During the current funding interval Dr. Chisari established the technology required to detect, quantitative and characterize the cytotoxic T lymphocyte (CTL) response to the hepatitis B and C viruses. Using this technology he defined the salient features of the host-virus relationship during the acute and chronic phases of these infections and, in the process, established the rationale and identified the immunological targets for antigen-specific immunotherapy of chronic hepatitis. Despite these advances, the very early aspects of the host-virus relationship during HBV and HCV infection are completely unexplored because, for practical and ethical reasons, it is extremely difficult to access the incubation period in infected patients. Nonetheless, these early host-virus interactions are likely to be key determinants of the outcome of these infections. In the next funding interval, he will examine the virological, immunological and pathological features of the host-virus relationship from the moment of HBV and HCV infection until their final outcome in experimentally infected chimpanzees. As in humans, almost all adult onset HBV infections in chimps are self limited, while only half of chimp HCV infections are self limited and the rest become persistent. Thus, he will compare and contrast the early intrahepatic T cell responses to HBV and HCV to test the hypothesis that the outcome of these infections is determined by the kinetics, vigor, diversity and cytokine profiles of the intrahepatic T cell response and the ability of the virus to spread and to evade immune recognition during the early incubation period of each infection. Thanks to the close relatedness of chimps and humans, most of the reagents and techniques required to define the intrahepatic antigen specific T cell response to these viruses are already available. The information forthcoming from these studies will, for the first time, define the virological and immunological features of early HBV and HCV infection and determine the extent to which they influence viral clearance and disease pathogenesis in these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI020001-19
Application #
6510302
Study Section
Pathology B Study Section (PTHB)
Program Officer
Taylor, Katherine A
Project Start
1983-07-01
Project End
2003-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
19
Fiscal Year
2002
Total Cost
$511,845
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
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
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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