This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Chimpanzees are the only animal other than man that can be infected by HBV. HBV infections often result in chronic infections that progress to cirrhosis and liver cancer. HBV infections are the fourth leading cause of death due to infectious disease worldwide and 350 million people are chronic carriers. Current antivirals are not satisfactory and do not lead to viral clearance. They must be taken for life and eventually resistance makes them useless. It is essential that improved therapies be developed for this disease. The long term goal of this program is to understand how the body eliminates HBV during successful viral clearance and to use this knowledge to generate new therapeutic regimes for antiviral therapy. In this specific proposal, 3 animals will be infected with HBV and analyzed by a group of 4 different laboratories, each bringing a specific specialty to the project. Blood and liver biopsy samples will be collected for 24 weeks after infection until the virus has been resolved. The liver will be examined for viral replication, changes in gene expression, cell death and activation of specific cell types, production of cytokines and infiltration of virus specific T cells. The liver tissue will also be used to determine the level of cell death and regeneration occurring during resolution of the infection. One of the unique features of this grant is the development of methods to monitor single infected cells over time during infection. This is possible because HBV randomly integrates in infected hepatocytes. Each integration can be cloned and is unique at the beginning of infection. As the infection progress and cells are killed by the immune response, the remaining cells divide and thus unique integrations become clusters of 2, 4 and 8 infected cells with the same integration site in the host chromosomal DNA. Mathematical modeling can determine how many times the liver has turned over, the average number of times a cell died and was replaced by division. Thus clonal expansion of cells can be monitored at different times during infection. The actual mechanism of viral clearance has been very controversial, and this grant should resolve the controversy.
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