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(丙型肝炎病毒)仍然是全球肝病的重要原因。新的直接演技 抗病毒药物提供了有效的治疗方法，但目前还没有预防传播的疫苗。对疫苗的需求是 突出表现在美国与以下疾病有关的新丙型肝炎病毒感染人数的急剧增加 不安全的注射用药。对丙型肝炎病毒感染和免疫的研究为预防感染提供了证据 可以通过接种疫苗复制的免疫力。急性丙型肝炎的自发缓解提供了长寿 在再次接触病毒时防止持续感染。此外，抗体介导的 免疫黑猩猩的CD4+或CD8+T细胞耗尽会导致持续或长期感染 在与病毒再次挑战之后。这些研究为抗丙型肝炎病毒的“T细胞”疫苗提供了概念上的支持， 包括一种目前处于I/II期临床试验的药物。然而，我们对丙型肝炎病毒如何逃避T的理解很差 细胞免疫对疫苗开发构成了潜在的风险。CD_4~+T细胞衰竭是预测 慢性后果，但无法解释。急性加重期CD8+T细胞如何从部分有效状态转变 感染到完全精疲力竭也没有定义。项目1中的研究旨在测试 程序性中心假设比较急性持续期和缓解期丙型肝炎病毒的T细胞应答 感染将分别揭示导致精疲力竭或记忆的独特分子途径。分析 急性丙型肝炎患者因无法获得肝脏而导致抗病毒T细胞免疫受阻 为了解决这个问题，我们将利用来自急性呼吸道感染的黑猩猩的存档肝脏和血液样本 丙型肝炎以确定CD4+和CD8+T细胞衰竭的机制。这些发现随后将被翻译成 我们的初步数据表明，许多急性期肝内CD4+和 CD8+T细胞即使在感染后自发消退也不能发挥作用。这表明，对 感染是一个比之前所认识到的更随机或随机的过程。提出了两个具体目标。 第一个是比较血液和肝脏中CD4+T细胞的频率、广度和转录图谱 患有急性消退和持续性感染的黑猩猩。CD_4~+T细胞转录分析 有望揭示导致丙型肝炎病毒特异性群体缺失或耗尽的分子途径 以急性持续性感染为特征的。将使用创新的微流控聚合酶链式反应技术，因为它具有很好的适应性 用于分析少量病毒特异性CD4+T细胞的基因表达。我们的初步数据 还表明，CD8+T细胞在持续几个月前部分控制了丙型肝炎病毒的复制 已经成立了。转录分析被建议用来确定这些细胞是如何从这部分 有效状态到完全耗尽，并定义可能控制的调控基因的表观遗传修饰 这一过程。这些涉及黑猩猩和人类的研究应该会为机制提供新的见解 保护性T细胞免疫和沉默对于丙型肝炎疫苗的开发和评估非常重要。