Chronic hepatitis B virus (HBV) infection remains a major global health problem despite of effective HBV vaccine, affecting 240 million people worldwide and 1.25 million Americans. HBV is a leading cause of liver diseases such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Prophylactic HBV vaccine is effective to prevent new HBV infection but does not offer therapeutic benefit to the hundreds of million people already infected with HBV. Current antiviral drugs consisting of interferon and nucleoside analogues are not curative of hepatitis B. The World Health Organization has called for the elimination of viral hepatitis as a public health threat by 2030. The biggest challenge for a cure of hepatitis B is how to eliminate HBV covalently closed circular DNA (cccDNA), which is the molecular basis for persistent viral replication. Thus, there is an urgent need to discover and develop new classes of more efficacious antiviral drugs for curing hepatitis B. The lack of robust cell culture and small animal models of HBV propagation is a major barrier towards finding a cure for hepatitis B. Recently, we have developed a robust HBV cell culture system. More significantly, we have discovered that human apolipoprotein E (apoE) is enriched on the HBV envelope and promotes HBV infection and production. Our preliminary studies also found that the low-density lipoprotein receptor (LDLR) and several core proteins of heparan sulfate proteoglycans (HSPGs) are important for HBV infection. We hypothesize that the LDLR family proteins and HSPGs serve as cell surface receptors promoting HBV infection. Our overall goal is to determine the roles and underlying molecular mechanism of the LDLR family proteins and HSPGs in HBV infection in vitro and in vivo. This objective will be addressed by three specific aims: 1) to determine the importance and molecular mechanism of the LDLR family proteins in HBV infection; 2) to define the role and molecular basis of HSPGs in HBV infection; and 3) to determine the physiological importance of LDLR in HBV infection in vivo using humanized mice and a new transgenic HBV mouse model. The successful completion of this application will fill a knowledge gap about new HBV attachment receptors and provide novel targets and transgenic HBV mouse model for discovery and development of new therapeutics towards a cure of chronic hepatitis B.