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

当循环分离株之间免疫应答的重要靶点不同时，HBV和HCV等病原体固有的序列多样性可能成为免疫控制的障碍。有充分的证据表明，HCV的宿主内进化有助于抗病毒CD8 T细胞免疫反应的失败。最近，有证据表明HBV也能够适应CD8 T细胞的选择压力。然而，与HCV相反，HBV基因组的可塑性更多地受到重叠阅读框存在的限制。因此，HBV对HLA i类相关选择压力的适应过程的总体程度在很大程度上尚不清楚。虽然针对HBV的有效预防性疫苗是可用的，但当自身病毒不再被免疫反应靶向时，选择逃逸突变将与治疗性疫苗接种策略相关。本项目将分析HBV对CD8 T细胞免疫压力的适应程度和机制。对于丙型肝炎病毒，除了宿主内进化之外，循环分离株之间固有的病毒序列多样性可能导致缺乏保护性免疫。这在高风险人群中最为明显，例如注射毒品的人（PWID），他们反复暴露于遗传上不同的分离物。丙型肝炎病毒的遗传变异与预防性免疫策略有关，因为任何选择的疫苗抗原序列都可能与暴露时的病毒序列不同。在这种情况下，针对表位的多种变体的CD8 T细胞可能是有益的。本文将研究交叉反应性CD8 T细胞的频率、功能和分子特征，并探讨其在乙型肝炎和丙型肝炎中的相关性。

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.