Identification and characterization of individuals with elite anti-HIV-1 ADCC

精英抗 HIV-1 ADCC 个体的鉴定和特征描述

• 批准号: 9757695
• 负责人: Manish Sagar
• 金额: $ 22.25万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-08 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757695
• 关键词: Achievement; Animals; Antibodies; Antibody-Producing Cells; Antigens; B-Lymphocytes; Binding; Biological Assay; Cell-Mediated Cytolysis; Cells; Characteristics; Chronic; Cloning; Development; Effector Cell; Engineering; Epitopes; Future; Goals; Grant; HIV; HIV-1; Human; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; Immunoglobulins; Individual; Infection; Infection prevention; Investigation; Laboratories; Mediating; Methods; Monoclonal Antibodies; Natural Killer Cells; Patients; Plasma; Predisposition; Property; Protein Isoforms; Publishing; Reagent; Risk; Sampling; Somatic Mutation; Study models; Technology; Time; Vaccinated; Vaccine Clinical Trial; Vaccines; Variant; Virus; Work; antibody-dependent cell cytotoxicity; base; density; design; glycosylation; high throughput screening; innovation; insight; interest; mouse model; neutralizing antibody; nonhuman primate; novel; prevent; recombinant virus; response; vaccine trial

Project Summary Isolation of broadly neutralizing antibodies (bnAbs) has been a monumental step forward in HIV-1 antibody directed vaccine efforts. The discovery of bnAbs was predicated on two major advancements. First, development of high throughput neutralization assays allowed for the identification of HIV-1 infected individuals that had broad and potent neutralization responses, termed “elite neutralizers.” Second, isolation of individual antibody producing cells and subsequent single cell PCR technologies made it possible to clone and produce bnAbs in an efficient manner from the elite neutralizers. At this time, no vaccine immunogens have been designed that can elicit bnAbs in uninfected at risk individuals. Nearly all bnAbs, isolated to date, have extensive level of somatic mutation, which may be one characteristic that will be especially difficult to elicit with current vaccine technologies. Human vaccine trials, correlate analysis, and animal studies all suggest that antibody dependent cellular cytotoxicity (ADCC) along with neutralization responses are also important in preventing virus acquisition. Despite the importance of ADCC responses, efforts similar to those that led to the discovery of bnAbs have not been undertaken for ADCC inducing antibodies. For instance, previous investigations have not identified individuals that possess exceptionally broad and potent anti-HIV-1 ADCC responses, termed “elite ADCC.” Identification and subsequent isolation of antibodies from individuals that have elite ADCC activity may yield novel anti-HIV-1 antibodies. These ADCC inducing antibodies may be more amenable for elicitation with current immunogens. Individuals with broad and potent ADCC responses have not been identified primarily because of assays and reagent limitations. We have developed a novel ADCC assay which, for the first time, will allow high throughput screening of a large number of samples for ADCC breadth and potency. We propose to examine ADCC responses against a diverse panel of viruses among a large number of chronically infected treatment naïve patients. Our studies will begin to identify individuals that harbor elite ADCC. Furthermore, we will examine if specific antibody characteristics, such as binding to infected cells, antibody glycosylation, and immunoglobulin subtype, confer ADCC breadth and potency. Future investigations will aim to isolate and characterize antibodies from individuals shown to have broad and potent ADCC responses. These proposed studies are the first step towards the goal of identifying novel anti-HIV-1 antibodies that can potentially both prevent virus acquisition and be elicited with current vaccine immunogens.

项目摘要 广泛中和抗体（bnAbs）的分离是HIV-1抗体研究的重大进展 指导疫苗接种工作。bnAbs的发现基于两项重大进展。第一、 高通量中和试验的发展允许鉴定HIV-1感染个体 具有广泛而有效的中和反应，被称为“精英中和剂”。第二，个体隔离 抗体产生细胞和随后的单细胞PCR技术使得克隆和产生抗体成为可能。 bnAbs以有效的方式从精英中和剂。目前还没有疫苗免疫原 其设计可以在未感染的高危个体中引发bnAb。迄今为止，几乎所有分离的bnAb都具有 广泛的体细胞突变水平，这可能是一个特点，将特别难以引起与 目前的疫苗技术。人类疫苗试验、相关分析和动物研究都表明， 抗体依赖性细胞毒性（ADCC）沿着中和反应也是重要的， 防止病毒感染。尽管ADCC的反应很重要，但类似于导致 还没有发现用于ADCC诱导抗体的bnAb。例如，上一个 研究尚未发现具有特别广泛和有效的抗HIV-1 ADCC的个体 被称为“精英ADCC”。从个体中鉴定并随后分离抗体， 具有优良的ADCC活性可能产生新的抗HIV-1抗体。这些ADCC诱导抗体可以是 更容易被现有的免疫原激发。具有广泛和有效ADCC应答的个体 主要是由于检测和试剂的限制，我们已经开发出一种新颖 ADCC测定，这是第一次，将允许高通量筛选大量样品， ADCC的广度和效力。我们建议检查ADCC对多种病毒的反应 在大量慢性感染的初治患者中。我们的研究将开始 拥有ADCC精英的人此外，我们将检查是否有特定的抗体特征，如 与感染细胞的结合、抗体糖基化和免疫球蛋白亚型赋予ADCC宽度， 力量未来的研究将致力于分离和表征来自表现出具有以下特征的个体的抗体： 广泛而有效的ADCC反应。这些拟议的研究是朝着确定以下目标迈出的第一步 新的抗HIV-1抗体，其可以潜在地防止病毒获得并被电流激发， 疫苗免疫原。