T Cell Immunity and HCV Infection Outcome

T 细胞免疫和 HCV 感染结果

• 批准号: 9325247
• 负责人: Christopher M. Walker
• 金额: $ 27.66万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-06 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325247
• 关键词: Acute; Acute Hepatitis; Acute Hepatitis C; Address; Antibodies; Antigens; Antiviral Agents; Antiviral Therapy; Blood; CD4 Positive T Lymphocytes; CD8B1 gene; Chronic Hepatitis; Chronic Hepatitis C; Data; Detection; Development; Epigenetic Process; Failure; Frequencies; Hepatitis C; Hepatitis C Transmission; Hepatitis C virus; Human; Immune; Immunity; Infection; Interferon Type I; Interleukin-2; Knowledge; Lead; Liver; Measures; Mediating; Memory; Methods; Modification; Molecular; Outcome; Pan Genus; Pathway interactions; Phase; Phenotype; Population; Preventive vaccine; Production; Research; Resolution; Risk; Sampling; Signal Transduction; Surrogate Markers; Symptoms; T cell response; T-Lymphocyte; Time; Translating; United States; Vaccinated; Vaccines; Virus; Virus Replication; Walkers; base; chronic liver disease; cohort; design; exhaustion; high risk; human subject; improved; injection drug use; innovative technologies; insight; intrahepatic; premature; prevent; programs; response; success; transcription factor; vaccine development

The hepatitis C virus (HCV) remains an important cause of liver disease globally. New direct acting antivirals provide effective therapy but there is no vaccine to prevent transmission. The need for a vaccine is highlighted by a sharp increase in the number of new HCV infections in the United States associated with unsafe injection drug use. Studies of HCV infection and immunity have provided evidence for protective immunity that might be replicated by vaccination. Spontaneous resolution of acute hepatitis C provides long-lived protection against persistent infection upon re-exposure to the virus. Moreover, antibody-mediated depletion of CD4+ or CD8+ T cells from immune chimpanzees resulted in persistent or prolonged infection after rechallenge with the virus. These studies provided conceptual support for “T-cell” vaccines against HCV, including one that is now in Phase I/II clinical trials. However, our poor understanding of how HCV evades T cell immunity poses a potential risk for vaccine development. Failure of CD4+ T cells is the best predictor of a chronic outcome but is unexplained. How CD8+ T cells transition from a partially effective state during acute infection to full exhaustion has also not been defined. Studies in Project 1 are designed to test the Programmatic central hypothesis that comparison of T cell responses in acute persisting and resolving HCV infections will reveal unique molecular pathways leading to exhaustion or memory, respectively. Analysis of antiviral T cell immunity is hampered by lack of access to liver in human subjects with acute hepatitis C. To address this issue, we will make use of archived liver and blood samples from chimpanzees with acute hepatitis C to define mechanisms of CD4+ and CD8+ T cell failure. These findings will then be translated to humans with acute hepatitis C. Our preliminary data suggest that many acute phase intrahepatic CD4+ and CD8+ T cells are not functional even in infections that spontaneously resolve. This suggests that control of infection is a more stochastic or random process than previously appreciated. Two specific aims are proposed. The first is to compare the frequency, breadth, and transcriptional profile of CD4+ T cells in the blood and liver of chimpanzees with acute resolving and persisting infections. Transcriptional analysis of CD4+ T cells is expected to reveal molecular pathways leading to deletion or exhaustion of HCV-specific populations characteristic of acute persisting infections. Innovative microfluidic PCR technology will be used as it is well-adapted for analysis of gene expression in small numbers of virus-specific CD4+ T cells. Our preliminary data also show that CD8+ T cells provide partial control of HCV replication for several months before persistence is established. Transcriptional analysis is proposed to determine how these cells transition from this partially effective state to full exhaustion, and to define epigenetic modifications to regulatory genes that might govern this process. These studies involving chimpanzees and humans should provide new insight into mechanisms of protective T cell immunity and silencing important for development and assessment of HCV vaccines.

丙型肝炎病毒（HCV）仍然是全球肝病的重要原因。新的直接表演 抗病毒药提供有效的治疗，但没有疫苗可以防止传播。对疫苗的需求是 美国的新HCV感染数量急剧增加。 不安全的注射药物使用。 HCV感染和免疫学的研究为保护性提供了证据 疫苗接种可能会复制的免疫力。急性肝炎的自发分辨率可提供长寿 重新暴露于病毒后，防止持续感染。此外，抗体介导 免疫黑猩猩的CD4+或CD8+ T细胞的耗竭导致持续或长时间感染 在与病毒进行补偿之后。这些研究为针对HCV的“ T细胞”疫苗提供了概念支持， 包括现在正在I/II期临床试验中的一个。但是，我们对HCV如何逃避T的糟糕理解 细胞免疫会带来疫苗开发的潜在风险。 CD4+ T细胞的失败是A的最佳预测指标 慢性结果，但是出乎意料的。 CD8+ T细胞如何从急性期间从部分有效状态过渡 还没有定义对充分疲惫的感染。项目1中的研究旨在测试 程序化中心假设是急性持续和解决HCV中T细胞反应的比较 感染将分别揭示出独特的分子途径，导致疲惫或记忆。分析 抗病毒T细胞免疫受到急性丙型肝炎患者缺乏肝脏的障碍。 解决这个问题，我们将利用急性的黑猩猩的存档肝和血液样本 丙型肝炎以定义CD4+和CD8+ T细胞衰竭的机制。这些发现将转化为 患有急性丙型肝炎的人类。我们的初步数据表明许多急性期epatitic CD4+和 CD8+ T细胞即使在发起的感染中也不起作用。这表明控制 感染比以前所欣赏的更随机或随机过程。提出了两个具体目标。 首先是比较血液和肝脏中CD4+ T细胞的频率，广度和转录曲线 具有急性解决和持续感染的黑猩猩。 CD4+ T细胞的转录分析是 预计会揭示分子途径导致删除或耗尽HCV特异性人群 急性持续感染的特征。将使用创新的微流体PCR技术，因为它适应了 用于分析少量病毒特异性CD4+ T细胞中的基因表达。我们的初步数据 还表明CD8+ T细胞在持久性之前几个月提供了对HCV复制的部分控制 已确立的。提出了转录分析以确定这些细胞如何从该部分过渡 有效的状态充分疲惫，并将表观遗传学修饰定义为可能控制的调节基因 这个过程。这些涉及黑猩猩和人类的研究应提供有关机制的新见解 受保护的T细胞免疫和沉默对于HCV疫苗的开发和评估很重要。