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T细胞功能中的高水平CD8+ T细胞激活和损伤。尽管是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的循环菌株的变化可能解释了这种变化。我们打算绘制HIV-1 NEF蛋白中T细胞活化的病毒遗传决定因素。 HIV-1 NEF蛋白反复与操纵人类免疫系统有关。采用非常广泛的功能，HIV-1 NEF下降调节关键表面受体的表达，例如CD4，CD28和MHC，促进了病毒的进入和释放，直接与信号蛋白（例如T细胞受体近端激酶，LCK和LCK和诱导IL-2表达）直接相互作用。站点c 将这些功能发挥到NEF的范围落在蛋白质区域的不同区域中，这些区域在HIV -1菌株之间的顺序变化。 NEF在感染的早期表达，是CTL免疫逃生的靶标。感染CD4+ T细胞中的HIV-1 NEF活性会影响细胞对刺激，细胞因子分泌模式的反应以及与CD8+ T细胞的相互作用。这样，NEF可能会影响CD8+ T细胞激活水平和T细胞成熟。尽管已在体外进行了广泛的研究，但NEF序列变化在体内的影响尚未得到很好的研究。我们建议通过使用先进的生物信息学映射工具将HIV-1病毒NEF序列与T细胞激活水平，T细胞表型和T细胞信号改变改变。我们将在220名最近受HIV-1感染的成年人中进行疾病良好的疾病病程，并与UCSF/CFAR核心免疫学实验室和UCSF临床病毒学实验室合作进行这些研究。我们将使用树结构的生物统计学方法及其扩展，这些方法非常适合处理高维生物学数据类型，例如遗传序列和流式细胞仪。该应用的优势包括来自特征良好的HIV-1感染成年人的标本；使用高级生物信息学映射工具；功能和信号传导的高维流式细胞仪度量；一个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。这项工作将有助于开发疗法，以提高T细胞反应和有效HIV疫苗的设计的有效性。 HIV疾病的特征是高水平的CD8+ T细胞激活和T细胞功能的损伤。尽管是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的循环菌株的变化可能解释了这种变化。我们打算绘制HIV-1 NEF蛋白中T细胞活化的病毒遗传决定因素。