Ackerman Margaret E, Mikhailova Anastassia, Brown Eric P, Dowell Karen G, Walker Bruce D, Bailey-Kellogg Chris, Suscovich Todd J, Alter Galit
Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire, United States of America.
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, United States of America.
PLoS Pathog. 2016 Jan 8;12(1):e1005315. doi: 10.1371/journal.ppat.1005315. eCollection 2016 Jan.
Elite controllers (ECs) represent a unique model of a functional cure for HIV-1 infection as these individuals develop HIV-specific immunity able to persistently suppress viremia. Because accumulating evidence suggests that HIV controllers generate antibodies with enhanced capacity to drive antibody-dependent cellular cytotoxicity (ADCC) that may contribute to viral containment, we profiled an array of extra-neutralizing antibody effector functions across HIV-infected populations with varying degrees of viral control to define the characteristics of antibodies associated with spontaneous control. While neither the overall magnitude of antibody titer nor individual effector functions were increased in ECs, a more functionally coordinated innate immune-recruiting response was observed. Specifically, ECs demonstrated polyfunctional humoral immune responses able to coordinately recruit ADCC, other NK functions, monocyte and neutrophil phagocytosis, and complement. This functionally coordinated response was associated with qualitatively superior IgG3/IgG1 responses, whereas HIV-specific IgG2/IgG4 responses, prevalent among viremic subjects, were associated with poorer overall antibody activity. Rather than linking viral control to any single activity, this study highlights the critical nature of functionally coordinated antibodies in HIV control and associates this polyfunctionality with preferential induction of potent antibody subclasses, supporting coordinated antibody activity as a goal in strategies directed at an HIV-1 functional cure.
精英控制者（ECs）代表了一种针对HIV-1感染的功能性治愈的独特模式，因为这些个体产生了能够持续抑制病毒血症的HIV特异性免疫力。由于越来越多的证据表明，HIV控制者产生的抗体具有增强的驱动抗体依赖性细胞毒性（ADCC）的能力，这可能有助于控制病毒，我们对不同程度病毒控制的HIV感染人群的一系列额外中和抗体效应功能进行了分析，以确定与自发控制相关的抗体特征。虽然在精英控制者中抗体滴度的总体水平和个体效应功能均未增加，但观察到一种功能上更协调的先天免疫招募反应。具体而言，精英控制者表现出多功能体液免疫反应，能够协调招募ADCC、其他自然杀伤细胞（NK）功能、单核细胞和中性粒细胞吞噬作用以及补体。这种功能上协调的反应与质量上更优的IgG3/IgG1反应相关，而在病毒血症患者中普遍存在的HIV特异性IgG2/IgG4反应与总体抗体活性较差相关。这项研究并非将病毒控制与任何单一活动联系起来，而是强调了功能协调抗体在HIV控制中的关键性质，并将这种多功能性与有效抗体亚类的优先诱导联系起来，支持将协调抗体活性作为针对HIV-1功能性治愈策略的一个目标。
