Molecular basis of ADCC-mediated HIV protection

ADCC介导的HIV保护的分子基础

• 批准号: 8102876
• 负责人: ERIC JOHN SUNDBERG
• 金额: $ 52.52万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-02 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102876
• 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; 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

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.

描述（由申请人提供）： 拟议研究的广泛、长期目标是提供精确的分子基础，说明赋予抗体的特定生物物理特征如何与抗体依赖性细胞毒性（ADCC）诱导相关，这似乎可以提供针对 HIV 感染的保护并抑制疾病进展。为此，我们将解决两个具体目标：(1) 确定抗体和 Fc 受体之间相互作用的生物物理基础，这种相互作用导致精英控制人群相对于慢性进展性疾病个体 ADCC 的诱导增加； (2) 确定差异抗体糖基化如何导致 ADCC 诱导增加和 HIV 保护的结构和能量基础。我们最近提供的实验证据表明：(i) HIV 精英控制者产生的抗体与 Fc?RIIIa 受体的结合亲和力明显高于慢性感染者产生的抗体； (ii) 在 HIV 感染的早期阶段，来自慢性感染者的抗体与 Fc?RIIIa 的结合亲和力越来越弱； (iii)一组广泛中和HIV抗体对FcRIIIa表现出广泛不同的亲和力。这些结果中的每一个都与 ADCC 诱导的功能读数相关。我们的研究结果表明，HIV 感染期间产生的抗体存在一种全新的、以前未被识别的生物物理特征，与免疫保护相关。这些数据表明，这是开发新型 HIV 疫苗技术的独特机会，该技术可以合理地利用 ADCC 功能来控制病毒复制。我们假设精英控制者产生的抗体的 ADCC 诱导特性可以保护这些个体免受疾病进展，并且通过新的疫苗接种策略在高危个体中重述这些抗体的生物物理特征将提供针对 HIV 感染的广泛保护。