HIV包膜表位富集及联合免疫诱导抗体回忆反应及机制研究

Researchers have understood that effective immunity of preventive HIV vaccines need neutralizing antibodies according to HIV vaccine clinical trials and animal studies. However, it is difficult to induce such antibodies and effective protection by immunization with HIV envelope. To date, the effects of antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell phagocytosis (ADCP) which induced by HIV accine are also unclear. The design of envelope immunogens is a big challenge in the field of HIV vaccine research in the world. The progression in HIV vaccine research in China is significant slow compared with that in developed countries. The International AIDS Vaccine Initiative（IAVI） database shows that hundreds of HIV vaccine clinical trials have been completed. Among them, only three have been conducted by China. We have been working on HIV envelope immunogen screening and immune mechanism research. We found the profiles of neutralizing antibodies of Chinese HIV infected individuals and the characteristics of HIV envelope mutations. Some envelope antigens from Chinese broad neutralizers and representing the locally prevalent subtypes in China have been isolated and the envelope immunogenicity has been studied. We have found that HIV envelope induced poor immune memories and immune presentation in animal. Meanwhile, we also designed novel epitope presenting virus-like particle (VLP). In the present study, we will focus on the immunogenicity of the new antigens, the induction of neutralizing antibodies and ADCC, as well as the molecular and cellular mechanisms. The present study will provide new candidate immunogens for further HIV vaccine preclinical study and the insights into development of new HIV vaccines.

有效疫苗需要中和抗体。但HIV疫苗临床试验以及动物实验结果表明，包膜正向免疫很难获得有效交叉中和及免疫保护；疫苗诱导的抗体介导的细胞毒（ADCC）和吞噬（ADCP）的作用也不清楚。包膜免疫原设计是世界上HIV疫苗研究领域最核心问题。但我国疫苗研究相对发达国家显著滞后。国际疫苗行动组织（IAVI）数据库中数百个临床试验HIV疫苗中，只有三个是中国疫苗。本课题组一直进行HIV包膜免疫原筛选及免疫机制研究。发现了我国感染者中和抗体及病毒包膜变异特征；从广谱中和者获得了我国流行亚型包膜；研究了筛选到的包膜的免疫原性；发现了包膜免疫诱导免疫呈递及免疫记忆不良等特征；同时，前期还设计了富集包膜广谱中和表位的新型病毒样颗粒（VLP）。本研究将依据前期发现，重点研究新设计的抗原诱导交叉中和抗体及ADCC作用以及免疫的细胞和分子机制。为获得下一步临床前研究候选免疫原及构建新型免疫原提供理论、实验和物质基础。

有效疫苗需要中和抗体。但HIV疫苗临床试验以及动物实验结果表明，包膜正向免疫很难获得有效交叉中和及免疫保护；包膜免疫原设计是世界上HIV疫苗研究领域最核心问题。本研究在前期发现的基础上，首先设计富集V1V2广谱中和表位的VLP。根据能够自组装VLP的蛋白载体特征，将HIV包膜V1V2区插入其中构建VLP，V1/V2呈现某种构象，并暴露于VLP 表面。继而研究体液免疫效果，探讨佐剂应用以及不同免疫策略对体液免疫的影响。第三，探讨诱导免疫记忆的机制。为获得下一步临床前研究候选免疫原及构建新型免疫原提供理论、实验和物质基础。完成了课题预期主要目标：①一定程度上明确了良好免疫原及免疫策略诱导B 细胞免疫记忆的细胞学机制；明确了佐剂（Addavax）应用的新策略及诱导体液免疫及免疫记忆的机制；验证了本项目提出的研究假设，为今后修饰免疫原获得良好的诱导广谱中和抗体免疫原奠定理论基础；②获得了一系列新型免疫原、获得良好免疫策略；③已经发表SCI文章2 篇，在投1篇，待总结文章一篇以上；采用GCE技术构建定点标记HIV包膜糖蛋白拟申请专利一项；总结前期及本项目成果，获得了省级科学技术成果奖一项；④培养博硕士研究生8人。在蛋白质结构和功能研究、免疫学研究、疫苗学研究领域的人才和队伍进一步成熟。