The pathogenetic mechanisms responsible for the induction of hepatocellular injury and viral clearance in hepatitis B virus (HBV) infection remain to be clarified. Our studies in this area have been focussed during the last 2 years on the peripheral blood helper T cell reactivity to HBV envelope and nucleocapsid antigens in order to compare the features of these responses in patients who successfully clear the virus with those who do not. Results of such studies indicate 1) that a strong magnitude peripheral blood helper T cell response to HBV nucleocapsid antigens is temporally associated with viral clearance and focussed on an immunodominant epitope within the hepatitis B core antigen (HBcAg); 2) that the peripheral blood helper T cell response to HBV envelope antigens is weak and inconstant during HBVjinfection, but is readily detectable in high responder vaccine recipients who are particularly responsive to multiple determinants within the preS 1 region of the envelope proteins. Although our results suggest that the helper T cell response to HBcAg plays an important role in HBV clearance, definitive demonstration requires parallel analysis of the helper, suppressor and cytotoxic T cell responses to HBV antigens in the peripheral blood and intrahepatic compartments, since the peripheral blood may only partially reflect the immune events taking place at the site of infection and injury. Therefore, our proposal is primarily aimed at investigating the relative importance of the different HBV antigens as sensitizing molecules for intrahepatic T cells from patients at different stages of HBV infection and the relative representation of the different T cell functions (helper, suppressor and cytotoxic) among T cell populations of different HBV antigen specificity. The study will be primarily carried out at the clonal level assessing phenotype, fine specificity, HLA-restriction, function and frequency of HBV-specific T cells. When the magnitude and quality of the peripheral blood and intrahepatic T cell responses to HBV encoded antigens have been compared, it should be possible to determine the extent to which the HBV antigen-specific T cell response is pathogenetically related to virus induced injury and to viral clearance in this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI026626-05
Application #
3140457
Study Section
Experimental Virology Study Section (EVR)
Project Start
1988-09-30
Project End
1997-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
5
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Boni, C; Bertoletti, A; Penna, A et al. (1998) Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B. J Clin Invest 102:968-75
Bertoni, R; Sidney, J; Fowler, P et al. (1997) Human histocompatibility leukocyte antigen-binding supermotifs predict broadly cross-reactive cytotoxic T lymphocyte responses in patients with acute hepatitis. J Clin Invest 100:503-13
Penna, A; Del Prete, G; Cavalli, A et al. (1997) Predominant T-helper 1 cytokine profile of hepatitis B virus nucleocapsid-specific T cells in acute self-limited hepatitis B. Hepatology 25:1022-7
Bertoletti, A; Southwood, S; Chesnut, R et al. (1997) Molecular features of the hepatitis B virus nucleocapsid T-cell epitope 18-27: interaction with HLA and T-cell receptor. Hepatology 26:1027-34
Bertoletti, A; D'Elios, M M; Boni, C et al. (1997) Different cytokine profiles of intraphepatic T cells in chronic hepatitis B and hepatitis C virus infections. Gastroenterology 112:193-9
Missale, G; Cariani, E; Lamonaca, V et al. (1997) Effects of interferon treatment on the antiviral T-cell response in hepatitis C virus genotype 1b- and genotype 2c-infected patients. Hepatology 26:792-7
Missale, G; Bertoni, R; Lamonaca, V et al. (1996) Different clinical behaviors of acute hepatitis C virus infection are associated with different vigor of the anti-viral cell-mediated immune response. J Clin Invest 98:706-14
Penna, A; Artini, M; Cavalli, A et al. (1996) Long-lasting memory T cell responses following self-limited acute hepatitis B. J Clin Invest 98:1185-94
Chisari, F V; Ferrari, C (1995) Hepatitis B virus immunopathology. Springer Semin Immunopathol 17:261-81
Chisari, F V; Ferrari, C (1995) Hepatitis B virus immunopathogenesis. Annu Rev Immunol 13:29-60

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