Bioinformatic Mapping of HIV-1 Nef Manipulation of T-Cell Activation and Function

HIV-1 Nef 操纵 T 细胞激活和功能的生物信息学图谱

基本信息

批准号：
7336749
负责人：
Jason David Barbour
金额：
$ 30.81万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-15 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7336749
关键词：
Accounting Adopted Adult Alleles Bioinformatics Biological Biostatistical Methods CD28 gene CD4 Positive T Lymphocytes CD8B1 gene Cell Differentiation process Cell Maturation Cell physiology Cell surface Cells Characteristics Class Clinical Clinical Virology Collaborations Data Dendritic Cells Development Disease Disease Outcome Effectiveness Environment Epitopes Evolution Flow Cytometry General Hospitals Genetic Genetic Determinism Genetic Variation Genome Goals Grant HIV HIV vaccine HIV-1 Human Immune Immune system Immunology Immunophenotyping Immunotherapeutic agent Impairment In Vitro Infection Interleukin-2 Laboratories Laboratory Markers Longitudinal Studies Lymphocyte-Specific p56LCK Tyrosine Protein Kinase MAPK14 gene Maps Measures Outcome Participant Pathway interactions Patients Pattern Personal Satisfaction Persons Phenotype Phosphorylation Population Positioning Attribute Protein Region Proteins Qualifying Reporting Research Role SCID-hu Mice SIV San Francisco Signal Pathway Signal Transduction Signaling Protein Site Specimen Stimulus Structure Surface T-Cell Activation T-Cell Receptor T-Lymphocyte Time Trees Variant Viral Virulence Virulence Factors Virulent Work base clinical phenotype cohort cytokine design falls improved in vivo killings loss of function mouse model nef Genes nef Protein p65 perforin pressure receptor response therapy development tool vaccination strategy virus genetics

项目摘要

DESCRIPTION (provided by applicant): HIV disease is characterized by high level CD8+ T cell activation and impairment in T cell function. Despite being the distinguishing characteristic of HIV-1 infection, the basis for the variation in CD8+ T cell activation in humans is not well understood. Variation in circulating strains of HIV-1 may account for this variation. We intend to map viral genetic determinants of T cell activation within the HIV-1 Nef protein. The HIV-1 Nef protein has been repeatedly implicated in manipulation of the human immune system. Adopting a very wide array of functions, HIV-1 Nef down modulates expression of key surface receptors, such as CD4, CD28, and MHC, facilitates viral entry and release, directly interacts with signaling proteins, such as the T cell receptor proximal kinase, Lck, and induce IL-2 expression. The sites c onferring these functions to Nef fall in distinct regions of the protein - regions which vary in sequence across HIV-1 strains. Nef is expressed early in infection, and is a target for CTL immune escape. HIV-1 Nef activity within infected CD4+ T cells influences cellular response to stimuli, cytokine secretion patterns, and interaction with CD8+ T cells. In this way, Nef may influence CD8+ T cell activation levels and T cell maturation. While Nef has been studied extensively in vitro, the impact of Nef sequence variation in vivo has not been well studied. We propose to relate HIV-1 viral nef sequence to T cell activation levels, T cell phenotype, and T cell signaling alterations by use of advanced bioinformatic mapping tools. We will perform these studies in a cohort of 220 recently HIV-1 infected adults with well-characterized disease course and in collaboration with the UCSF/CFAR Core Immunology Laboratory and the UCSF Laboratory of Clinical Virology. We will use tree- structured biostatistical methods and their extensions which are well suited to handling of high-dimensional biological data types, such as genetic sequence and flow cytometry. The strengths of this application include the availability of specimens from a well-characterized cohort of HIV-1 infected adults; the use of advanced bioinformatic mapping tools; high-dimensional flow cytometric measures of function and signaling; a highly qualified inter-disciplinary research team; and a longitudinal approach to study of a genetically diverse entity, HIV-1. This work will facilitate development of therapies to improve the effectiveness of T cell responses and design of an effective HIV vaccine. HIV disease is characterized by high level CD8+ T cell activation and impairment in T cell function. Despite being the distinguishing characteristic of HIV-1 infection, the basis for the variation in CD8+ T cell activation in humans is not well understood. Variation in circulating strains of HIV-1 may account for this variation. We intend to map viral genetic determinants of T cell activation within the HIV-1 Nef protein.

描述（由申请人提供）：HIV 疾病的特征是高水平的 CD8+ T 细胞激活和 T 细胞功能损伤。尽管这是 HIV-1 感染的显着特征，但人类 CD8+ T 细胞激活变化的基础尚不清楚。 HIV-1 流行毒株的变异可能是造成这种变异的原因。我们打算绘制 HIV-1 Nef 蛋白内 T 细胞激活的病毒遗传决定因素。 HIV-1 Nef 蛋白已多次与人类免疫系统的操纵有关。 HIV-1 Nef 采用非常广泛的功能，下调关键表面受体（例如 CD4、CD28 和 MHC）的表达，促进病毒进入和释放，直接与信号蛋白（例如 T 细胞受体近端激酶）相互作用， Lck，并诱导IL-2表达。网站 c 赋予 Nef 这些功能的蛋白落在蛋白质的不同区域，这些区域在不同 HIV-1 毒株中的序列各不相同。 Nef 在感染早期表达，是 CTL 免疫逃逸的目标。受感染的 CD4+ T 细胞内的 HIV-1 Nef 活性影响细胞对刺激的反应、细胞因子分泌模式以及与 CD8+ T 细胞的相互作用。通过这种方式，Nef 可能会影响 CD8+ T 细胞的激活水平和 T 细胞的成熟。虽然 Nef 在体外已被广泛研究，但 Nef 序列变异在体内的影响尚未得到充分研究。我们建议通过使用先进的生物信息学绘图工具将 HIV-1 病毒 nef 序列与 T 细胞激活水平、T 细胞表型和 T 细胞信号传导改变联系起来。我们将与 UCSF/CFAR 核心免疫学实验室和 UCSF 临床病毒学实验室合作，在 220 名最近感染 HIV-1 且具有明确病程的成年人中进行这些研究。我们将使用树结构生物统计方法及其扩展，它们非常适合处理高维生物数据类型，例如基因序列和流式细胞术。该应用程序的优点包括可以从一组特征明确的 HIV-1 感染成年人中获得样本；使用先进的生物信息学绘图工具；功能和信号传导的高维流式细胞术测量；高素质的跨学科研究团队；以及研究遗传多样性实体 HIV-1 的纵向方法。这项工作将促进治疗方法的开发，以提高 T 细胞反应的有效性，并设计有效的 HIV 疫苗。 HIV 疾病的特征是高水平 CD8+ T 细胞激活和 T 细胞功能受损。尽管这是 HIV-1 感染的显着特征，但人类 CD8+ T 细胞激活变化的基础尚不清楚。 HIV-1 流行毒株的变异可能是造成这种变异的原因。我们打算绘制 HIV-1 Nef 蛋白内 T 细胞激活的病毒遗传决定因素。