Molecular basis of ADCC-mediated HIV protection

描述(由申请人提供)： 拟议研究的广泛和长期目标是提供一个精确的分子基础，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，ADCC诱导似乎提供了对艾滋病毒感染的保护和抑制疾病的进展。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，这些相互作用导致相对于慢性进展性疾病患者而言，精英控制者人群中ADCC的诱导增加；以及(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。我们最近产生的实验证据表明：(I)由HIV精英控制者产生的抗体与Fc？RIIIa受体结合的亲和力显著高于慢性感染者产生的抗体；(Ii)来自慢性感染者的抗体在HIV感染的早期阶段与Fc？RIIIa的亲和力越来越弱；以及(Iii)一组广泛中和的HIV抗体与Fc？RIIIa的亲和力差异很大。这些结果中的每一个与ADCC诱导的功能读数相关。我们的发现表明，在HIV感染期间产生的抗体存在一种全新的、以前未被认识到的生物物理特征，与免疫保护相关。这些数据表明，开发合理利用ADCC功能来控制病毒复制的新型艾滋病毒疫苗技术是一个独特的机会。我们假设，精英控制者产生的抗体的ADCC诱导特性保护这些人免受疾病进展，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赋予对艾滋病毒感染的广泛保护。

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.