Funtional T-cell Failure in Chronic HCV Infection

基于我们在病毒感染的LCMV模型以及人类HCV感染中的结果，病毒逃逸突变和与t细胞功能障碍和抑制相关的分子组合似乎是病毒持续存在的关键因素。重要的是，急性HCV感染的数据表明，HCV感染在疾病早期引起PBMC中可检测到的CD4和CD8 T细胞反应，但在进展为慢性感染的患者中反应迅速下降。在肝脏中，反应仍然可以检测到，通常持续数十年，而且频率很高，但病毒仍然保持在高水平。我们的总体假设是，T细胞功能障碍是HCV感染控制失败的主要因素，通过结合小鼠和人类对T细胞功能障碍的研究，我们可以确定HCV感染免疫控制不良的关键途径或免疫缺陷。为了验证这一假设，我们建议进一步定义与不同水平的病毒控制相关的t细胞的不同亚群，并在人类和小鼠实验中相互通知。基于最近在LCMV中的发现，我们将利用hcv特异性t细胞在人PBMC和肝源性t细胞中定义抑制分子组合的功能特征和表达。与此同时，我们将通过详细区分不同功能障碍阶段t细胞和不同t细胞亚群的转录谱，进一步完善我们的小鼠模型。我们还将建立人类t细胞的转录谱，这些数据集将共同指导我们未来的研究方向。除了定义HCV特异性t细胞的特性外，我们还将定义慢性HCV感染的肝脏环境如何通过表达t细胞抑制性配体或调节细胞因子来促进t细胞功能障碍和病毒持久性。此外，我们还将研究hcv特异性CD4+ t细胞，它们对病毒控制同样重要，但研究的细节要少得多。这些研究对于理解HCV的发病机制，指导预防性疫苗和免疫治疗干预的设计，以及改进人类持续病毒感染的一般模型至关重要。

ased on our results in the LCMV model of viral infection as well as in human HCV Infection it seems likely that viral escape mutations and a combination of molecules associated with T-cell dysfunction and inhibition are key contributors to viral persistence. Importantly, data in acute HCV infection indicate that HCV infection elicits both CD4 and CD8 T cell responses detectable in PBMC during early disease, but the responses decline quickly in persons who progress to chronic infection. In the liver, responses remain detectable, often for decades and at substantial frequencies, yet virus persists at high levels. Our overall hypothesis is that T-cell dysfunction is a major factor in failure to control HCV infection and that by combining both mouse and human studies of T cell dysfunction we can define key pathways or immunological defects underlying poor immunological control of HCV infection. To test this hypothesis we propose to further define the different subsets of T-cells associated with different levels of viral control with experiments in humans and mice informing each other. We will define the functional profile and expressions of a combination of inhibitory molecules using HCV-specific T-cells in human PBMC and liver derived T-cells based on recent findings in LCMV. In parallel we will further refine our murine model by differentiating in detail the transcriptional profiles of T-cells in different stages of dysfunction and different T-cell subsets. We will also establish transcription profiles of human T-cells and the datasets together will direct the future direction of our investigations. In addition to defining the properties of HCV-specific T-cells we will define how the liver environment in chronic HCV infection contributes to T-cell dysfunction and thus viral persistence, e.g. by the expression of T-cell inhibitory ligands or regulatory cytokines. In addition we will also investigate HCV-specific CD4+ T-cells that are equally critical for viral control but have been investigated in much less detail. These studies will be critical for understanding HCV pathogenesis, for guiding the design of prophylactic vaccines and immunotherapeutic interventions, but also for improved general model of persistent viral infections in humans.