Characterization of Novel Polyreactive Anit-HIV Anitbodies Autoimmunity

新型多反应性抗 HIV 抗体自身免疫的表征

• 批准号: 7591140
• 负责人: Maureen M Goodenow
• 金额: $ 18.33万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7591140
• 关键词: AIDS prevention; AIDS/HIV problem; Adolescent; Antibodies; Antibody Formation; Antibody Repertoire; Arts; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B cell repertoire; B-Lymphocyte Subsets; B-Lymphocytes; Biochemical; Biological Sciences; Cells; Characteristics; Clinical; Color; Complex; Complex Mixtures; Custom; Development; Effectiveness; Epitopes; Exploratory/Developmental Grant; Flow Cytometry; Future; Generations; Genes; Goals; HIV; HIV Antibodies; HIV Infections; HIV vaccine; HIV-1; Human; Immune; Immune response; Immunity; Immunoglobulin G; Immunoglobulin M; Immunology; Individual; Infection prevention; Lead; Length; Libraries; Light; Messenger RNA; Methods; Molecular; Molecular Analysis; Outcome; Performance; Peripheral; Phage Display; Phase; Phenotype; Population; Population Study; Prevention therapy; Reagent; Recombinants; Research; Research Project Grants; Role; Sampling; Source; Specificity; Structure of germinal center of lymph node; Technology; Testing; Translating; Vaccination; Vaccine Design; Vaccines; Virion; Virus; base; cell type; clinically relevant; complementarity-determining region 3; design; env Glycoproteins; hydropathy; innovation; interdisciplinary approach; neutralizing antibody; novel; novel vaccines; pandemic disease; peripheral blood; response

DESCRIPTION (provided by applicant): An effective HIV vaccine should induce in a diverse human population broadly-neutralizing anti-HIV antibodies [bnHIV-Ab] that target most or all HIV subtypes. Although inducing neutralizing antibodies against HIV by vaccination has proven to be a challenge, individuals with autoimmune disease frequently make polyreactive antibodies that also neutralize HIV infection. The long-term goal for the research proposed is to develop strategies that lead to induction of broadly reactive neutralizing antibodies that can prevent infection by a wide variety of clinically relevant strains. The hypothesis is that adolescents with autoimmunity with or without concurrent HIV infection are likely to harbor unique peripheral B cells that produce polyreactive antibodies with long and hydrophobic VH CDR3 regions, which are characteristics of known bnHIV-ab. The strategy to accomplish the research goals uses the exploratory/developmental R21 mechanism and an interdisciplinary approach to apply high impact basic immunology studies and innovative methods to explore the depth of the B-cell repertoire, to increase the panel of broadly neutralizing HIV-1 antibodies available by creating a novel phage display library, and to identify the B cell subset[s] that produce these antibodies. The study population includes a unique group of HIV infected adolescents with autoimmunity, as well as individuals with autoimmunity or HIV infection. Two related Specific Aims are proposed: 1. to search for specific B cell types producing broad reactive neutralizing antibodies with long VH CDR3; and 2. to develop and characterize broadly-neutralizing HIV antibodies. Specific Aim 1 will characterize peripheral blood B cell populations by multi-color flow cytometry, examine the depth of IgG and IgM antibody repertoires in subjects by high-throughput 454 Life Science pyrosequencing of VH CDR3 domains, and determine the localization of long, hydrophobic VH CDR3 domains within subsets of B cells. Specific Aim 2 combines the power of antibody phage display with autoimmune individuals, who are enriched for B cells that produced polyreactive autoantibodies, to develop a custom library that will be screened against a complex mixture of virion subtypes to isolate bnHIV-Ab. The proposed research will provide significant fundamental information about cellular aspects of human immunity and the molecular diversity of the antibody repertoire, and result in generation of broadly neutralizing HIV antibodies with novel specificities and/or biochemical characteristics. HIV/AIDS is a global pandemic for which there is currently no vaccine and no cure. Although inducing neutralizing antibodies against HIV by vaccination has proven to be a significant challenge, individuals with autoimmune disease frequently make antibodies that also neutralize HIV infection. The exploratory/developmental research proposed will apply state-of-the-art technology for a comprehensive cellular and molecular analysis of HIV-specific antibody responses in autoimmune individuals. The results will provide major advancements in understanding the immune response to HIV and will form a basis for developing novel vaccine strategies to induce an effective anti-HIV response.

描述（由申请人提供）： 有效的HIV疫苗应诱导大多数或所有HIV亚型的抗HIV抗体（BNHIV-AB）中和抗体抗体（BNHIV-AB）。尽管事实证明，通过疫苗接种诱导对HIV的中和抗体是一项挑战，但自身免疫性疾病的个体经常会导致多反应性抗体也可以中和HIV感染。提出的研究的长期目标是制定策略，从而导致诱导广泛反应性的中和抗体，以防止各种临床相关菌株感染。假设是，有或没有并发HIV感染的自身免疫性的青少年可能含有独特的外围B细胞，这些外周B细胞产生具有长而疏水的VH CDR3区域的多反应性抗体，这是已知BNHIV-AB的特征。实现研究目标的策略采用探索性/发展性R21机制和跨学科方法来应用高影响基本的免疫学研究和创新方法来探索B细胞曲目的深度，以增加广泛中和HIV HIV-1抗体的面板通过创建一个新颖的噬菌体显示库获得，并识别产生这些抗体的B细胞子集。该研究人群包括一群自身免疫性的独特的HIV感染青少年，以及自身免疫性或HIV感染的个体。提出了两个相关的特定目的：1。搜索具有长VH CDR3的广泛反应性中和抗体的特定B细胞类型；和2。开发和表征广泛中和的HIV抗体。具体目标1将通过多色流式细胞术表征外周血B细胞群体，检查受试者IgG和IgM抗体库的深度通过高通量454的VH CDR3域的高通道454 Life Science pyrosequering，并确定长，氢生物VH的本地化B细胞子集中的CDR3结构域。特定的目标2结合了抗体噬菌体显示的功能与自身免疫性个体，这些个体富含产生多反应性自身抗体的B细胞，以开发一种定制库，该库将与Virion子类型的复杂混合物进行筛选以分离BNHIV-AB。拟议的研究将提供有关人免疫的细胞方面以及抗体库的分子多样性的重要基本信息，并导致具有新型特异性和/或生化特征的广泛中和HIV抗体的产生。艾滋病毒/艾滋病是目前没有疫苗且没有治愈的全球大流行。尽管事实证明，通过疫苗接种诱导对HIV的中和抗体是一个重大挑战，但患有自身免疫性疾病的个体经常会产生抗体，也可以中和HIV感染。提出的探索性/发展研究将应用最新技术，以对自身免疫性个体中HIV特异性抗体反应进行全面的细胞和分子分析。结果将在理解对艾滋病毒的免疫反应方面提供主要的进步，并将为开发新型疫苗策略诱导有效的抗HIV反应构成基础。