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：
8604683
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 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8604683
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 HIV HIV Infections Hepatitis Hepatitis B Virus Hepatitis C Hepatitis C Transmission Hepatitis C virus Human Immune Immune response Immune system Immunity Immunotherapeutic agent Immunotherapy Impairment Individual Infection Infection Control Intervention Knowledge Lead Liver Lymphocyte Measurable Mediating Modality Modeling Mus Mutate Mutation Outcome Pathway interactions Pattern Peptide Library Peripheral Blood Mononuclear Cell Persons Phase Plasma Population Procedures Production Property Prophylactic treatment Recruitment Activity Resources Rest Role Sampling Sorting - Cell Movement Specimen Staging 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 intrahepatic programs prophylactic public health relevance receptor repository response transcription factor vaccine development

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病毒感染至关重要。然而，令人惊讶的是，什么构成保护性CD4响应以及导致CD4 T细胞衰竭的机制知之甚少。在识别和隔离病毒特异性CD4 T细胞以及分析少量细胞的功能和转录状态方面的最新技术进步现在可以回答有关CD4 T细胞在慢性感染与急性感染中的作用和命运的基本问题，并有期望结果将使原子疫苗设计以及有针对性的免疫治疗干预措施的开发。为了更好地定义人类CD4 T细胞反应的关键方面，我们将使用丙型肝炎病毒（HCV）感染的模型。 HCV在全球范围内感染了近200万人，尽管最近在可预见的未来，抗病毒疗法的进展将仍然是一个紧迫的临床问题。因此，替代性治疗方式以及预防性疫苗仍然是高度优先级。最重要的是，对于该提案，HCV允许研究急性和慢性病毒感染，从而保护性和无效的免疫力，因为估计有30％的感染受试者自发地清除了该病毒，而其余受试者则发展了慢性感染和肝炎。作为我们研究的关键资源，我们建立了一个标本库，该标本库具有超过30,000个PBMC和15,000多个等离子体样本，来自1000多名HCV+受试者，包括在感染后6个月内近300名个人。基于我们最近的发现，几乎所有受试者都可以测量且通常在HCV感染后的可测量的多特异性CD4反应，我们假设HCV特异性CD4 T细胞之间的功能差异定义了HCV感染的结果，持续的感染会导致CD4耗尽。 T细胞抑制途径的激活，该病毒能够通过向较低的可识别变异变异来绕过CD4反应。因此，在AIM 1中，我们将测试急性HCV感染中CD4反应的分泌能力有助于协调免疫系统的不同臂，并启动与T细胞存活相关的细胞内程序。 AIM 2将通过询问HCV特异性CD4 T细胞的不同功能和不同命运是否由不同的T细胞抑制途径的激活驱动，并特别考虑肝内CD4 T细胞的驱动。在AIM 3中，我们将定义病毒逃生突变在HCV持久性方面的作用。在拟议的研究结束时，我们期望对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反应有什么区别。这些结果可能对仅超出HCV感染的预防和治疗慢性病毒感染具有重大影响。