Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
Science. 2019 May 3;364(6439):480-484. doi: 10.1126/science.aav5095.
Mutationally constrained epitopes of variable pathogens represent promising targets for vaccine design but are not reliably identified by sequence conservation. In this study, we employed structure-based network analysis, which applies network theory to HIV protein structure data to quantitate the topological importance of individual amino acid residues. Mutation of residues at important network positions disproportionately impaired viral replication and occurred with high frequency in epitopes presented by protective human leukocyte antigen () class I alleles. Moreover, CD8 T cell targeting of highly networked epitopes distinguished individuals who naturally control HIV, even in the absence of protective alleles. This approach thereby provides a mechanistic basis for immune control and a means to identify CD8 T cell epitopes of topological importance for rational immunogen design, including a T cell-based HIV vaccine.
变异性病原体的突变限制表位是疫苗设计的有前途的靶点，但不能通过序列保守性可靠地识别。在这项研究中，我们采用了基于结构的网络分析，该方法将网络理论应用于 HIV 蛋白结构数据，以定量个体氨基酸残基的拓扑重要性。在重要网络位置发生突变的残基会不成比例地损害病毒复制，并且在保护性人类白细胞抗原 (HLA) 类 I 等位基因呈递的表位中高频发生。此外，高度网络化表位的 CD8 T 细胞靶向可以区分自然控制 HIV 的个体，即使没有保护性 HLA 等位基因也是如此。这种方法为免疫控制提供了机制基础，并为确定对合理免疫原设计具有拓扑重要性的 CD8 T 细胞表位提供了一种手段，包括基于 T 细胞的 HIV 疫苗。
