Liu Chang-Cheng, Zhai Canjia, Zheng Xiu-Jing, Ye Xin-Shan
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University , Xue Yuan Rd No. 38, Beijing 100191, China.
ACS Chem Biol. 2016 Jun 17;11(6):1702-9. doi: 10.1021/acschembio.6b00224. Epub 2016 Apr 18.
Some conserved glycans on the HIV envelope protein are targets of broadly neutralizing antibodies (bnAbs) of HIV. BnAbs provide a precise definition of broadly neutralizing epitopes on the envelope protein of HIV. These epitopes are promising for vaccine design. Many glycan-related antigens with high affinity to bnAbs have been tested as immunogens in vivo. However, it was found that no bnAb-like antibodies were induced. Vaccination with different immunogens containing the same neutralizing epitope may enhance the affinity maturation of antibodies which focus on the shared epitope. This combined immunization strategy showed great potential in peptide epitope-based vaccine design. However, it has not yet been explored on glycan-related epitopes to date. Herein, we take 2G12 as a model to validate this strategy on glycan-related epitopes. A high-affinity antigen of 2G12 was constructed by conjugating the D1 arm tetramannoside to bovine serum albumin. Then, the glycoconjugate was coimmunized with a recombinant gp120, which was expected to selectively benefit the induction of antibodies recognizing the neutralizing epitope of 2G12 on gp120. Mice were inoculated with the two antigens simultaneously or alternately to determine the suitable regimen for this strategy. The serological assays demonstrated that the antibody titers and subtypes responded to the whole gp120 were not improved, and the proportion of antibodies competitively bound to the 2G12 epitope was not enhanced significantly either. However, the coimmunized glycoconjugate selectively raised the proportion of antibodies recognizing D1 arm tetramannoside-related structures on gp120. These results provide important experience for the design of glycan-dependent bnAb-based vaccines.
人类免疫缺陷病毒（HIV）包膜蛋白上的一些保守聚糖是HIV广泛中和抗体（bnAbs）的靶点。bnAbs精确界定了HIV包膜蛋白上的广泛中和表位。这些表位对疫苗设计很有前景。许多与聚糖相关且对bnAbs具有高亲和力的抗原已在体内作为免疫原进行了测试。然而，发现并未诱导出类似bnAb的抗体。用含有相同中和表位的不同免疫原进行疫苗接种可能会增强聚焦于该共享表位的抗体的亲和力成熟。这种联合免疫策略在基于肽表位的疫苗设计中显示出巨大潜力。然而，迄今为止尚未在与聚糖相关的表位上进行探索。在此，我们以2G12为模型，在与聚糖相关的表位上验证该策略。通过将D1臂四甘露糖苷与牛血清白蛋白偶联构建了2G12的高亲和力抗原。然后，将该糖缀合物与重组gp120共同免疫，预期这将选择性地有利于诱导识别gp120上2G12中和表位的抗体。同时或交替给小鼠接种这两种抗原，以确定该策略的合适方案。血清学检测表明，对整个gp120产生反应的抗体滴度和亚型并未提高，竞争性结合2G12表位的抗体比例也未显著增强。然而，共同免疫的糖缀合物选择性地提高了识别gp120上与D1臂四甘露糖苷相关结构的抗体比例。这些结果为基于聚糖依赖性bnAb的疫苗设计提供了重要经验。
