Immunologic and Metabolic Profiles of T cells that control diverse HCV infections

丙型肝炎疫苗计划项目1摘要 来自黑猩猩和人类研究的证据支持CD4和CD8 T淋巴细胞反应的关键作用 在控制丙型肝炎病毒感染方面，定义保护性丙型肝炎病毒免疫的相关因素一直是具有挑战性的。 识别抗多种不同丙型肝炎病毒感染的CD4和CD8 T细胞记忆 而亚型是丙型肝炎预防性疫苗设计的基石。我们在约翰霍普金斯大学的团队和 马萨诸塞州总医院为目前对丙型肝炎病毒的理解贡献了许多关键发现。 特异性T细胞免疫，基于大量和有充分证据的患者队列与稳健和 用于评估针对丙型肝炎病毒的CD8和CD4反应的灵敏实验工具。 我们将在这些专业知识的基础上，采用新开发的方法来研究新陈代谢和 丙型肝炎病毒特异性CD_4和CD_8 T细胞的转录谱以评估T细胞免疫功能 病人队列。我们先前已经证明，再感染时的清除比初次感染时更频繁。 感染，与最初的T细胞反应扩大相关的病毒血症的高峰和持续时间减少 同一人的感染。这表明，记忆的诱导可以预防多发性硬化的感染 不同的丙型肝炎病毒基因和亚型--预防性丙型肝炎疫苗设计的中心目标。使用总体 对于已经清除了多达六种不同的丙型肝炎病毒感染的患者，我们计划更好地定义特定的 T细胞介导的慢性丙型肝炎病毒感染保护作用的相关性。此外，我们还将利用 在高危人群中测试的唯一预防性丙型肝炎疫苗组的研究样本。 这种方案是先注射ChAd3 NS，然后再注射MVA-NS，并不能预防慢性 感染，但确实诱导了疫苗NS抗原的特异性T细胞并抑制了几何平均峰值丙型肝炎病毒 RNA与安慰剂接受者的对比。这项试验的样本提供了一个独特的机会来研究疫苗的效果- 诱导T细胞感染丙型肝炎病毒，使我们能够进一步验证与对照相关的T细胞特性 不仅是为了确定这种以T细胞为基础的有效疫苗失败的原因。具体来说，我们建议： 目的1：明确丙型肝炎病毒特异性CD8T细胞应答在自然恢复中的关键特征。 丙型肝炎病毒反复感染是保护性免疫的决定因素。目的2确定特异性CD8 T细胞 这些特征与疫苗诱导抑制随后的丙型肝炎病毒感染中的病毒血症高峰有关。 目的3：确定急性感染中有效的CD4T细胞应答和丙型肝炎病毒特异性的CD4记忆T细胞 多次成功控制丙型肝炎病毒感染的患者。目的4：确定丙型肝炎病毒特异性 丙型肝炎病毒感染后免疫后的CD_4记忆T细胞群及其反应 我们在研究CD8和CD4T细胞反应方面结合了广泛的专业知识，以确定 控制各种丙型肝炎病毒感染的效应器和记忆性T细胞反应，定义了T细胞诱导的目标 将在项目3(非人灵长类动物)和项目5(小鼠)以及最终在人类身上进行测试的丙型肝炎疫苗。

HCV Vaccine Program Project 1 Summary Evidence from chimpanzee and human studies support critical roles for CD4 and CD8 T lymphocyte responses in the control HCV infection, yet defining the correlates of protective HCV immunity has been challenging. Identifying CD4 and CD8 T cell memory that protects against infection from multiple different HCV genotypes and subtypes is a cornerstone in prophylactic HCV vaccine design. Our groups at Johns Hopkins University and Massachusetts General Hospital have contributed many key findings to the current understanding of HCV- specific T cell immunity, based on the combination of large and well documented patient cohorts with robust and sensitive experimental tools for the assessment of both CD8 and CD4 responses targeting HCV. We will build on this expertise and employ newly developed approaches to study the metabolism and transcriptional landscape of HCV-specific CD4 and CD8 T cells in order to assess T cell immunity in unique patient cohorts. We previously demonstrated that clearance occurs more often in reinfection than in primary infection, with reduced peak and duration of viremia associated with broadened T cell responses vs. initial infection of the same person. This suggests induction of memory that protects against infection from multiple different HCV genotypes and subtypes - a central goal of prophylactic HCV vaccine design. Using a population of patients who have cleared as many as six distinct HCV infections, we plan to better define the specific correlates of T cell mediated protection from chronic HCV infection. In addition, we will leverage access to research specimens from the only prophylactic HCV vaccine regiment tested in an at-risk human population. This regimen, consisting of a ChAd3NS prime followed by an MVA-NS boost, did not protect against chronic infection, but did induce T cells specific for vaccine NS antigens and suppressed geometric mean peak HCV RNA vs. placebo recipients. Specimens from this trial provide a unique opportunity to study the effect of vaccine- induced T cells on incident HCV infection, allowing us to further validate T cell properties associated with control of HCV, but also to identify the reasons for failure of this potent T cell based vaccine. Specifically, we propose: Aim 1: To define the critical characteristics of HCV-specific CD8 T-cell responses in spontaneous recovery from repeated HCV infection as determinants of protective immunity. Aim 2 To determine if specific CD8 T cell characteristics are associated with vaccine induced suppression of peak viremia in subsequent HCV infection. Aim 3: To define effective CD4 T cell responses in acute infection and HCV-specific CD4 memory T cells in patients with multiple episodes of successfully controlled HCV infection. Aim 4: To characterize the HCV-specific CD4 memory T cell population post vaccination and its response after HCV exposure. We build on our combined extensive expertise in studying both CD8 and CD4 T cell responses in order to define the effector and memory T cell responses that control diverse HCV infections, defining goals for T cell induction in HCV vaccines to be tested in Projects 3 (non-human primates) and 5 (mice) and, ultimately, in humans.