现有的靶向HIV-1包膜蛋白的中和单克隆抗体均靶向gp120和gp41表面暴露的抗原位点，这些位点突变易产生中和抗体逃逸株。HIV-1 gp41 NHR三聚体的口袋区非常保守，且只在病毒发生融合时瞬间暴露，是一个研发广谱单抗的理想靶点。但由于瞬时暴露所造成的空间位阻和动力学障碍，完整的抗体分子很难进入该靶点发挥作用。因此，我们拟构建模拟NHR三聚体的抗原，对本室拥有的超大型全人源纳米抗体（HnAb）库进行筛选，期望获得具有广谱HIV中和活性的小分子量HnAb，并使用抗体-药物偶联策略将HnAb与靶向gp120高保守区的CD4单域（mD1）分子和可溶解HIV感染细胞膜的溶膜素（LP）共价连接形成三功能生物大分子（mD1-HnAb-LP）。它既可抑制HIV感染，又可杀灭HIV感染细胞和被激活的HIV潜伏感染的细胞，可清除病毒潜伏库。 因此，本课题研究为艾滋病的治疗尤其是功能性治愈提供了新的方向

The currently available HIV-1 neutralizing monoclonal antibodies (nmAbs) mainly target the epitopes on gp120 surface (e.g., CD4 binding site, CD4-induced epitope, high-mannose oligosaccharides) or that of gp41 (e.g., membrane-proximal external region), which are susceptible to mutations with resistance to these nmAbs. The highly conserved pocket in the HIV-1 gp41 NHR-trimer with transit exposure for a very short period of time during the virus-cell fusion is an ideal target for the development of broad-spectrum nmAbs. However, the whole antibody IgG molecule (~ 150kD) is too big to access to this target site because of the Steric and kinetic barriers. Here, we intend to construct gp41 NHR-trimer antigens and use them to screen our established extremely large human nanobody (HnAb) library for obtaining broad-spectrum HIV neutralizing HnAbs with small molecular weight (~ 15kD). Next, we will use antibody-drug conjugate strategies to link HnAb with a single CD4 domain (mD1) and a cell membrane-lytic peptide (LP). This three-specific anti-HIV molecule (mD1-HnAb-LP) is expected to attack HIV with three hits at once, which not only inhibits HIV infection and inactivates HIV virions, but also kill HIV-infected cells and the activated latent HIV-infected cells, thus accelerating HIV latent library cleared achieve functional HIV cure purposes. Therefore, the present study will open a new avenue for developing strategies for AIDS treatment and HIV cure.