Wang Shenshen, Mata-Fink Jordi, Kriegsman Barry, Hanson Melissa, Irvine Darrell J, Eisen Herman N, Burton Dennis R, Wittrup K Dane, Kardar Mehran, Chakraborty Arup K
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139.
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
Cell. 2015 Feb 12;160(4):785-797. doi: 10.1016/j.cell.2015.01.027. Epub 2015 Feb 5.
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.
通过一种称为亲和力成熟的突变选择过程产生强效抗体是有效免疫反应的关键组成部分。抵御高度可变病原体的抗体必须中和多种毒株。制定有效的免疫策略来推动其进化需要了解在存在相同抗原变体的环境中亲和力成熟是如何发生的。我们提出了一种由抗原变体驱动的亲和力成熟的计算机模拟模型，该模型表明交叉反应性抗体的诱导通常发生概率较低，因为不同抗原变体施加的相互冲突的选择力会阻碍亲和力成熟。我们描述了诸如抗原给药的时间模式等变量如何影响这种受阻进化过程的结果。我们的计算预测，并且在具有HIV包膜蛋白变体gp120构建体的小鼠中进行的实验证实，与混合疫苗相比，用抗原变体进行序贯免疫更有利于诱导针对共享CD4结合位点表位的交叉反应性抗体。
