Department of Chemistry and Chemical Biology, Harvard, Cambridge, Massachusetts, United States of America.
Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, Colorado, United States of America.
PLoS Comput Biol. 2022 Apr 20;18(4):e1009391. doi: 10.1371/journal.pcbi.1009391. eCollection 2022 Apr.
The design of vaccines against highly mutable pathogens, such as HIV and influenza, requires a detailed understanding of how the adaptive immune system responds to encountering multiple variant antigens (Ags). Here, we describe a multiscale model of B cell receptor (BCR) affinity maturation that employs actual BCR nucleotide sequences and treats BCR/Ag interactions in atomistic detail. We apply the model to simulate the maturation of a broadly neutralizing Ab (bnAb) against HIV. Starting from a germline precursor sequence of the VRC01 anti-HIV Ab, we simulate BCR evolution in response to different vaccination protocols and different Ags, which were previously designed by us. The simulation results provide qualitative guidelines for future vaccine design and reveal unique insights into bnAb evolution against the CD4 binding site of HIV. Our model makes possible direct comparisons of simulated BCR populations with results of deep sequencing data, which will be explored in future applications.
针对高度易变病原体（如 HIV 和流感）的疫苗设计需要深入了解适应性免疫系统如何应对遇到多种变异抗原（Ags）。在这里，我们描述了一种 B 细胞受体（BCR）亲和力成熟的多尺度模型，该模型采用实际的 BCR 核苷酸序列，并详细研究 BCR/Ag 相互作用。我们应用该模型模拟针对 HIV 的广泛中和抗体（bnAb）的成熟过程。从针对 HIV 的 VRC01 抗体制备的原始胚系前体序列开始，我们模拟了 BCR 对不同疫苗接种方案和不同 Ag 的进化反应，这些 Ag 是我们之前设计的。模拟结果为未来的疫苗设计提供了定性指导，并揭示了针对 HIV 的 CD4 结合位点的 bnAb 进化的独特见解。我们的模型使得模拟的 BCR 群体与深度测序数据的结果可以直接进行比较，这将在未来的应用中进行探索。
