Project Summary The overarching goal of this multi-PI R01 proposal is to identify the mediators of functional cure of hepatitis B virus (HBV) infection in the cellular and humoral immune responses. Understanding the immune correlates of HBV functional cure, but also the molecular pathways involved in the immune dysregulation leading to persistent HBV infection and hepatitis will greatly facilitate design of effective immunotherapies and therapeutic vaccinations. HBV chronically infects >250 million people and remains a significant public health burden, despite the availability of an effective prophylactic vaccine for more than 30 years. While some infected individuals can naturally control viral replication, known as functional cure, the required immune conditions, particularly in the CD4 T cell and B cell responses, are undefined. Similarly, the exact mechanisms of how HBV-specific CD4 T cell and B cell responses are subverted in persistent infection remains unclear. In this study, we will study the immune responses of well-defined clinical cohorts across the different HBV infection outcomes. The two aims are: (1) to define HBV-specific CD4 T cell functions and the molecular signatures important in immune suppression versus cure; (2) to define HCV-specific humoral responses and the molecular signatures in B cells associated with viral pathogenesis and cure. The two highly complementary and synergistic aims will be analyzed in a highly integrated systems approach, allowing novel understanding of how CD4 T cells, antibodies and B cells synergize in order to control HBV infection. By using the same tissue specimens from the clinical cohorts for all we will achieve a holistic and integrated understanding of the immune landscapes presented in the different manifestations caused by HBV infection. The results have the potential to guide novel immunotherapeutic approaches aimed at inducing sustained control of HBV without the need for life-long antiviral treatments.