T Cell Immunity and HCV Infection Outcome

T 细胞免疫和 HCV 感染结果

• 批准号: 9346587
• 负责人: Christopher M. Walker
• 金额: $ 27.55万
• 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/9346587
• 关键词: Acute; Acute Hepatitis; Acute Hepatitis C; Address; Antibodies; Antigens; Antiviral Agents; Antiviral Therapy; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Chronic Hepatitis; Chronic Hepatitis C; Data; Detection; Development; Direct Costs; Effector Cell; Epigenetic Process; Failure; Frequencies; Genetic Transcription; Hepatitis C; Hepatitis C Transmission; 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; Predictive Factor; 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 Diseases; Virus Replication; Walkers; base; chronic liver disease; cohort; cost; 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。新的直接作用 抗病毒药物提供了有效的治疗方法，但没有预防传播的疫苗。对疫苗的需求是 美国新的HCV感染人数急剧增加， 不安全注射毒品。HCV感染和免疫的研究为保护性治疗提供了证据。 可以通过接种疫苗复制的免疫力。急性丙型肝炎的自发消退提供了长期的 在再次暴露于病毒时防止持续感染。此外，抗体介导的 免疫黑猩猩的CD 4+或CD 8 + T细胞耗竭导致持续或延长的感染 在病毒再激发后这些研究为抗HCV的“T细胞”疫苗提供了概念支持， 包括一种正在进行I/II期临床试验的药物。然而，我们对HCV如何逃避T 细胞免疫对疫苗开发构成潜在风险。CD 4 + T细胞的失败是一个最好的预测因子。 慢性结果，但无法解释。CD 8 + T细胞如何从急性期的部分有效状态转变 感染到完全衰竭也没有定义。项目1中的研究旨在测试 丙型肝炎病毒急性迁延期和消退期T细胞反应的程序中心假说比较 感染将揭示独特的分子途径，分别导致疲惫或记忆。分析 在患有急性丙型肝炎的人类受试者中，抗病毒T细胞免疫由于缺乏进入肝脏的途径而受到阻碍。到 为了解决这个问题，我们将利用存档的黑猩猩肝脏和血液样本， 丙型肝炎，以确定CD 4+和CD 8 + T细胞衰竭的机制。这些发现将被翻译成 急性丙型肝炎患者我们的初步数据表明，许多急性期肝内CD 4+和 即使在自发消退的感染中，CD 8 + T细胞也不起作用。这表明，控制 感染是一个比以前认识到的更随机或随机的过程。提出了两个具体目标。 首先是比较血液和肝脏中CD 4 + T细胞的频率、宽度和转录谱。 有急性感染和持续感染的黑猩猩CD 4 + T细胞的转录分析是 有望揭示导致HCV特异性群体缺失或耗竭的分子途径 急性持续感染的特征。创新的微流控PCR技术将被使用，因为它适应性很好 用于分析少量病毒特异性CD 4 + T细胞中的基因表达。我们的初步数据 还表明，CD 8 + T细胞在HCV持续存在之前的几个月内提供了HCV复制的部分控制。 确立了习转录分析提出，以确定这些细胞如何从这部分过渡 有效状态完全耗尽，并定义可能控制的调节基因的表观遗传修饰 这个过程这些涉及黑猩猩和人类的研究应该为机制提供新的见解 保护性T细胞免疫和沉默对于HCV疫苗的开发和评估非常重要。