The Role of CD8+ T-cell Responses In Acute HCV Infection

最近的研究令人鼓舞，丙型肝炎病毒感染的病毒控制是可能的。 迫切需要预防性疫苗或有效的免疫疗法来减轻这一全球流行病的疾病负担。据估计，HCV感染全世界1.7亿人，并在发达国家和发展中国家引起显著的发病率。我们对控制病毒复制的机制和控制HCV感染失败的认识仍然相当有限。显然，结果是在疾病的早期阶段确定的，因此，研究为病毒的清除与持久性奠定基础的最早期事件似乎至关重要。各种研究报告了CD4+和CD8+在对照中的重要作用。 病毒复制的过程。然而，大多数人HCV感染研究使用的技术不允许全面和详细评估细胞免疫应答，并且仅限于少数急性感染受试者。我们建议在这里的CD8+ T细胞免疫的分析在一个大的队列的受试者急性HCV感染和不同的传播途径与目前最精确和全面的技术。这些研究包括在具有不同疾病结果的受试者的感染过程中在单个表位水平上的CDS响应的全宽度和幅度的分析，通过使用MHC I类四聚体和通过纵向进化数据检测选择压力下的区域来解剖检测到的特异性的功能和表型特性。此外，通过利用允许内源性加工和呈递自体病毒抗原的测定，我们将能够以更生理学的方法比较针对原型HCV序列（H77）的CDS应答与针对自体病毒的应答。与解决病毒如何逃避感染的研究相一致， 通过研究激活的宿主免疫系统以及它们如何与个体的CD4+ T细胞免疫相互作用，这将为有助于控制和持续病毒感染的机制提供重要见解。这些机制的剖析将是一个重要的贡献，开发预防性疫苗或免疫治疗。

Recent studies have been encouraging that viral control of hepatitis C virus infection is possible. Prophylactic vaccines or efficient immunotherapies are urgently needed to reduce the disease burden of this global epidemic. HCV infects estimated 170 million people worldwide, and causes significant morbidity in developed and developing countries. Our knowledge about the mechanisms of control of viral replication and the failure to control HCV infection is still rather limited. Clearly, the outcome is determined in the early phase of the disease, therefore it seems paramount to study the earliest events that set the stage for clearance versus persistence of the virus. Various studies report an important role for both CD4+ and CD8+ in the control of viral replication. However, the majority of studies in human HCV infection utilized techniques that do not allow comprehensive and detailed assessment of the cellular immune response and were restricted to small numbers of subjects with acute infection. We propose here the analysis of the CD8+ T cell immunity in a large cohort of subjects with acute HCV infection and different transmission routes with the most precise and comprehensive techniques currently available. These studies include the analysis of the full breadth and magnitude of the CDS response on the single epitope level over the course of infection in subjects with different disease outcome, dissection of the functional and phenotypical properties of the detected specificities by the use of MHC class I tetramers and the detection of regions under selection pressure by longitudinal evolutionary data. Moreover, by utilizing an assay that allows for endogenous processing and presentation of autologous viral antigens we will be able to compare in a more physiological approach the CDS responses against the prototype HCV sequence (H77) with the response against the autologous virus. In concert with studies that address how the virus evades the activated host immune system and how they interact with the individual's CD4+ T-cell immunity this will provide important insights into the mechanisms that contribute to control and persistence of viral infection. Dissection of these mechanisms will be an important contribution to develop prophylactic vaccines or immunotherapies.