Development of antibody-dependent cell cytotoxicity function in HIV-1 antibodies.
Development of antibody-dependent cell cytotoxicity function in HIV-1 antibodies.
复制标题
HIV-1 抗体中抗体依赖性细胞毒性功能的开发。
DOI：
10.7554/elife.63444
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发表时间：
2021-01-11
期刊：
影响因子：
7.7
通讯作者：
Overbaugh JM
中科院分区：
文献类型：
--
作者：
Doepker LE;Danon S;Harkins E;Ralph DK;Yaffe Z;Garrett ME;Dhar A;Wagner C;Stumpf MM;Arenz D;Williams JA;Jaoko W;Mandaliya K;Lee KK;Matsen FA 4th;Overbaugh JM
设计一种能产生保护性抗体的HIV疫苗的先决条件是了解产生理想抗体特征的发育途径。介导抗体依赖性细胞毒性（ADCC）的抗体的发展尤其重要，因为这种抗体与人类的HIV保护有关。我们利用纵向抗体测序数据重建了六种人类hiv特异性ADCC抗体的发育途径。大多数推断的初始抗体不介导可检测的ADCC。抗原结合和ADCC功能的获得通常需要在一条或两条链的互补决定区域发生突变。ADCC效力的增强通常需要在框架区域进行额外的突变。抗原结合亲和力与ADCC活性相关，但仅亲和力不足以预测ADCC效力。因此，激发广泛活性的ADCC抗体可能需要能够高亲和力抗原识别的突变，以及优化有助于ADCC活性的因子的突变。在人类免疫缺陷病毒（简称HIV）首次被发现近40年后，对疫苗的研究仍在继续。有效的免疫需要诱导人体免疫系统产生hiv特异性抗体的元素，这种抗体是一种能够识别、结合并使病毒失活的蛋白质。至关重要的是，抗体还可以帮助白细胞瞄准并摧毁感染艾滋病毒的细胞。这种“依赖抗体的细胞毒性”可能是成功疫苗的一个关键因素，但它受到的关注不如抗体直接中和病毒的能力。特别是，目前还不清楚抗体是如何发展出标记hiv感染细胞并杀死它们的能力的。事实上，在HIV感染的过程中，免疫细胞会经历基因变化，从而改变其产生的抗体的3D结构。这一过程可以提高抗体抵抗病毒的能力，但目前尚不清楚它如何形成依赖抗体的细胞毒性。为了研究这个问题，Doepker等人追溯了hiv携带者体内6个抗体家族的基因编码是如何随时间变化的。这表明抗体最初不能触发抗体依赖性细胞毒性。由于基因序列的两种类型的改变，这种特性得以出现并得到改善。一组变化增加了抗体与病毒结合的紧密程度，针对的是经常变化的抗体部分。第二组可能以其他方式改变了3D结构，可能影响抗体如何结合病毒或它们如何与帮助杀死hiv感染细胞的免疫系统成分相互作用。这些改变发生在随着时间变化较少的抗体片段上。最终，Doepker等人的发现表明，一种有效的HIV疫苗可能依赖于帮助抗体进化，使它们能够更紧密地与病毒结合，并更强烈地触发细胞毒性。
A prerequisite for the design of an HIV vaccine that elicits protective antibodies is understanding the developmental pathways that result in desirable antibody features. The development of antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC) is particularly relevant because such antibodies have been associated with HIV protection in humans. We reconstructed the developmental pathways of six human HIV-specific ADCC antibodies using longitudinal antibody sequencing data. Most of the inferred naive antibodies did not mediate detectable ADCC. Gain of antigen binding and ADCC function typically required mutations in complementarity determining regions of one or both chains. Enhancement of ADCC potency often required additional mutations in framework regions. Antigen binding affinity and ADCC activity were correlated, but affinity alone was not sufficient to predict ADCC potency. Thus, elicitation of broadly active ADCC antibodies may require mutations that enable high-affinity antigen recognition along with mutations that optimize factors contributing to functional ADCC activity. Nearly four decades after the human immunodeficiency virus (HIV for short) was first identified, the search for a vaccine still continues. An effective immunisation would require elements that coax the human immune system into making HIV-specific antibodies – the proteins that can recognise, bind to and deactivate the virus. Crucially, antibodies can also help white blood cells to target and destroy cells infected with HIV. This ‘antibody-dependent cellular cytotoxicity’ could be a key element of a successful vaccine, yet it has received less attention than the ability for antibodies to directly neutralize the virus. In particular, it is still unclear how antibodies develop the ability to flag HIV-infected cells for killing. Indeed, over the course of an HIV infection, an immune cell goes through genetic changes that tweak the 3D structure of the antibodies it manufactures. This process can improve the antibodies' ability to fight off the virus, but it was still unclear how it would shape antibody-dependent cellular cytotoxicity. To investigate this question, Doepker et al. retraced how the genes coding for six antibody families changed over time in an HIV-carrying individual. This revealed that antibodies could not initially trigger antibody-dependent cellular cytotoxicity. The property emerged and improved thanks to two types of alterations in the genetic sequences. One set of changes increased how tightly the antibodies could bind to the virus, targeting sections of the antibodies that can often vary. The second set likely altered the 3D structure in others ways, potentially affecting how antibodies bind the virus or how they interact with components of the immune system that help to kill HIV-infected cells. These alterations took place in segments of the antibodies that undergo less change over time. Ultimately, the findings by Doepker et al. suggest that an efficient HIV vaccine may rely on helping antibodies to evolve so they can bind more tightly to the virus and trigger cellular cytotoxicity more strongly.