T Cell Immunity and HCV Infection Outcome

T 细胞免疫和 HCV 感染结果

• 批准号: 10000824
• 负责人: Christopher M. Walker
• 金额: $ 27.04万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000824
• 关键词: Acute; Acute Hepatitis; Acute Hepatitis C; Address; Antibodies; Antigens; Antiviral Agents; Antiviral Therapy; Archives; Blood; Blood specimen; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Chronic; Chronic Hepatitis; Chronic Hepatitis C; Data; Detection; Development; Direct Costs; Epigenetic Process; Exposure to; Failure; Frequencies; Gene Expression Profiling; Genetic Transcription; Hepatitis C; Hepatitis C Transmission; Hepatitis C Vaccine; Hepatitis C virus; Human; Immune; Immunity; Infection; Infection Control; Interferon Type I; Interleukin-2; Knowledge; Lead; Liver; Liver diseases; Measures; Mediating; Memory; Methods; Microfluidics; Modification; Molecular; Outcome; Pan Genus; Pathway interactions; Phase; Phase I/II Clinical Trial; Phenotype; Population; Population Characteristics; Predictive Factor; Preventive vaccine; Process; Production; Regulator Genes; Resolution; Risk; Sampling; Signal Transduction; Surrogate Markers; Symptoms; T cell response; T-Lymphocyte; Technology; Testing; Time; Translating; United States; Vaccinated; Vaccination; Vaccines; Virus; Virus Replication; acute infection; base; chronic infection; chronic liver disease; cohort; cost; design; effective therapy; effector T cell; exhaustion; high risk; human subject; improved; injection drug use; innovation; innovative technologies; insight; intrahepatic; premature; prevent; programs; response; success; transcription factor; transmission process; 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病因。 抗病毒药物提供有效的治疗，但没有疫苗可以预防传播。 与此相关的美国新发丙肝病毒感染人数急剧增加凸显了这一点 HCV 感染和免疫研究为保护性注射药物的不安全使用提供了证据。 急性丙型肝炎的自然消退可以通过疫苗接种来复制，从而获得长期的免疫力。 此外，抗体介导的保护，防止再次接触病毒后持续感染。 免疫黑猩猩中 CD4+ 或 CD8+ T 细胞的耗竭导致持续或长期感染 这些研究为抗 HCV 的“T 细胞”疫苗提供了概念支持。 然而，我们对 HCV 如何逃避 T 的了解还很有限。 CD4+ T 细胞的失败是细胞免疫对疫苗开发构成潜在风险的最佳预测因素。 慢性结果，但尚不清楚 CD8+ T 细胞如何在急性期间从部分有效状态转变。 项目 1 中的研究旨在测试感染至完全衰竭的情况。 程序性中心假设：急性持续性和消退性 HCV 中 T 细胞反应的比较 感染将揭示分别导致疲劳或记忆的独特分子途径。 患有急性丙型肝炎的人类受试者无法进入肝脏，从而阻碍了抗病毒 T 细胞免疫。 为了解决这个问题，我们将利用存档的患有急性发作的黑猩猩的肝脏和血液样本 丙型肝炎来定义 CD4+ 和 CD8+ T 细胞衰竭的机制，然后这些发现将转化为 患有急性丙型肝炎的人。我们的初步数据表明，许多急性期肝内 CD4+ 和 即使在自发消退的感染中，CD8+ T 细胞也不起作用，这表明对病毒的控制。 感染是一个比以前理解的更加随机的过程。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、广度和转录谱 对具有急性缓解和持续感染的黑猩猩进行 CD4+ T 细胞的转录分析。 有望揭示导致 HCV 特异性群体缺失或耗尽的分子途径 将使用创新的微流控 PCR 技术，因为它具有良好的适应能力。 用于分析少量病毒特异性 CD4+ T 细胞的基因表达。 还表明，CD8+ T 细胞在持续存在之前的几个月内可以部分控制 HCV 复制。 建立了转录分析来确定这些细胞如何从这部分转变。 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 这些涉及黑猩猩和人类的研究应该为这一过程提供新的见解。 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。

项目成果

A Tale of Two Viruses: Immunological Insights Into HCV/HIV Coinfection.

• DOI: 10.3389/fimmu.2021.726419
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Gobran ST;Ancuta P;Shoukry NH
• 通讯作者: Shoukry NH

Differential immune transcriptomic profiles between vaccinated and resolved HCV reinfected subjects.

• DOI: 10.1371/journal.ppat.1010968
• 发表时间: 2022-11
• 期刊: PLoS pathogens
• 影响因子: 6.7

Where to Next? Research Directions after the First Hepatitis C Vaccine Efficacy Trial.

• DOI: 10.3390/v13071351
• 发表时间: 2021-07-13
• 期刊: Viruses
• 作者: Phelps CC;Walker CM;Honegger JR
• 通讯作者: Honegger JR

T cell responses during HBV and HCV infections: similar but not quite the same?

• DOI: 10.1016/j.coviro.2021.08.011
• 发表时间: 2021-12
• 期刊: Current opinion in virology
• 影响因子: 5.9

Designing an HCV vaccine: a unique convergence of prevention and therapy?

设计 HCV 疫苗：预防和治疗的独特融合？

• DOI: 10.1016/j.coviro.2017.03.014
• 发表时间: 2017
• 期刊: Current opinion in virology
• 影响因子: 5.9
• 作者: Walker,ChristopherM