This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hepatitis B virus (HBV) infections represent a major worldwide health problem with an estimated 300 million chronic carriers many of whom will develop cirrhosis and liver cancer. A great need exists to better understand the molecular biology of hepadnaviral replication to accelerate the development of new antiviral strategies to eliminate the chronic carrier state. One component to creating better antivirals is evaluation in animal models. The current models (ducks, woodchucks and chimpanzees) have limitations that make them less than optimal models. Therefore, a great need exists to create a better animal model for evaluating antiviral strategies. This proposal directly addresses this need by more fully characterizing the recently isolated woolly monkey hepatitis B virus (WMHBV) and a non-human primate model for research with this virus. In addition, the availability of two closely related viruses (WMHBV and HBV) with distinct phenotypic differences offers many opportunities for exploring the molecular biology of hepadnavirus replication. Thus, we hypothesize that the host range differences between these closely related viruses is dictated by sequence divergence in the perS1 domain that leads to differences in species-specific receptor interactions, and furthermore that appropriate exploitation of this virus-animal model will lead to identification of the human HBV cell receptor.
The specific aims are the following: 1) to determine the host range of WMHBV; 2) to develop an infectious clone of WMHBV DNA; 3) to develop a primary hepatocyte tissue culture system susceptible to infection with WMHBV; 4) to explore the viral sequences in the preS1 domain of the large surface protein as determinants of host range using hepatitis D virus (HDV) pseudotyped with HBV and WMHBV surface proteins; and 5) to identify potential hepadnavirus cell receptor proteins by defining the hepatocyte binding proteins for HBV and WMHBV preS1 proteins.
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