The mechanism(s) responsible for hepatocellular injury and malignant transformation following hepatitis B virus (HBV) infection are entirely unknown. Since HBV infection is not directly cytopathic for hepatocytes, the dominant current hypothesis proposes that the cellular immune response destroys infected hepatocytes that express one or more virus encoded antigens on their surface in the context of autologous HLA determinants. This hypothesis has not been testable due to the unavailability of human target cells that co-express the necessary viral and histocompatibility antigens required for a definitive study of antigen specific, HLA restricted T cell mediated cytotoxicity in this disease. Our long term programmatic objective is to test the above hypothesis. Thus, we have developed the technology necessary to produce high level expression of HBV encoded antigens at high efficiency in primary human cell lines of defined HLA phenotype. Using recombinant retroviral, vaccinia and Epstein-Barr virus based expression vectors we are able to express several of the HBV gene products in primary human cells. We have shown that antigens so produced and expressed are recognizable by lymphocytes sensitized in vivo during natural HBV infection. We have also crated the organizational framework necessary for the identification and recruitment of large numbers of patients with acute and chronic hepatitis B virus infection who will provide the materials needed to analyze the peripheral and intrahepatic cellular immune response to HBV. Particular emphasis will be placed on assessment of the prevalence, phenotype, function and antigenic fine specificity of HBV specific cytotoxic T cell lines and clones established in response to cell associated HBV antigens expressed by autologous cell lines engineered to contain our recombinant expression vectors. These results will be correlated with clinical and biochemical parameters of disease activity to examine the possibility of a causal relationship between the two. The results of these studies will elucidate the immunopathogenetic mechanisms responsible for viral clearance and liver cell injury in HBV infection and should also have significant implications for advanced vaccine development and, perhaps, specific immunotherapy of the chronic carrier state, as well.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI020001-09
Application #
3129467
Study Section
Pathology A Study Section (PTHA)
Project Start
1983-07-01
Project End
1993-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
9
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Guidotti, Luca G; Isogawa, Masanori; Chisari, Francis V (2015) Host-virus interactions in hepatitis B virus infection. Curr Opin Immunol 36:61-6
Wieland, Stefan F (2015) The chimpanzee model for hepatitis B virus infection. Cold Spring Harb Perspect Med 5:
Wieland, S F; Asabe, S; Engle, R E et al. (2014) Limited hepatitis B virus replication space in the chronically hepatitis C virus-infected liver. J Virol 88:5184-8
Sitia, Giovanni; Aiolfi, Roberto; Di Lucia, Pietro et al. (2012) Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B. Proc Natl Acad Sci U S A 109:E2165-72
Sitia, Giovanni; Iannacone, Matteo; Aiolfi, Roberto et al. (2011) Kupffer cells hasten resolution of liver immunopathology in mouse models of viral hepatitis. PLoS Pathog 7:e1002061
Bissig, Karl-Dimiter; Wieland, Stefan F; Tran, Phu et al. (2010) Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment. J Clin Invest 120:924-30
Chisari, F V; Isogawa, M; Wieland, S F (2010) Pathogenesis of hepatitis B virus infection. Pathol Biol (Paris) 58:258-66
Asabe, Shinichi; Wieland, Stefan F; Chattopadhyay, Pratip K et al. (2009) The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J Virol 83:9652-62
Sidney, John; Peters, Bjoern; Moore, Carrie et al. (2007) Characterization of the peptide-binding specificity of the chimpanzee class I alleles A 0301 and A 0401 using a combinatorial peptide library. Immunogenetics 59:745-51
Meuleman, Philip; Libbrecht, Louis; Wieland, Stefan et al. (2006) Immune suppression uncovers endogenous cytopathic effects of the hepatitis B virus. J Virol 80:2797-807

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