Cell：科学家发现可以产生HIV高亲和力抗体的方法

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Cell：科学家发现可以产生HIV高亲和力抗体的方法

B细胞是人体在生理状态下唯一可以发生体细胞高频突变的场所，而这一过程正是B细胞产生高效抗体的过程。近日，科学家通过在硅载体上的研究发现了可以产生HIV高亲和力抗体的方法。相关研究结果发表于国际生命科学顶尖杂志Cell上。

抗体是由成熟的B细胞或记忆性B细胞分化成浆细胞后分泌产生的免疫球蛋白，可以特异性地结合相应的抗原。亲和力成熟是指浆细胞内基因高频突变从而产生高特异性抗体的过程，是抗体生成所经历的选择过程，是机体有效免疫应答的关键因素。在这样的选择过程中会面临来自细胞内的选择压力，使得不能与抗原特异性结合或者可与自身抗原反应的克隆得以清除。

能够保护机体抵御高度变异抗原的抗体必须能够中和多种病原。只有了解某个抗原的多种变体在真实情况下如何诱导亲和力成熟，才能有助于开发有效的抗体制备的免疫方案。作者介绍了一种由抗原变体诱导的亲和力成熟的硅载体模型，发现由于不同抗原变体导致矛盾的选择压力可以摧毁亲和力成熟体系，因此直接诱导产生交叉反应抗体的可能性是非常低的。作者描述了不同时间格局排布的抗原诱导方式会如何影响这种进化过程的结果。作者通过计算模型预期，并经过构建了HIV包膜蛋白gp120载体的小鼠模型的确认，证明了使用抗原变体进行有序的免疫诱导比将各种抗原的混合物直接进行免疫更有利于产生可针对CD4表位的高特异性抗体。（生物谷Bioon.com）

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DOI: http://dx.doi.org/10.1016/j.cell.2015.01.027

Manipulating the Selection Forces during Affinity Maturation to Generate Cross-Reactive HIV Antibodies.

Shenshen Wang, Jordi Mata-Fink, Barry Kriegsman, Melissa Hanson, Darrell J. Irvine, Herman N. Eisen, Dennis R. Burton, K. Dane Wittrup, Mehran Kardar, Arup K. Chakraborty

Generation of potent antibodies by a mutation-selection process called affinity maturation is a key component of effective immune responses. Antibodies that protect against highly mutable pathogens must neutralize diverse strains. Developing effective immunization strategies to drive their evolution requires understanding how affinity maturation happens in an environment where variants of the same antigen are present. We present an in silico model of affinity maturation driven by antigen variants which reveals that induction of cross-reactive antibodies often occurs with low probability because conflicting selection forces, imposed by different antigen variants, can frustrate affinity maturation. We describe how variables such as temporal pattern of antigen administration influence the outcome of this frustrated evolutionary process. Our calculations predict, and experiments in mice with variant gp120 constructs of the HIV envelope protein confirm, that sequential immunization with antigen variants is preferred over a cocktail for induction of cross-reactive antibodies focused on the shared CD4 binding site epitope.