Next Generation Broadly Neutralizing Antibodies to Clear HIV-1 Reservoir

项目总结 治愈HIV-1是艾滋病干预的首要任务之一。最近分离出了许多强有力的 而针对HIV包膜糖蛋白(Env)的广谱中和抗体(BNAbs)提供 发掘其作为被动给药治疗药物的潜力的大好机会 已确定的感染。BNAbs的保护作用主要是通过其极强的 高能力抑制病毒感染性和细胞间病毒传播(中和)，以及它们的 促进杀死在细胞上表达同源环境抗原的受感染细胞的能力 通过抗体依赖的细胞介导的细胞毒作用(ADCC)形成抗体病毒 免疫复合体导致病毒清除。不幸的是，最近一次 以bNAb为治疗剂的临床试验表明，抗原性多样化和 持续进化的HIV-1Env可以迅速获得逃避bNAbs的突变 单一特工。同时通过物理方式靶向不同的同源表位 结合多个bNAbs可以实现几乎100%的病毒覆盖率，即使用一种“单一”试剂 由这些多官能结合部分组成的，对于调节和 制造目的，除了由于 通过双价或多价环境结合增加亲和力，以及可能的协同效应 BNAbs。此外，最近的一项研究表明，在非人类灵长类动物模型中，与 通过bNAb治疗，CD8+细胞溶解T细胞可有效控制停药后病毒反弹 抗病毒治疗。因此，设计一种能够有效桥接的治疗剂是非常及时的。 感染细胞和溶细胞T细胞介导对感染细胞的杀伤。此外， 先前的研究证实，抗体Fc区域的修饰增加了他们的 具有调节细胞毒性和延长半衰期的能力。然而，这样的修改并没有 已被很好地应用于bNAbs治疗HIV。本研究旨在填补海量知识的空白 通过具有以下具体目的的调查在该领域存在差距：1)产生艾滋病毒环境bNAbs 多个表位结合部分通过以下方式具有改进的效力、亲和力和广度 基于结构的设计；2)设计bNAbs，有效地招募CD8+细胞溶解T细胞 潜伏感染CD4+T细胞并杀死感染细胞；3)提高Fc区效应器 功能(ADCC)。这项研究的总体结果将促进我们对 对持续病毒感染的保护性免疫，有助于SAFE的发展 以及有效的艾滋病毒缓解和根除干预战略。

Project summary HIV-1 curing is one of the top priorities for AIDS interventions. The recent isolation of many potent and broadly neutralizing antibodies (bNAbs) against HIV envelope glycoproteins (Env) offers great opportunities for exploring their potential as passively administered agents to treat established infections. The protective efficacy of bNAbs is primarily mediated by their extremely high capacity to inhibit virus infectivity and cell-cell virus spread (neutralization), as well as their ability to facilitate the killing of infected cells that express the cognate Env antigens on the cell surface through antibody-dependent cell-mediated cytotoxicity (ADCC) and to form antibody-virus immune complexes leading to viral clearance. Unfortunately, the outcome of the most recent clinical trials with bNAb as therapeutic agent demonstrated that the antigenically diverse and persistently evolving HIV-1 Env can rapidly acquire mutations that evade bNAbs administered as single agents. While simultaneously targeting distinct cognate epitopes by physically combining multiple bNAbs can result in virtually 100% virus coverage, the use of a “single” agent consisting of these multiple functional binding moieties is preferred for both regulatory and manufacturing purposes, in addition to the potential of augmented potency resulting from the increased avidity through bi- or multi- valence Env binding and possible synergistic effect between bNAbs. In addition, a recent study demonstrated in non-human primate model that in conjunction with bNAb therapy, CD8+ cytolytic T cells can effectively control virus rebound after the cessation of anti-viral therapy. Therefore, it is timely to engineer therapeutic agent that can effectively bridge the infected cells and the cytolytic T cells to mediate the killing of infected cells. Furthermore, previous studies established that modifications in the antibody Fc regions that increase their abilities to mediate cytotoxicity and extend their half-lives. However, such modifications have not been well applied to bNAbs for HIV treatment. This study aims to fill in the tremendous knowledge gap in the field by investigations with the following specific aims: 1) To generate HIV Env bNAbs with multiple epitope binding moieties possessing improved potency, avidity and breadth by structure-based design; 2) To engineer bNAbs that will efficiently recruit CD8+ cytolytic T cells to latently infected CD4+ T cells and kill the infected cells; and 3) To improve Fc region effector function (ADCC). The overall outcome of this study will advance our basic understanding of protective immunity against persistent virus infection and contribute to the development of safe and effective intervention strategies for HIV remission and eradication.