The he'patitiS'Bvirus (HBV) is a major cause of infectious liver disease throughout the world. There are 1.2 million carriers of HBV in the U.S. and approximately 400 million worldwide. Neonatal HBV infection is rarely cleared and as many as 90% of perinatally infected children become chronically infected. Therefore, in addition to worldwide vaccine programs to prevent new infections, methods for treating HBV chronic carriers will be necessary to eradicate this disease. This proposal is focused on understanding the mechanisms responsible for inducing and maintaining chronic HBV infection and more specifically the role of HBV nucleoprotein antigens, the nueleocapsid (HBcAg) and the secreted non-particulate HBeAg. Armed with this information we are designing immunotherapeutic vaccine candidates for the treatment of chronic hepatitis B infection.
The specific aims are addressed through the use of HBc/HBeAg-expressing and HBV replicating tra'nsgehic(Tg) mice and three recently developed HBc/HBeAg-specific T cell receptor (TCR)-Tg lineages and the Various combinations of "double and triple-Tg" hybrids.
The specific aims are: (1) determine mechanisms of HBeAg-induced t cell tolerance at the cellular and molecular levels;(2) examine the relationship between HBc/HBeAg-specific CD4+ and CD8+ T cells;(3) explore the reasons for "split tolerance" between the HBcAg and the HBeAg at the cellular and molecular levels;and (4) develop strategies to reverse or bypass HBeAg-induced T cell tolerance as possible immunotherapies for chronic HBV infection. During the previous years of this project we have developed a number of Tg model systems that will facilitate the pursuit of the current specific aims. For example, four in vivo models of HBeAg-induced T cell tolerance mediate'd by clohal deletion, clonal anergy, clonal ignorance and T regulatory (Treg) cells have been developed. Furthermore, models of in vivo anti-HBc and anti-HBe seroconversion and CD4+ T cell-mediated liver injury have been developed. These model systems should be very useful in elucidating the mechanisms of T cell tolerance that play an important role in promoting viral persistence during chronic HBV infection and in designing candidate vaccines for treating chronic HBV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI020720-28
Application #
8009781
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Berard, Diana S
Project Start
1984-05-01
Project End
2012-06-30
Budget Start
2011-01-01
Budget End
2012-06-30
Support Year
28
Fiscal Year
2011
Total Cost
$777,154
Indirect Cost
Name
Vaccine Research Institute of San Diego
Department
Type
DUNS #
198527298
City
San Diego
State
CA
Country
United States
Zip Code
92109
Lee, Byung O; Jones, Joyce E; Peters, Cory J et al. (2011) Identification of a unique double-negative regulatory T-cell population. Immunology 134:434-47
Nystrom, Jessica; Chen, Antony; Frelin, Lars et al. (2010) Improving on the ability of endogenous hepatitis B core antigen to prime cytotoxic T lymphocytes. J Infect Dis 201:1867-79
Ameiss, Keith; Ashraf, Shamaila; Kong, Wei et al. (2010) Delivery of woodchuck hepatitis virus-like particle presented influenza M2e by recombinant attenuated Salmonella displaying a delayed lysis phenotype. Vaccine 28:6704-13
Frelin, Lars; Wahlstrom, Therese; Tucker, Amy E et al. (2009) A mechanism to explain the selection of the hepatitis e antigen-negative mutant during chronic hepatitis B virus infection. J Virol 83:1379-92
Lee, Byung O; Tucker, Amy; Frelin, Lars et al. (2009) Interaction of the hepatitis B core antigen and the innate immune system. J Immunol 182:6670-81
Whitacre, David C; Lee, Byung O; Milich, David R (2009) Use of hepadnavirus core proteins as vaccine platforms. Expert Rev Vaccines 8:1565-73
Billaud, Jean-Noel; Peterson, Darrell; Lee, Byung O et al. (2007) Advantages to the use of rodent hepadnavirus core proteins as vaccine platforms. Vaccine 25:1593-606
Frelin, L; Brenndorfer, E D; Ahlen, G et al. (2006) The hepatitis C virus and immune evasion: non-structural 3/4A transgenic mice are resistant to lethal tumour necrosis factor alpha mediated liver disease. Gut 55:1475-83
Billaud, Jean-Noel; Peterson, Darrell; Barr, Margaret et al. (2005) Combinatorial approach to hepadnavirus-like particle vaccine design. J Virol 79:13656-66
Billaud, Jean-Noel; Peterson, Darrell; Schodel, Florian et al. (2005) Comparative antigenicity and immunogenicity of hepadnavirus core proteins. J Virol 79:13641-55

Showing the most recent 10 out of 73 publications