Project Summary/Abstract Among people living with HIV (PLWH), hepatitis B virus (HBV) is a common coinfection that contributes to high rates of liver-related mortality. Even with early initiation of antiretroviral therapies that include HBV-active nucleoside analogs (NA), mortality in people with HBV/HIV coinfection remains unacceptably high. There is a strong rationale for additional HBV therapies for people with HBV/HIV infection. The HBV cure research agenda is to (1) understand HBV biology, particularly the mechanisms that lead to HBV functional cure (FC), which is defined as seroclearance of the hepatitis B surface antigen in blood, and (2) to evaluate novel antiviral and/or immunotherapies that can increase HBV FC from its current rate of ~1% per year. However, at the present, PLWH are poorly represented in HBV cure research, and HIV infection is an exclusion criterion in virtually all clinical trials of novel HBV therapeutics. To accelerate the use of novel therapies in patients with HBV/HIV coinfection, a better understanding is needed of host control of HBV in the setting of HIV. This project focuses on cellular immune mechanisms of HBV control, particularly HBV-specific T cells. Our central hypothesis is that in HBV/HIV coinfection, CD4 T cells represent a critical component of the immune response mediating HBV control, including FC. This hypothesis will be tested through 3 specific aims. In Aim 1, we will investigate the impact of HIV coinfection-associated immune dysregulation, especially CD4 depletion, on the quantity and quality of HBV-specific T cell responses. In Aim 2, we will investigate the T-cell responses mediating HBV FC in patients with HBV/HIV coinfection who are treated during inactive HBV infection (i.e., low HBV DNA, normal ALT, no-minimal liver disease). In this group, we previously reported relatively high rates of HBV FC. In Aim 3, we will characterize the evolution of HBV-specific T cell responses and the intrahepatic immune landscape during adult acute HBV infection that typically results in HBV FC, with and without HIV coinfection. The above scientific investigation will occur within a unique HBV clinical cohort in Zambia (Southern Africa), which includes adult patients with chronic and acute HBV infection, with and without HIV coinfection, and features longitudinal large volume blood and liver sampling before and during NA therapy. To date HBV FC has been ascertained >40 times in the cohort, mainly in participants with HBV/HIV coinfection. Successful completion of this project will change the field by identifying immune mediators associated with HBV FC in HBV/HIV coinfection and by defining specific immunological barriers to HBV FC in PLWH. It also will help to identify patient groups with coinfection who may be more or less amenable to cure with emerging drugs based on their current or nadir CD4 and current level of HBV control. In-depth analysis of specific CD4 T cells and the intrahepatic immune milieu will al...