Molecular basis of ADCC-mediated HIV protection

描述（由申请人提供）： 拟议研究的广泛，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，这些相互作用导致精英控制者群体中ADCC诱导相对于慢性进展性疾病个体增加;（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。我们最近产生的实验证据表明：（i）HIV精英控制者产生的抗体与Fc结合？RIIIa受体具有显着更高的亲和力比抗体产生的慢性感染的个人;（ii）抗体从慢性感染的个人结合越来越弱的亲和力Fc？RIIIa在整个艾滋病毒感染的早期阶段;及（iii）一组广泛中和的艾滋病毒抗体表现出广泛不同的亲和力Fc？RIIIa.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，存在一种全新的和以前未被认识到的生物物理签名的抗体在HIV感染过程中产生的免疫保护相关。这些数据表明，一个独特的机会，开发新的艾滋病毒疫苗技术，合理利用ADCC功能，以控制病毒复制。我们假设精英控制者产生的抗体的ADCC诱导特性保护这些个体免于疾病进展，并且通过新的疫苗接种策略在高危个体中重现这些抗体的生物物理特征将赋予广泛的抗HIV感染保护。 项目叙述。 目前，全世界有3 000多万人感染了人类免疫缺陷病毒（HIV）-1，仅在2007年，又有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广泛使用，约95%的HIV-1感染者居住在发展中国家，因此，开发有效的HIV-1疫苗仍然是一个突出的全球卫生目标。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，通过这些机制，一些个体的免疫系统可能控制HIV感染和进展为AIDS，以推动HIV疫苗设计的创新。

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.