The long-term goal is to develop a novel immune therapeutic approach to treating chronic HBV infection. There is currently no cure for the 350 million patients who are already chronically infected with hepatitis B virus (HBV). HBV replication can be effectively inhibited by anti-HBV drugs, but HBsAg is still expressed from HBV cccDNA or integrated genomes. The mechanisms of HBV-induced liver diseases, including chronic infection, immune responses, fibrosis/cirrhosis and liver cancer, are unclear due to a lack of relevant animal models. This project will take advantage of four key novel advancements in the PIs'groups: i) a novel humanized mouse model with human immune system &human liver (AFC8-hu HSC/Hep mice) that supports HBV infection, immune responses, hepatitis and fibrosis in the humanized liver;ii) human monoclonal antibodies (mAb) with high affinity to HBsAg that can neutralize HBV and clear extracellular HBs in vivo;iii) the newly developed AAV/HBV1.3 model in immune competent neonate and young adult mice;and iv) the LIGHT-based therapeutic vaccine approach that overcomes immune tolerance in the liver. We hypothesize that, by reducing HBV virions/HBsAg with antivirals and high affinity HBs mAb, the LIGHT-based HBV therapeutic vaccine will be effective to break HBV-induced immune tolerance, induce anti-HBV immunity and cure HBV infection. With complementary expertise, the two PIs will thus address the following specific questions related to HBV- induced immunopathology and immune therapeutics: (i) How does HBV infection modulate human T cell function in the liver and spleen/LN in vivo? (ii) What is the role of HBV persistence and PD1/TIM3 in impaired human immune responses in the liver? (iii) Will Ad-LIGHT-HBs vaccination (with HBs clearance mAb and antiviral) be able to cure an ongoing HBV infection? (iv) Is preS1 a better target than HBsAg to break tolerance to induce HBV neutralizing antibodies? Answers to these questions will have a significant impact on the field. The key findings will be confirmed in HBV-infected patients, and in future clinical trials.

Public Health Relevance

This project proposes to develop a novel immune therapeutic approach to treating chronic hepatitis B virus (HBV) infection, using a novel humanized mouse model with both a human immune system and human liver cells. The findings will establish the foundation for future study and shed light on novel therapeutic strategies of chronic diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Immunity and Host Defense Study Section (IHD)
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Doo, Edward
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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