Discovery of Novel Epitopes for Antibody Dependent Cell-mediated Cytotoxicity Against HIV-1 Infected Cells

发现抗体依赖性细胞介导的针对 HIV-1 感染细胞的细胞毒性的新表位

• 批准号: 10113530
• 负责人: Cynthia Ann Derdeyn
• 金额: $ 22.31万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-24 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10113530
• 关键词: AIDS/HIV problem; Africa South of the Sahara; Antibodies; Antibody Response; Antibody-mediated protection; Antiviral Agents; Autologous; B-Lymphocytes; Binding; Biological Assay; CCR5 gene; Cell Separation; Cells; Collection; Cryopreservation; Detection; Disease Progression; Effector Cell; Enrollment; Epitopes; Evaluation; Event; Genetic; Glycocalyx; Goals; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; Heterosexuals; Human; Human Volunteers; Individual; Infection; Maps; Measures; Mediating; Mediator of activation protein; Modeling; Molecular Cloning; Monoclonal Antibodies; Patients; Peripheral Blood Mononuclear Cell; Phase; Proteins; Recombinants; Research; Rwanda; Signal Transduction; Site; Statistical Data Interpretation; Surface; Testing; Vaccinated; Vaccination; Vaccines; Variant; Viral; Virion; Virus; Zambia; antibody-dependent cell cytotoxicity; base; cohort; cross reactivity; efficacy trial; innovation; insight; neutralizing antibody; nonhuman primate; novel; response; simian human immunodeficiency virus; transmission process; vaccine efficacy; vaccine trial

Project Summary/Abstract HIV research efforts are strongly focused on developing vaccines that can elicit highly protective antibody responses. There is evidence from human and nonhuman vaccine studies that both neutralizing and non- neutralizing antibody activities contribute to protection against acquisition. Importantly, the only phase III vaccine efficacy trial to show a signal of protection in human volunteers demonstrated that antibody dependent cell- mediated cytotoxicity (ADCC) was associated with reduced acquisition, compelling us to know more about this Fc-mediated antiviral function. We previously recovered a unique collection of more than 300 monoclonal antibodies from 6 recently HIV-1 infected individuals from Zambia and Rwanda and found that a subset of these antibodies mediated ADCC against target cells coated with the envelope gp120 protein from the autologous, transmitted/founder (T/F) variant. This activity was associated with antibodies that had shorter CDRH3 regions and lower neutralization activity against the T/F envelope pseudovirus than antibodies lacking ADCC activity. Modeling and competition studies suggested that some of the ADCC-mediating antibodies recognize novel epitopes. Here, we will test these monoclonal antibodies for ADCC against target cells infected with the authentic T/F variant created by molecular cloning, and compare the results with ADCC against target cells coated with the T/F gp120 protein and neutralization of the T/F Env, the latter being the hallmark of antibody binding to the functional, virion-associated envelope spike. By using a large number of autologous T/F envelope-antibody combinations, where the envelope presents the exact epitope or a very close approximation to that which the antibody was selected against, and two widely used ADCC assays, our studies have the potential to reveal previously unappreciated mechanistic features of ADCC and identify novel epitopes that can be further developed and explored for vaccines.

项目摘要/摘要 艾滋病毒研究工作非常集中于开发可以引起高度保护抗体的疫苗 回答。人类和非人类疫苗研究中有证据表明中和 中和抗体活性有助于防止获取。重要的是，唯一的III期疫苗 疗效试验显示，人类志愿者的保护信号表明抗体依赖性细胞 - 介导的细胞毒性（ADCC）与减少的获取有关，迫使我们对此有更多的了解 FC介导的抗病毒功能。我们以前收回了300多个单克隆的独特集合 来自赞比亚和卢旺达的6种HIV-1感染了6种的抗体，发现其中的一部分 抗体介导了与自体的包膜GP120蛋白覆盖的靶细胞介导的ADCC 传输/创建者（T/F）变体。该活性与CDRH3区域较短的抗体有关 与缺乏ADCC活性的抗体相比，针对T/F包膜的中和活性较低。 建模和竞争研究表明，某些ADCC - 实用抗体识别出新颖的抗体 表位。在这里，我们将测试ADCC的这些单克隆抗体，针对感染了真实的靶细胞 通过分子克隆产生的T/F变体，并将结果与​​ADCC与覆盖的靶细胞进行比较 T/F GP120蛋白和T/F Env的中和，后者是抗体结合的标志 功能性，病毒体相关的包膜尖峰。通过使用大量自体T/F信封抗体 组合，信封呈现确切的表位或非常接近近似的组合 选择了抗体，并且两种广泛使用的ADCC分析，我们的研究有可能揭示 以前未经批准的ADCC机械特征并确定可以进一步的新型表位 开发和探索疫苗。