aDuke Human Vaccine Institute, Duke University Medical Center, Durham bNational Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Curr Opin HIV AIDS. 2014 May;9(3):224-34. doi: 10.1097/COH.0000000000000049.
This review discusses progress in understanding the impact of immune tolerance on inducing broadly neutralizing antibodies (bnAbs), and how such knowledge can be incorporated into novel immunization approaches.
Over 120 bnAbs have now been isolated, all of which bear unusual features associated with host tolerance controls, but paradoxically may also be required for their function. Evidence that poly/autoreactivity of membrane proximal external region bnAbs can invoke such controls has been demonstrated by knock-in technology, highlighting its potential for studying the impact of tolerance in the generation of bnAb lineages to distinct HIV-1 envelope targets. The requirement for extensive affinity maturation in developing neutralization breadth/potency during infection is being examined, and similar studies in the setting of immunization will be aided by testing novel vaccine approaches in knock-in models that either selectively express reverted V(D)J rearrangements, or unrearranged germline segments, from which bnAb lineages originate.
It is increasingly apparent that immune tolerance, sometimes invoked by self-reactivity that overlaps with bnAb epitope specificity, adds to a formidable set of roadblocks impeding bnAb induction. The path to an effective HIV-1 vaccine may thus benefit from a deeper understanding of host controls, including categorizing those that are unique or common at distinct bnAb targets, and ranking those most feasible to overcome by immunization. Ultimately, such emerging information will be critical to incorporate into new vaccine approaches that can be tested in human trials.
本综述讨论了在理解免疫耐受对诱导广泛中和抗体（bnAbs）的影响方面的进展，以及如何将这些知识纳入新的免疫接种方法中。
目前已经分离出超过 120 种 bnAbs，它们都具有与宿主耐受控制相关的不寻常特征，但矛盾的是，它们的功能也可能需要这些特征。通过敲入技术证明了膜近端外部区域 bnAbs 的多反应性/自身反应性可以引发这种控制，这突出了其在研究耐受对不同 HIV-1 包膜靶标 bnAb 谱系产生的影响方面的潜力。正在研究在感染过程中产生中和广度/效力时广泛亲和力成熟的必要性，在免疫接种的背景下，通过在敲入模型中测试新型疫苗方法将有助于这项研究，这些模型可以选择性地表达从 bnAb 谱系起源的重新排列的 V(D)J 重排或未重排的种系片段。
越来越明显的是，免疫耐受（有时由与 bnAb 表位特异性重叠的自身反应性引起）增加了一系列阻碍 bnAb 诱导的艰巨障碍。因此，有效的 HIV-1 疫苗的途径可能受益于对宿主控制的更深入了解，包括对独特或在不同 bnAb 靶标上常见的控制进行分类，并对最可行的通过免疫接种克服的控制进行分类。最终，这些新出现的信息对于纳入新的疫苗方法至关重要，这些方法可以在人体试验中进行测试。
