Molecular characterization of HBV-specific CD4 T cells in acute and chronic hepatitis B infection and HBV Functional Cure with and without HIV co-infection

• Applicant: Dr. Jasmin Mischke
• Subject Area: Immunology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 564169994

Hepatitis B virus remains a global health challenge with worldwide more than 296 million individuals chronically HBV infected. Chronic hepatitis B virus infection can be classified into five stages based on the presence of serological markers, viral load, and levels of the liver enzyme ALT. We know that HBV-specific T cell responses are essential for the control of HBV infection, however, studying HBV-specific T cells is challenging due to their low frequency in blood. Multiple previous investigations have been done to investigate HBV-specific CD8 T cells, however, knowledge about HBV-specific CD4 T cells is rather low and studies have exclusively been performed after in vitro stimulation. Even though analysis of these cells is extremely challenging, there is wide agreement in the field that HBV-specific CD4 T cells are critical for HBV control and that a detailed molecular description of these cells directly ex vivo, would be a critical step for understanding HBV immunopathogenesis and the development of new immunotherapeutic approaches. Co-infection with HIV complicates the natural history of CHB and is found in about 1% of PLWHB worldwide, but in some regions (e.g. Africa), the prevalence of HBV-HIV co-infection is up to 15%. Interestingly, there is increasing evidence that initiation of antiviral treatment for both HIV and HBV in this population has higher rates of FC compared to HBV alone, opening a window to study the immunological correlation of HBV cure. With our project, we aim to characterize the different molecular profiles of HBV-specific CD4 T cells in acute HBV, the different stages of chronic HBV infection and in HBV Functional Cure in HBV mono-infected and HBV/HIV co-infected individuals. To define what molecular profiles and functions of HBV-specific CD4 T cell responses associate with HBV FC, but also what states of dysfunction or dysregulation in chronic infection need to be overcome by curative immunotherapies, it is essential to deeply characterize HBV CD4 immunity on the molecular level in the different stages of HBV infection. It is also important to study persons living with HBV and HIV, since they will pose significant additional challenges for CD4 mediated HBV control. Therefore, we will work together with cooperation partners in Zambia and Brazil, where we recruit large numbers of newly diagnosed and thus untreated people living with HBV or HBV/HIV. As a first approach, we plan to expand our library of HBV-specific CD4 T cell epitopes for multimer construction together with our cooperation partner in Denmark. This allows us to generate a much larger HBV CD4 epitope library, which we can use to study more of our participants, and this will also be helpful for many other investigators in the field. We then plan to characterize HBV-specific CD4 T cells in our different participant groups ex vivo in terms of function and phenotype by ICS, single cell RNA-sequencing and high dimensional spectral flow phenotyping.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Georg M. Lauer