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 their surface in the context of autologous HLA determinants. This hypothesis has not been tested due to the unavailability of human target cells that co-express the appropriate viral and histocompatibility antigens that are required for 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 stable, high level, expression of HBV encoded antigens at high efficiency in primary human cell lines of defined HLA phenotype. Using a unique family of recombinant amphotropic retroviruses containing a postitive selectable marker (neo) plus the coding regions for all the known hepatitis B virus antigens, drug resistant lines of primary human fibroblasts that synthesize and secrete native HBsAg have recently been produced. The gene product is authentic in terms of buoyant density, morphology, mean diameter, polypeptide composition, and antigenicity. This illustrates that the constructs faithfully represent the native coding regions and it suggests that they will direct the synthesis by human target cells of native HBV encoded antigens. Antigens so produced and expressed should be recognizable by lymphocytes sensitized in vivo during natural HBV infection. We have also created the organizational framework necessary for the identification and recruitment of large numbers of patients with acute and chronic hepatitis B virus infection and the collection, processing and storage of specimens for immunologic analysis. To date nearly 50 patient volunteers have entered our program and we are adding new subjects at a rate of about one each week. At this rate between 200-250 subjects will constitute the study group for these experiments. Using these tools we will analyze the cellular immune response to each of the HBV encoded antigens in the context of self HLA. 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 effector cell(s) will be identified and the important regulatory events that may influence the quality and magnitude of the cellular immune response will be examined.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI020001-06S1
Application #
3129462
Study Section
Pathology B Study Section (PTHB)
Project Start
1983-07-01
Project End
1990-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
6
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92037
Wieland, Stefan F (2015) The chimpanzee model for hepatitis B virus infection. Cold Spring Harb Perspect Med 5:
Guidotti, Luca G; Isogawa, Masanori; Chisari, Francis V (2015) Host-virus interactions in hepatitis B virus infection. Curr Opin Immunol 36:61-6
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
Guidotti, Luca G; Chisari, Francis V (2006) Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol 1:23-61

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