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.

尽管最近引入了用于HCV感染的高效抗病毒药物，但HCV疫苗的开发仍然是一个挑战。 仍然是一个高度优先事项，以便在世界各地和正在发生艾滋病毒/艾滋病的人口中遏制这一流行病。 暴露风险鉴于目前还不清楚是否可以实现绝育免疫， 通过预防慢性感染提供保护的疫苗方法。这种模式 大约20-30%的人能够控制HCV， 通常在感染后6个月内自发发生。 通过我们的临床核心，我们收集了大量急性HCV感染患者， 系统地定义是什么区分这种保护性免疫反应和不能 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，提供最佳的免疫反应，以保护免受HCV感染。 总的来说，该项目的科学假设是，HCV特异性CD 4 T细胞应答对于指导HCV感染至关重要。 复杂的宿主对HCV的应答，因此诱导的CD 4应答的质量是 保护性疫苗的成功两个关键要素定义有效的T辅助反应; 1）持久性 在面对高病毒滴度的反应和2）T辅助反应的质量和什么样的 免疫反应由免疫系统的其他分支协调。因此，在我们的第一个目标中，我们将定义 关键的细胞网络与持久和有效的CD 4帮助有关。我们还将测试 HCV特异性CD 4 T细胞反应的克隆库与反应的持久性相关， 具有相同CD 4特异性的不同克隆是否在它们提供的T辅助中具有不同的质量， 以不同的方式进行转录控制。在目标2中，我们将进一步定义HCV特异性抗体的基本性质。 介导HCV控制的CD 8 T细胞应答以及这些有效的CD 8应答是如何 由HCV特异性CD 4辅助调节。 总之，我们的研究将确定CD 4和CD 8应答的质量，这些应答应通过以下方式引起： 保护性HCV疫苗我们的CD 4分析还将为整个中心的其他调查提供信息， 它的合作者与其他武器的免疫反应依赖于有效的CD 4的帮助。除了HCV， 这些结果对于一般的人类免疫学领域也将是非常重要的;虽然它是普遍的， 假设CD 4 T细胞是有效的宿主免疫反应的核心，CD 4 T细胞如何 协调人类的免疫反应仍然知之甚少。