Human Ig knockin mice to study the development and regulation of HIV-1 broadly neutralizing antibodies.
Human Ig knockin mice to study the development and regulation of HIV-1 broadly neutralizing antibodies.
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DOI：
10.1111/imr.12505
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发表时间：
2017-01
影响因子：
8.7
通讯作者：
Tian M
中科院分区：
文献类型：
--
作者：
Verkoczy L;Alt FW;Tian M
HIV-1疫苗研究的一个主要挑战是开发一种成功的免疫方法来诱导广泛中和抗体（bnAbs）。应对这一挑战的一个关键缺陷是缺乏能够识别限制bnAb诱导的障碍的动物模型，并根据疫苗策略促进bnAb发展的能力对其进行排名。自2010年以来，免疫球蛋白敲入（KI）技术已被用于在小鼠中表达bnAbs，该技术涉及将功能重排的人类可变外显子插入小鼠的IgH和IgL位点。这种方法使限制bnAb产生的免疫耐受机制得以阐明，并对克服这种限制的策略进行了评估。从这些研究中，再加上对重组基于igg的bnAb结构的分析所提供的丰富知识，很明显，bnAb的关键功能特征往往难以通过经典疫苗范式在小鼠中激发出来，因此需要对新疫苗概念进行更多的迭代测试。在这方面，表达成熟bnAb前体V(D)J重排或未重排的种系V， D， J片段（可以组装成编码bnAb前体的可变区域外显子）的bnAb KI模型已被设计用于评估驱动bnAb反应的新免疫原/方案的有效性。从这些研究中出现的一个有希望的方法是顺序施用，修饰的免疫原（设计用于结合逐渐成熟的bnAb前体）启动亲和力成熟的能力。在这里，我们回顾了从bnAb KI研究中获得的关于bnAb的调控和诱导的见解，并讨论了新的Ig KI方法来操纵bnAb在体内的产生和/或表达，以进一步促进疫苗引导的bnAb诱导研究。
A major challenge for HIV-1 vaccine research is developing a successful immunization approach for inducing broadly neutralizing antibodies (bnAbs). A key shortcoming in meeting this challenge has been the lack of animal models capable of identifying impediments limiting bnAb induction and ranking vaccine strategies for their ability to promote bnAb development. Since 2010, immunoglobulin knock-in (KI) technology, involving inserting functional rearranged human variable exons into the mouse IgH and IgL loci has been used to express bnAbs in mice. This approach has allowed immune tolerance mechanisms limiting bnAb production to be elucidated and strategies to overcome such limitations to be evaluated. From these studies, along with the wealth of knowledge afforded by analyses of recombinant Ig-based bnAb structures, it became apparent that key functional features of bnAbs often are problematic for their elicitation in mice by classic vaccine paradigms, necessitating more iterative testing of new vaccine concepts. In this regard, bnAb KI models expressing deduced precursor V(D)J rearrangements of mature bnAbs or unrearranged germline V, D, J segments (that can be assembled into variable region exons that encode bnAb precursors), have been engineered to evaluate novel immunogens/regimens for effectiveness in driving bnAb responses. One promising approach emerging from such studies is the ability of sequentially administered, modified immunogens (designed to bind progressively more mature bnAb precursors) to initiate affinity maturation. Here, we review insights gained from bnAb KI studies regarding the regulation and induction of bnAbs, and discuss new Ig KI methodologies to manipulate the production and/or expression of bnAbs in vivo, to further facilitate vaccine-guided bnAb induction studies.