The hepatitis B virus (HBV) is a noncytopathic, hepatotropic DMAvirus that causes acute and chronic hepatitis and kills a million people each year from cirrhosis of the liver and hepatocellular carcinoma. Delineation of the mechanisms responsible for viral persistence and disease pathogenesis during HBV infection and the use of that information to develop strategies to terminate chronic HBV infection are the long term objectives of this application. Building on our prior studies showing that the course and severity of acute HBV infection are related to the kinetics, magnitude, and quality of the intrahepatic T cell response, we recently developed a model of persistent HBV infection in young adult chimpanzees. Preliminary evidence suggests that viral persistence in these animals reflects the failure to prime the T cell response at the outset of infection, thus compromising the kinetics, magnitude and quality of the downstream effector functions required to terminate the infection. The establishment of this model is a practical as well as a conceptual breakthrough because, for the first time, it creates the opportunity to study the host-virus interactions responsible for the establishment, maintenance, and termination of chronic HBV infection under controlled experimental conditions in healthy immunocompetent adults. The main objectives of the current application, therefore, are to define the early immunological and molecular events that precede the onset of persistent HBV infection and that evolve during its progression, to apply that knowledge to establish a cohort of persistently infected animals, and to use those animals to examine the therapeutic potential of novel immunomodulatory strategies to eliminate the virus and, hopefully, cure this deadly disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI020001-29
Application #
8204928
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Koshy, Rajen
Project Start
1983-07-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
29
Fiscal Year
2012
Total Cost
$644,514
Indirect Cost
$304,401
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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; 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
Dryden, Kelly A; Wieland, Stefan F; Whitten-Bauer, Christina et al. (2006) Native hepatitis B virions and capsids visualized by electron cryomicroscopy. Mol Cell 22:843-50
Murray, John M; Purcell, Robert H; Wieland, Stefan F (2006) The half-life of hepatitis B virions. Hepatology 44:1117-21
Sidney, John; Asabe, Shinichi; Peters, Bjoern et al. (2006) Detailed characterization of the peptide binding specificity of five common Patr class I MHC molecules. Immunogenetics 58:559-70

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