Molecular basis of ADCC-mediated HIV protection

ADCC介导的HIV保护的分子基础

基本信息

批准号：
7989238
负责人：
ERIC JOHN SUNDBERG
金额：
$ 64.56万
依托单位：
BOSTON BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-02 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7989238
关键词：
ALVAC Acquired Immunodeficiency Syndrome Address Affinity Alleles Anti-Retroviral Agents Antibodies Antibody Affinity Antibody Formation Antigens B-Lymphocytes Binding CD4 Positive T Lymphocytes CD8B1 gene Characteristics Chronic Complex Country Data Dependence Development Disease Progression Event Exhibits Fc Receptor Goals HIV HIV vaccine HIV-1 HLA Antigens Immune Immune Targeting Immune response Immune system Immunology Individual Infection Control Lead Mediating Molecular Patients Pattern Polysaccharides Population Progressive Disease Property Relative (related person)Research Risk Roentgen Rays Staging Structure T cell response Technology Thailand Therapeutic Time Vaccine Design Vaccines Viral Virus Virus Diseases antibody-dependent cell cytotoxicity arm base cohort global health glycosylation improved in vivo innovation neutralizing antibody neutralizing monoclonal antibodies novel pandemic disease polyclonal antibody prophylactic receptor receptor binding vaccination strategy vaccine development vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): The broad, long-term goal of the proposed studies is to provide a precise molecular basis of how particular biophysical signatures endowed to antibodies correlate to antibody-dependent cellular cytotoxicity (ADCC) induction, which appears to confer protection against HIV infection and inhibits disease progression. To do so, we will address two Specific Aims: (1) to determine the biophysical basis of interactions between antibodies and Fc receptors that lead to increased induction of ADCC in elite controller populations relative to individuals with chronic progressive disease; and (2) to determine the structural and energetic bases for how differential antibody glycosylation results in increased ADCC induction and HIV protection. We have recently produced experimental evidence showing: (i) that antibodies generated by HIV elite controllers bind to the Fc?RIIIa receptor with significantly higher affinity than antibodies generated by chronically infected individuals; (ii) that antibodies from chronically infected individuals bind with increasingly weaker affinity to Fc?RIIIa throughout the early stages of HIV infection; and (iii) that a panel of broadly neutralizing HIV antibodies exhibits widely varying affinities to Fc?RIIIa. Each of these results correlates to functional readouts of ADCC induction. Our findings indicate that there exists an entirely novel and previously unrecognized biophysical signature of antibodies produced during HIV infection that correlates to immunological protection. These data suggest a unique opportunity to develop novel HIV vaccine technologies that rationally harness ADCC function to control viral replication. We hypothesize that the ADCC-inducing properties of antibodies generated by elite controllers protect these individuals from disease progression and that recapitulation of the biophysical characteristics of these antibodies in at-risk individuals via novel vaccination strategies will confer broad protection against HIV infection. PROJECT NARRATIVE. More than 30 million individuals are currently infected with human immunodeficiency virus (HIV)-1 worldwide, and in the year 2007 alone 2.7 million additional individuals were infected with the virus and a further 2 million individuals died of AIDS. While relatively effective anti-retroviral therapy exists, it is widely available only in first world countries, and some 95 percent of HIV-1-infected individuals reside in the developing world, and thus, the development of an effective HIV-1 vaccine remains an outstanding global health goal. Our proposed studies are aimed at elucidating critical molecular mechanisms of antibody-dependent cellular cytotoxicity (ADCC) by which the immune systems of some individuals may be controlling HIV infection and progression to AIDS to drive innovation in HIV vaccine design.

描述（由申请人提供）：拟议的研究的广泛，长期目标是提供一个精确的分子基础，即赋予抗体与抗体依赖性细胞毒性（ADCC）诱导的特定生物物理特征如何相关，这似乎赋予了针对HIV感染的保护并抑制疾病进展的保护。为此，我们将解决两个具体的目的：（1）确定抗体和FC受体之间相互作用的生物物理基础，这些基础导致相对于患有慢性进行性疾病的个体而导致精英控制器人群中ADCC的诱导增加；（2）确定差异抗体糖基化如何导致ADCC诱导和HIV保护增加的结构和能量碱基。我们最近产生了实验证据：（i）HIV Elite Controller产生的抗体与Fc？RIIIA受体的亲密关系明显高于长期感染个体产生的抗体；（ii）在艾滋病毒感染的早期阶段，来自慢性感染个体的抗体与Fc？riiia的亲和力越来越弱；（iii）一组广泛中和的艾滋病毒抗体表现出与fc？riiia的亲和力差异很大。这些结果中的每一个都与ADCC诱导的功能读数有关。我们的发现表明，存在一种完全新颖且以前未识别的生物物理特征，其在HIV感染过程中产生的抗体与免疫保护相关。这些数据提出了一个独特的机会来开发新型的HIV疫苗技术，该技术合理利用ADCC功能控制病毒复制。我们假设精英控制者产生的抗体的ADCC诱导特性保护了这些个体免受疾病的进展，并且通过新型疫苗接种策略对这些抗体的生物物理特征概括将赋予广泛的保护侵害HIV感染。项目叙述。目前，超过3000万人感染了全球人类免疫缺陷病毒（HIV）-1的感染，仅在2007年，仅270万年，有270万人感染了该病毒，另有200万人死于艾滋病。虽然存在相对有效的抗逆转录病毒疗法，但仅在第一世界国家就可以广泛使用，而大约95％的HIV-1感染者居住在发展中国家，因此，有效的HIV-1疫苗的开发仍然是一种杰出的全球健康目标。我们提出的研究旨在阐明抗体依赖性细胞毒性（ADCC）的关键分子机制，通过该抗体的细胞毒性（ADCC），某些人的免疫系统可能正在控制HIV感染并进展到AIDS，以驱动HIV疫苗设计的创新。