Immune response dynamics and hepatitis B cure in persons with and without HIV infection

Summary This proposal aims to understand the role of hepatitis B virus (HBV)-specific B and T cell responses in cure of hepatitis B virus, and how these responses differ in people living with HIV and chronic hepatitis B (PWHHB) relative to people with HBV mono-infection (PWHB). To answer these questions, we will study longitudinal blood samples from a multi-national cohort of persons initiating nucleos(t)ide analog (NUC) treatment for HBV and HIV. The first Aim focuses on defining the relationship between the frequency and function of HBV-specific B cells and HBV cure during NUCs in PWHHB and PWHB. We hypothesize that persons who achieve cure will have stronger HBV-specific B cell responses, and that these responses will be reduced in PWHHB. In the second Aim, we will define the relationship between the specificity and potency of HBV-specific B cells and HBV cure during NUCs in PWHHB and PWHB. We hypothesize that persons with HBV cure will generate a variety of neutralizing antibodies targeting diverse HBV epitopes, and that these responses will be less diverse and less potent in PWHHB who do not achieve HBV cure. In the third Aim, we will define the relationship between the frequency and function of HBV-specific T cells and HBV cure in PWHHB and PWHB. We expect that people with cure will have higher magnitude and more highly functional T cells, and that this response will correlate with better HBV-specific B cell responses. We expect that these T cell responses will be reduced in PWHHB due to HIV-induced CD4 depletion, and improve with NUC treatment. Innovative aspects of this project include the unique cohort of a large number of PWHHB and PWHB followed longitudinally as they experience HBV cure or persistence, and the ability to isolate very rare HBV-specific B cells and T cells for ex vivo study. To date, these cohorts and methods have not existed, explaining the lack of understanding of the role of the immune response in HBV cure. The results from this proposal can be directly translated to the development of novel approaches towards an HBV cure in PWHHB and PWHB, and further our understanding of immune control of chronic viral infections.