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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：
7433916
负责人：
Jason David Barbour
金额：
$ 11.33万
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 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7433916
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CD8+ T细胞高水平活化和T细胞功能受损。尽管这是HIV-1感染的显著特征，但人类CD8+ T细胞活化变异的基础尚不清楚。HIV-1流行毒株的变异可能解释了这种变异。我们打算在HIV-1 Nef蛋白内绘制T细胞活化的病毒遗传决定因素。HIV-1 Nef蛋白多次被认为与人体免疫系统的操纵有关。HIV-1 Nef具有非常广泛的功能，下调关键表面受体（如CD4、CD28和MHC）的表达，促进病毒进入和释放，直接与信号蛋白（如T细胞受体近端激酶Lck）相互作用，诱导IL-2表达。网站c