Immune Control and Evadion during Acute HCV Infection

急性 HCV 感染期间的免疫控制和逃避

• 批准号: 9982171
• 负责人: GEORG Michael LAUER
• 金额: $ 27.6万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-20 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982171
• 关键词: Acute; Antibodies; Antiviral Agents; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Survival; Characteristics; Chronic; Chronic Disease; Chronic Hepatitis C; Clinical; Complex; Data; Development; Elements; Epidemic; Failure; Funding; Gene Expression; Generations; Genetic Transcription; Helper-Inducer T-Lymphocyte; Hepatitis C; Hepatitis C Vaccine; Hepatitis C virus; Human; Immune; Immune response; Immune system; Immunity; Immunology; Infection; Infection Control; Investigation; Mediating; Mediator of activation protein; Methods; Modeling; Natural Killer Cells; Outcome; Patients; Phase; Population; Prevention; Receptor Cell; Reporting; Risk; Role; Specificity; T cell response; T-Lymphocyte; Testing; Transcriptional Regulation; Vaccines; Viral; Viral Antibodies; arm; chronic infection; cohort; design; exhaustion; novel vaccines; programs; response; single-cell RNA sequencing; success; synergism

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.

尽管最近引入了高效的HCV感染抗病毒药，但开发了HCV疫苗 为了遏制世界各地的流行病以及持续的人口， 暴露风险。鉴于尚不清楚是否可以实现灭菌性，因此探索至关重要 疫苗通过预防慢性感染提供保护。这种模型 慢性感染和疾病的保护是能够控制HCV的人中约有20-30％ 自发，通常在感染后6个月内。 我们通过临床核心组装的大量急性HCV感染患者使我们能够 系统地定义什么区分这种保护性免疫反应与无法反应的反应 控制感染。更好地定义保护性免疫的关键和必要特征将允许 设计和测试HCV疫苗，以提供最佳的免疫反应提单以保护HCV。 总体而言，项目的科学假设是HCV特异性CD4 T细胞反应对于指导至关重要 复杂的宿主对HCV的反应，因此诱导的CD4响应的质量是 保护性疫苗的成功。两个关键要素定义了有效的T辅助响应； 1）持久性 面对高病毒滴度的反应和2）T助手响应的质量以及什么样的 免疫反应它通过免疫系统的其他臂进行策划。因此，在我们的第一个目标中，我们将定义 与持久和有效的CD4帮助相关的关键蜂窝网络。我们还将测试是否 HCV特异性CD4 T细胞反应的克隆曲目与响应的持久性和 同一CD4特异性的不同克隆是否具有不同的t帮助或有不同的质量 通过不同方式进行转录控制。在AIM 2中，我们将进一步定义HCV特异性的基本品质 CD8 T细胞响应介导HCV控制以及这些有效CD8的反应是如何的 由HCV特异性CD4帮助调节。 总之，我们的调查将定义CD4和CD8响应的质量，应由 保护性HCV疫苗。我们的CD4分析还将为整个中心的其他调查提供信息， 它的合作者与免疫反应的其他臂有关，具体取决于有效的CD4帮助。超越HCV， 总体而言，结果对人类免疫学领域也非常重要。虽然它是普遍的 假设CD4 T细胞是有效宿主免疫反应的核心，CD4 T细胞的细节 策划人类的免疫反应仍然很众所周知。