Hepatitis C virus (HCV) leads to chronic hepatitis in the majority of infected individuals. To establish viral persistence HCV has to evade the host`s cellular and humoral immune system but the mechanisms are not well understood. It has been shown in patients and murine model systems that the HCV core protein (HCV-C) has a strong immune modulatory impact e.g., on dendritic cell functions, interferon signalling or cell surface expression of MHC class-I molecules. The project aims to elucidate regulatory effects of HCV-C in different antigen presenting cells that drive down-regulation of well-defined CD8 T-cell responses.

DNA- and protein-based vaccines did not induce HCV-C specific CD8 T-cell responses in C57BL/6 mice. It is thus attractive to study the regulatory effects of HCV-C on co-expressed antigens:

during the induction of CD8 T-cell responses directed against other antigens (e.g., OVA or hepatitis B antigens) by DNA-based vaccination and in transgenic mice co-expressing HCV-C and other antigens in hepatocytes (e.g., HCV/OVA or HCV/HBV. Three main strategies will be tested:

(1) we will generate HCV-C- and OVA-expressing stable transfectants and evaluate Kb/OVA presentation to CD8 T-cells

(2) we will design immunization experiments with HCV-C / OVA co-expressing vectors and single antigen expressing vectors and compare the frequencies and cytokine-secretion (e.g., IFNγ) of OVA-specific CD8 T-cells by flow cytometry

(3) we will breed HCV/OVA double tg mice and analyze whether direct immunization or adoptive transfer of OVA-specific CD8 T-cells differ in OVA tg and HCV/OVA tg mice.

The results of these studies may contribute to understand HCV-C specific immune regulatory functions in vivo. We further expect to get new informations on HBV / HCV interactions in hepatocytes that operate in chronic HBV/HCV co-infected patients.

methods:
expression-cloning vectors
cell culture-
-expression of recombinant antigens
-immunization of mice
-detection of humoral and cellular immune responses in mice
FACS analyzes

Start date: 15 September 2013

Estimated Duration: 3 years

Payment: 50%

Subjects: Biology
Theme: Thesis: Characterization of hepatitis C core protein-mediated immune regulation in different antigen-presenting cells.
Contact: Prof. Reinhold Schirmbeck
Reply to: reinhold.schirmbeck @ uni-ulm.de
Institution: University of Ulm, Internal Medicine
Location: 89081 Ulm, Albert Einstein Allee 23

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