Project TP 2

(R. Thimme)

Immunopathogenesis of hepatitis B virus and hepatitis C virus infection

Virus-specific CD8+ T cell responses play a major role in outcome and pathogenesis of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. By using immunological cell culture models provided by the FOR, our group has yielded several novel insights into success and failure of these virus-specific CD8+ T cell responses in controlling infection. During the second funding period we will address two main aspects. The first one deals with the relative contribution of HBV specific effector functions to antiviral efficacy. The relative contribution of cytolytic versus non-cytolytic effector mechanisms in HBV control is poorly defined. Indeed, studies in HBV-transgenic mice have indicated a dominant role of non-cytolytic effector functions while studies in chimpanzees have also shown an important function of cytolytic effector molecules. In this subproject, we will analyze the ex vivo effector function of HBV-specific CD8+ T cells from patients with acute and chronic HBV infection by using a novel human immunological HBV cell culture model. This newly established model is based on an HBV producing, HLA-A2 expressing human hepatoma cell line (HepG2.117) that endogenously processes HBV antigen. In own preliminary work, we could show that CD8+ T cell-mediated antiviral efficacy is primarily mediated by perforin-depending cytolytic effector functions. With this model, we will also analyze different approaches to restore HBV-specific CD8+ T cell function, e.g. by addition of cytokines and blockade of inhibitory receptors. In addition to our established cell culture system, we will also use primary human hepatocytes to further define the important interactions between immune cells and HBV-infected hepatocytes and their impact on viral control. The second subproject deals with the restoration of HCV-specific CD8+ T cell dysfunction. By using HLA-A2 replicon cells, we could show that HCV-specific CD8+ T cells inhibit replication by non-cytolytic (IFNγ-mediated) and cytolytic effector functions and that HCV specific CD8+ T cells obtained from chronically HCV-infected patients show an impaired antiviral efficacy that can not be restored by cytokines. By using the infectious cell culture model, we will now analyze whether HCV infection influences HCV-specific CD8+ T cell function and antiviral efficacy and to what degree innate immune responses (e.g. IFNα) impact on CD8+ T cell function, e.g. by reducing antigen load beyond the level of T cell recognition. Since it is also not known whether the dysfunction of HCV-specific CD8+ T cells is directly linked to ongoing viral replication and whether inhibition of viral replication would thus lead to restoration of HCV-specific T cell functions, we will address this important question in a well defined patient cohort of chronically HCV infected patients undergoing antiviral IFN-free therapy. Overall, these comprehensive analyses should provide important new insights into HBV and HCV immunobiology.
© Dep. of Infectious Diseases, Molecular Virology. University of Heidelberg
Activation of Type I and III Interferon Response by Mitochondrial and Peroxisomal MAVS and Inhibition by Hepatitis C Virus.Bender S, Reuter A, Eberle F, Einhorn E, Binder M, Bartenschlager R. PLoS Pathog. 2015 Nov 20;11(11):e1005264.

Virus-specific CD4+ T Cells Have Functional and Phenotypic Characteristics of Follicular T-helper Cells in Patients With Acute and Chronic HCV Infections. Raziorrouh B, Sacher K, Tawar RG, Emmerich F, Neumann-Haefelin C, Baumert TF, Thimme R, Boettler T. Gastroenterology. 2015 Nov 13. pii: S0016-5085(15)01622-4.

Evidence that hepatitis B virus replication in mouse cells is limited by the lack of a host cell dependency factor. Lempp FA, Mutz P, Lipps C, Wirth D, Bartenschlager R, Urban S. J Hepatol. 2015 Nov 11. pii: S0168-8278(15)00736-9. doi: 10.1016/j.jhep.2015.10.030. [Epub ahead of print]