as cirrhosis and hepatocellular carcinoma. HCV infection results in chronicity in most cases (85%) despite the presence of antiviral immune response. While the basis for high rate of persistent infection is not well defined, the role of cellular immunity in the outcome of HCV infection can be directly examined by comparing patients with HCV clearance, persistence and resistance The central hypothesis in this application is that viral clearance is mediated by phenotypically distinct T cell response and that these features are present in patients with spontaneous viral clearance, in patients who successfully eradicate the virus after antiviral therapy and in resistant individuals who remain uninfected despite recurrent high risk exposures. Furthermore, the role of virus sequence heterogeneity in modifying this process is examined. The four hypotheses being tested in this application are as follows: First, HCV clearance is mediated by phenotypically distinct Thl/Tcl type T cell responses; Second, HCV clearance during antiviral therapy is mediated by a switch in the phenotype of virus-specific T cell response; Third, viral epitope sequence variations modify HCV-specific CTL response; Fourth, protective cellular immunity to HCV is present in individuals who remain uninfected despite frequent exposure. It is hoped that a better understanding of the cellular immune response during successful viral clearance would lead to development of strategies to eliminate chronic HCV infection and prevent its long term sequelae.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047519-02
Application #
6171208
Study Section
Special Emphasis Panel (ZDK1-GRB-5 (M1))
Program Officer
Johnson, Leslye D
Project Start
1999-09-30
Project End
2004-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
2
Fiscal Year
2000
Total Cost
$224,698
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ojiro, Keisuke; Qu, Xiaowang; Cho, Hyosun et al. (2017) Modulation of Hepatitis C Virus-Specific CD8 Effector T-Cell Function with Antiviral Effect in Infectious Hepatitis C Virus Coculture Model. J Virol 91:
Park, Jang-June; Wong, David K; Wahed, Abdus S et al. (2016) Hepatitis B Virus--Specific and Global T-Cell Dysfunction in Chronic Hepatitis B. Gastroenterology 150:684-695.e5
Bunchorntavakul, Chalermrat; Jones, Lisa M; Kikuchi, Masahiro et al. (2015) Distinct features in natural history and outcomes of acute hepatitis C. J Clin Gastroenterol 49:e31-40
Cho, Hyosun; Kikuchi, Masahiro; Li, Yun et al. (2014) Induction of Multiple Immune Regulatory Pathways with Differential Impact in HCV/HIV Coinfection. Front Immunol 5:265
Aleksic, Milos; Liddy, Nathaniel; Molloy, Peter E et al. (2012) Different affinity windows for virus and cancer-specific T-cell receptors: implications for therapeutic strategies. Eur J Immunol 42:3174-9
Doi, Hiroyoshi; Iyer, Tara K; Carpenter, Erica et al. (2012) Dysfunctional B-cell activation in cirrhosis resulting from hepatitis C infection associated with disappearance of CD27-positive B-cell population. Hepatology 55:709-19
Chang, Kyong-Mi (2010) Hepatitis B immunology for clinicians. Clin Liver Dis 14:409-24
Lanford, Robert E; Evans, Matthew J; Lohmann, Volker et al. (2009) The accelerating pace of HCV research: a summary of the 15th International Symposium on Hepatitis C Virus And Related Viruses. Gastroenterology 136:9-16
Cox, Andrea L; Page, Kimberly; Bruneau, Julie et al. (2009) Rare birds in North America: acute hepatitis C cohorts. Gastroenterology 136:26-31
Carpenter, Erica L; Mick, Rosemarie; Rech, Andrew J et al. (2009) Collapse of the CD27+ B-cell compartment associated with systemic plasmacytosis in patients with advanced melanoma and other cancers. Clin Cancer Res 15:4277-87

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