CD4+ T Cells in Acute Versus Chronic HCV Infection

CD4 T 细胞在急性与慢性 HCV 感染中的作用

基本信息

批准号：
9208086
负责人：
GEORG Michael LAUER
金额：
$ 43.5万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9208086
关键词：
Activities of Daily Living Acute Acute Hepatitis C Affect Alleles Animals Antigens Antiviral Therapy Biological Biological Assay Blood CD4 Positive T Lymphocytes CD8B1 gene Cell Count Cell Maintenance Cell Survival Cells Characteristics Chronic Chronic Disease Chronic Hepatitis C Clinical Data Development Differentiation Antigens Epitopes Evolution Failure Foundations Future Gene Expression Profiling Genes Genetic Polymorphism Genetic Transcription HIV HIV Infections Hepatitis Hepatitis B Hepatitis C Hepatitis C Transmission Hepatocyte Human Immune response Immune system Immunity Immunologics Immunotherapeutic agent Immunotherapy Impairment Individual Infection Infection Control Intervention Knowledge Lead Liver Lymphocyte Measurable Mediating Modality Modeling Mutate Mutation Outcome Pathway interactions Pattern Peptide Library Peripheral Blood Mononuclear Cell Persons Phase Plasma Population Preventive vaccine Procedures Production Property Prophylactic treatment Recruitment Activity Resources Rest Role Sampling Sorting - Cell Movement Specimen T cell response T-Cell Activation T-Lymphocyte Technology Testing Therapeutic Time Translations Vaccine Design Vaccines Variant Viral Viral Antigens Viremia Virus Virus Diseases arm base cohort cytokine design exhaust exhaustion expectation human disease immunological intervention intrahepatic mouse model programs public health relevance receptor repository response therapy development transcription factor vaccine development virtual

项目摘要

DESCRIPTION (provided by applicant): CD4 T cell responses are of critical importance for the control of viral infections in animals and humans. Yet surprisingly little is known about what constitutes a protective CD4 response as well as the mechanisms that lead to CD4 T cell failure. Recent technological advances in identifying and isolating virus-specific CD4 T cells and in analyzing the functional and transcriptional state of small numbers of cells now allow to answer basic questions about the role and fate of CD4 T cells in chronic versus acute infection, with the expectation that the results will enable rationale vaccine design as well as the development of targeted immunotherapeutic interventions. In order to better define critical aspects of the CD4 T cell response directly in humans, we will use the model of hepatitis C virus (HCV) infection. HCV infects almost 200 millions people worldwide and despite recent progress in antiviral therapies will remain a pressing clinical problem in the world for the foreseeable future. Thus alternative therapeutic modalities as well as prophylactic vaccines remain a high priority. Most importantly for this proposal, HCV allows to study both acute and chronic viral infection and thus protective and ineffective immunity, since an estimated 30% of infected subjects clear the virus spontaneously while the rest develop chronic infection and hepatitis. As a critical resource for our studies we have established a specimen bank with more than 30,000 PBMC and over 15,000 plasma samples from cohorts with more than 1000 HCV+ subjects, including almost 300 individuals within 6 months post infection. Based on our recent findings that virtually all subjects prime a measurable and typically multi-specific CD4 response upon HCV infection we hypothesize that functional differences between HCV-specific CD4 T cells define the outcome of HCV infection, that persistent infection gives rise to CD4 exhaustion through the activation of T cell inhibitory pathways and that the virus is able to circumvent the CD4 response by mutating towards less recognizable variants. Thus in aim 1 we will test whether CD4 responses in acute HCV infection differ in their capacity to secrete cytokines that help coordinate the different arms of the immune system and in the initiation of intracellular programs associated with T cell survival. Aim 2 will extend these studies by asking whether different functions and a different fate of the HCV-specific CD4 T cells is driven by the activatio of distinct T cell inhibitory pathways, with special consideration of intrahepatic CD4 T cells. In aim 3 we will define the role of viral escape mutations for persistence of HCV. At the end of the proposed studies we expect to have established a detailed understanding of how CD4 T cells can help to control viral infections and what differentiates protective CD4 immunity from a failed CD4 response. These results could have major implications for the prophylaxis and treatment of chronic viral infections, beyond HCV infection alone.

描述（由申请人提供）：CD4 T 细胞反应对于控制动物和人类的病毒感染至关重要。然而令人惊讶的是，人们对保护性 CD4 反应的构成以及导致 CD4 T 细胞衰竭的机制知之甚少。最近在识别和分离病毒特异性 CD4 T 细胞以及分析少量细胞的功能和转录状态方面取得的技术进步现在可以回答有关 CD4 T 细胞在慢性与急性感染中的作用和命运的基本问题，并有望研究结果将使疫苗设计合理化以及有针对性的免疫治疗干预措施的开发成为可能。为了更好地直接定义人类 CD4 T 细胞反应的关键方面，我们将使用丙型肝炎病毒 (HCV) 感染模型。 HCV 感染了全世界近 2 亿人，尽管抗病毒治疗最近取得了进展，但在可预见的未来，HCV 仍将是世界上紧迫的临床问题。因此，替代治疗方式以及预防性疫苗仍然是重中之重。对于该提案来说，最重要的是，HCV 可以研究急性和慢性病毒感染，从而研究保护性和无效免疫，因为估计 30% 的感染受试者会自发清除病毒，而其余受试者则发展为慢性感染和肝炎。作为我们研究的重要资源，我们建立了一个样本库，其中包含 30,000 多个 PBMC 和 15,000 多个血浆样本，这些样本来自超过 1000 名 HCV+ 受试者的队列，其中包括感染后 6 个月内的近 300 名受试者。基于我们最近的发现，几乎所有受试者在 HCV 感染后都会引发可测量的、通常多特异性的 CD4 反应，我们假设 HCV 特异性 CD4 T 细胞之间的功能差异决定了 HCV 感染的结果，持续感染通过以下方式导致 CD4 耗竭： T 细胞抑制途径的激活，并且病毒能够通过突变为难以识别的变体来规避 CD4 反应。因此，在目标 1 中，我们将测试急性 HCV 感染中的 CD4 反应在分泌细胞因子的能力方面是否存在差异，这些细胞因子有助于协调免疫系统的不同分支，以及启动与 T 细胞存活相关的细胞内程序。目标 2 将扩展这些研究，询问 HCV 特异性 CD4 T 细胞的不同功能和不同命运是否是由不同 T 细胞抑制途径的激活驱动的，特别考虑肝内 CD4 T 细胞。在目标 3 中，我们将定义病毒逃逸突变对 HCV 持续存在的作用。在拟议的研究结束时，我们希望能够详细了解 CD4 T 细胞如何帮助控制病毒感染，以及保护性 CD4 免疫与失败的 CD4 反应的区别。这些结果可能对慢性病毒感染的预防和治疗产生重大影响，而不仅仅是丙型肝炎病毒感染。