Impact of HBV and HCV Sequence Diversity on the CD8 T Cell Immune Response

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The inherent sequence diversity of pathogens such as HBV and HCV can represent an obstacle to immune control when important targets of the immune response differ between circulating isolates. It is well documented that intra-host evolution of HCV contributes to failure of the antiviral CD8 T cell immune response. Recently, evidence emerged that HBV is also able to adapt to CD8 T cell selection pressure. In contrast to HCV, however, it has been highlighted that the plasticity of the HBV genome is more constrained by existence of overlapping reading frames. Accordingly, the overall extent of the adaptation process of HBV to HLA class I-associated selection pressure is largely unclear. Although an effective prophylactic vaccine is available against HBV, selection of escape mutations would be relevant for therapeutic vaccination strategies, when the autologous virus is not targeted by the immune response anymore. In this project the extent and mechanisms of adaptation of HBV to CD8 T cell immune pressure will be analyzed. For HCV, beyond intra-host evolution, the inherent viral sequence diversity between circulating isolates likely contributes to lack of protective immunity. This is most evident in high-risk groups such as people how inject drugs (PWID), being repeatedly exposed to genetically distinct isolates. The genetic variability of HCV is relevant for prophylactic immunization strategies, because any chosen vaccine antigen sequence will likely differ from the viral sequence upon exposure. CD8 T cells directed against multiple variants of an epitope may be beneficial in this setting. Here, the frequency, function and molecular characteristics of cross-reactive CD8 T cells will be studied and their relevance in the context of hepatitis B and hepatitis C will be addressed.