病毒性感染的预防和有效的抗原设计是全球公共卫生领域所面临的挑战。HIV-1病毒表面的抗原蛋白Env通过序列的突变与糖基化保护层来逃离人体免疫系统的识别，造成了HIV-1疫苗设计中的主要困难。基于结构的理性抗原设计可以将机体的免疫应答导向特定的表位结构，从而提高相应中和抗体的特异性。针对HIV-1 Env的结构特点，我们通过结构片段嫁接的方法设计与表达两类新型抗原：（1）基于糖基孔表位的CONE抗原；（2）基于广谱中和抗体1-18的保守表位抗原。理性设计的抗原具有分子量小、热稳定性高、易表达等特点。本项目结合了计算机辅助的蛋白质设计、分子动力学模拟、生物化学与结构生物学等手段，对设计的蛋白进行生物物理性质与免疫能力的表征，为新型抗原的开发提供可靠的手段。

The prevention of viral infections and design of effective immunogens are major challenges for global public health. The HIV-1 surface protein Env escapes humoral immune system recognition through mutagenesis and a layer of glycosylation sites; hence, it is a major hurdle for developing HIV-1 vaccines. Structure-based rational immunogen design can direct the immunological response toward specific epitopes, elevating the specificity of corresponding neutralizing antibodies. In the current project, we will design two kinds of novel HIV-1 immunogens through fragment grafting, using newly identified epitopes from glycan holes (CONE) and conserved epitopes from broadly neutralizing antibody (1-18). The rationally designed immungoens are small, easy to be produced in large amounts, and thermodynamically stable. We will combine techniques of computational protein design, molecular dynamics simulation, biochemistry, and structural biology, to characterize the biophysical and immunological properties of designed proteins, and provide robust methods for developing novel immunogens.