Project TP 3

(V. Lohmann)

Mechanisms of immune evasion by hepatitis C virus and their role in establishment of viral persistence

An estimated 170 million people worldwide are chronically infected with hepatitis C virus (HCV), leading in many cases to severe liver damage. The reasons for the high rate of persistence are not fully understood yet, but it is clear that the failure of innate and adaptive immune responses to eliminate the virus is of particular importance. During the first funding period TP3 analyzed interference of HCV with functional antigen presentation and escape of HCV from interferon-γ response, the central cytokine mediating non-cytolitic T-cell response to HCV. An immunological model for authentic HLA-A2 restricted CD8+ T-cell response was established, providing a powerful system to study modulation of antigen presentation. The data of TP3 furthermore demonstrated that HCV persistence in presence of IFN-γ can be achieved and identified a number of novel candidate genes potentially involved in IFN-γ response to HCV. In continuation of this work we will analyze the functional role of fifty candidate genes differentially regulated in cell populations maintaining high levels of HCV replication in presence of efficient IFN-γ response. Validated candidates will be subjected to in depth studies on their mechanism of action. This work will reveal the contribution of IFN-γ resistance to HCV persistence and shed light on the general regulation of IFN-γ response and antiviral effector proteins targeting HCV.
© 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]