Hepatitis B virus (HBV) infection is a global public health concern; however, current approval therapies rarely lead to a complete cure. Hepatitis B surface antigen (HBsAg) is the serological marker for HBV infection. It is characterized by three transmembrane proteins having the same C-termini with variable in-frame extension at the N-terminal ends. Naturally, HBsAg proteins are incorporated in the viral envelope or assembled into genome-free and capsid-free subviral particles (SVPs) with the lipid membrane derived from the host cells. Recently, a new therapeutic approach by blocking assembly and release of SVPs has shown promising results in rapidly reducing HBsAg level in chronic HBV- infected patients. Despite its potential clinically relevant applications, there is no structural information available for HBsAg and yet different models of SVPs have been proposed. In this proposal we focus on obtaining the high resolution structures of SVPs from different model systems using cryo-electron microscope (cryo-EM). We will test the central hypothesis that changes in the structural organizations of SVPs will have important implications on their secretion pathway. In Aim 1, we will determine the structures of SVP from woodchuck hepatitis virus (WHV). Woodchuck infected with WHV is a critical experimental model for studying pathogenesis of HBV infection. In Aim 2, we will elucidate the structural details of HBV SVP from carrier's sera and hepatoma cell line. We will use antibodies to spatially label different regions of HBsAg. Finally, all structures determined from this proposal will be compared and used to build a complete picture of SVP with the detailed structural information of Hepadnavirus surface antigen. Successful completion of the proposed project will reveal new structural information of SVPs and will deepen our understanding of HBV particles morphogenesis to facilitate current efforts in finding a cure for HBV infection.
|Effective start/end date||5/19/21 → 4/30/23|
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