Correlates of protective immunity to HCV and rational vaccine design: Project 1

项目1：保护性丙型肝炎病毒特异性CD4T细胞的高分辨率分析 摘要 丙型肝炎病毒(丙型肝炎病毒)是一种感染肝脏并通过受污染的血液传播的病毒。丙型肝炎病毒 感染仍然是公共卫生的优先事项，也是全世界肝病的主要原因，特别是在发展中国家 像埃及这样的国家。在北美，与阿片类药物有关的新的丙型肝炎病毒感染也在上升 流行病。虽然新的抗病毒药物可以治愈95%的感染者，但许多人并不知道它们是 被感染的人仍然有发展成肝病的风险，并且是新感染的活跃来源。此外， 如果患者再次接触病毒，成功的治疗并不能防止再次感染。因此，有一个 迫切需要能够预防这种病毒的疫苗。不幸的是，尽管我们知道 针对丙型肝炎病毒的免疫应答，我们还没有有效的疫苗。唯一的疫苗的最新结果 进入大规模(2期)临床试验的候选药物对注射的人没有任何保护作用 有感染丙型肝炎病毒风险的药物(PWID)。这意味着我们需要更好地了解免疫因素和 在能够自发清除病毒的患者队列中保护免受丙型肝炎病毒感染的细胞。这个 本提案的首要目标是界定实现保护性免疫所必需的这些因素。 这个特定项目(项目1)的目的是描述一组白血球的作用和功能 在一组被称为辅助性CD4淋巴细胞的PWID患者中，他们不断地接触到病毒 一些人能够多次清除它，另一些人则不能。我们将找出那些清除了 反复感染病毒的人和那些无法做到的人。我们还将比较清除者的免疫反应 病毒自发与那些在治疗后清除病毒的人比较，以确定他们是否对病毒的保护力较弱 如果他们再次接触到丙型肝炎病毒。我们将使用两个独特的受试者队列，一个来自蒙特利尔的PWID队列， 加拿大和来自埃及的一群正在接受抗病毒治疗的受试者，埃及是流行率最高的国家 丙型肝炎病毒。在这个项目中获得的结果将是对将检测抗体的项目2的补充 相同受试者对丙型肝炎病毒的反应。我们将使用最新的技术来检查免疫反应 功能和基因组水平，并确定细胞通路和关键分子，涉及到 发展和维持保护性免疫反应。我们将尝试使用化合物 以纠正在无法清除病毒的人身上观察到的缺陷。这些化合物可以组合在一起 使用不同的候选疫苗，如项目3所述，以增强其免疫原性和保护性 容量。

Project 1: High resolution profiling of protective HCV-specific CD4 T cells Abstract Hepatitis C virus (HCV) is a virus that infects the liver and is transmitted through contaminated blood. HCV infection is still a public health priority and a major cause of liver disease worldwide, especially in developing countries like Egypt. New HCV infections are also on the rise in North America in association with the opioid epidemic. While new antiviral drugs can cure >95% of infected individuals, many do not know that they are infected and remain at risk of developing liver disease and an active source of new infections. Furthermore, successful treatment does not prevent reinfection if the individual is re-exposed to the virus. Hence, there is an urgent need for vaccines that can protect against this virus. Unfortunately, despite our knowledge about the immune response against HCV, we still do not have an effective vaccine. Recent results from the only vaccine candidate that made it into a large scale (Phase 2) clinical trial did not show any protection in people who inject drugs (PWID) at risk of HCV infection. This means that we need to understand better the immune factors and cells that protect against HCV in cohorts of patients who are able to clear the virus spontaneously. The overarching goal of this proposal t is to define these factors that are essential to achieve protective immunity. The aim of this specific project (Project 1) is to characterize the role and functions of a subset of white blood cells known as helper CD4 lymphocytes in a group of PWID who are constantly being exposed to the virus where some are able to clear it several times and others that cannot. We will identify the differences in those who clear the virus repeatedly and those who cannot. We will also compare the immune response in individuals who clear the virus spontaneously versus those who clear it post treatment to determine if they are less protected against HCV if they are re-exposed to it. We will use two unique cohorts of subjects, a PWID cohort from Montreal, Canada and a cohort of subjects undergoing antiviral therapy from Egypt, the country with the highest prevalence of HCV. The results obtained in this project will be complementary to Project 2 that will examine the antibody response to HCV in the same subjects. We will use the latest technology to examine the immune response at the functional and genomic level and identify cellular pathways and key molecules that are implicated in the development and maintenance of a protective immune response. We will attempt to use chemical compounds to correct the defects observed in those who are unable to clear the virus. Such compounds may be combined with different vaccine candidates, as described in project 3, to enhance their immunogenicity and protective capacity.