T Cell Immunity and HCV Infection Outcome

T 细胞免疫和 HCV 感染结果

• 批准号: 9759758
• 负责人: Christopher M. Walker
• 金额: $ 25.06万
• 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/9759758
• 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; Clinical Trials; 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; 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）仍然是全球肝病的一个重要病因。新型直接作用