Immune Control and Evadion during Acute HCV Infection

尽管最近推出了治疗丙型肝炎病毒感染的高效抗病毒药物，但丙型肝炎病毒疫苗的开发 仍然是一个高度优先事项，以遏制世界各地和正在进行的人口中的这一流行病 暴露风险。鉴于目前还不清楚是否可以实现绝育免疫，探索这一点至关重要。 通过预防慢性感染提供保护的疫苗方法。这类产品的模型 预防慢性感染和疾病的人大约有20%-30%能够控制丙型肝炎病毒 自发性的，通常在感染后6个月内。 我们通过临床中心收集的大量急性丙型肝炎感染患者使我们 系统地定义这种保护性免疫反应与无法 控制感染。更好地定义保护性免疫的关键和必要特征将使 设计和测试可提供最佳免疫应答的丙型肝炎病毒疫苗，以保护其免受丙型肝炎病毒感染。 总体而言，该项目的科学假设是，丙型肝炎病毒特异性的CD4T细胞反应对于指导 复杂的宿主对丙型肝炎病毒的反应，因此诱导的CD4反应的质量是 保护性疫苗的成功。两个关键要素定义了有效的T助手响应：1)持久性 面对高病毒滴度时的反应以及2)T辅助反应的质量和什么样的 它通过免疫系统的其他手臂来协调免疫反应。因此，在我们的首要目标中，我们将定义 与持久有效的CD4帮助相关的关键细胞网络。我们还将测试是否 丙型肝炎病毒特异性CD4T细胞应答的克隆谱系与应答的持久性和 具有相同CD4特异性的不同克隆在它们所提供的T帮助中是否具有不同的性质 转录上以不同的方式控制。在目标2中，我们将进一步定义丙型肝炎病毒特异性的基本品质 介导丙型肝炎病毒控制的CD8 T细胞反应以及这些有效的CD8反应是如何 受丙型肝炎病毒特异性的CD4 HELP调节。 总之，我们的研究将确定应由一种 保护性丙型肝炎疫苗。我们的CD4分析还将为整个中心的其他调查提供信息，并 它的合作者依赖于有效的CD4帮助其他手臂的免疫反应。除了丙型肝炎病毒， 这一结果对整个人类免疫学领域也将是非常重要的；尽管它是普遍的 假设CD4T细胞是有效的宿主免疫反应的中心，CD4T细胞如何 在人类中协调免疫反应仍然知之甚少。

Despite the recent introduction of highly effective antivirals for HCV infection, development of an HCV vaccine remains a high priority in order to curb the epidemic in all parts of the world and in populations with ongoing exposure risk. Given that it is unclear whether sterilizing immunity can be achieved, it is paramount to explore vaccine approaches that deliver protection through prevention of chronic infection. The model for this kind of protection from chronic infection and disease are the roughly 20-30% of people who are able to control HCV spontaneously, usually within 6 months of infection. The large cohorts of patients with acute HCV infection we have assembled through our clinical cores allow us to systematically define what distinguishes such a protective immune response from responses unable to control infection. A better definition of the critical and necessary characteristics of protective immunity will allow to design and test HCV vaccines that deliver the optimal immune response lading to protection from HCV. Overall the scientific hypothesis of project is that HCV-specific CD4 T cell responses are critical for directing the complex host response to HCV and thus that the quality of the induced CD4 response is a key factor for the success of a protective vaccine. Two key elements define effective T helper responses; 1) The persistence of the response in the face of high viral titers and 2) the quality of the T helper response and what kind of immune response it orchestrates by other arms of the immune system. Thus in our first aim we will define the critical cellular networks that are associated with lasting and effective CD4 help. We will also test whether the clonal repertoire of the HCV-specific CD4 T cell response is related to the durability of the response and whether distinct clones of the same CD4 specificity possess different qualities in the T help they provide or are transcriptionally controlled in different ways. In aim 2 we will further define the essential qualities of HCV-specific CD8 T cell responses that mediate HCV control and how these effective CD8 responses are modulated by HCV-specific CD4 help. Together, our investigations will define the qualities of the CD4 and CD8 response that should be elicited by a protective HCV vaccine. Our CD4 analysis will also inform additional investigations throughout the center and its collaborators related to other arms of the immune response depending on effective CD4 help. Beyond HCV, the results will also be of great importance to the field of human immunology in general; while it is universally assumed that CD4 T cells are central to an effective host immune response, the details of how CD4 T cells orchestrate the immune response in humans remain poorly understood.