JCI：对抗体重新改造来控制HIV传播

  近日，一篇发表于国际杂志The Journal of Clinical Investigation上的研究论文中，来自范德堡大学的研究人员在一种名为Rosetta的计算机程序的帮助下，重新设计了一种可增加潜能的抗体，相比天然抗体而言，这种抗体可以中和许多引发AIDS的HIV毒株；研究者表示，这种基于计算机程序重新设计的抗体或可加速HIV有效疗法或者疫苗的开发。
  研究者James Crowe表示，目前我们已经开始从HIV感染患者机体的血液中分离出了亲本的抗体，在实验室检测中这种亲本抗体具有较强的能力来中和HIV；随后研究者利用Rosetta计算机程序，其可以预测蛋白质氨基酸序列的结构，并且对抗体进行重新设计修饰，通过改变单一的氨基酸，研究者就可以增强结合HIV包膜蛋白的抗体的稳定性。
  通过改变单一的氨基酸，研究者就可以制造出具有四倍潜能和活性的“更新版”的抗体，相比亲本抗体而言，其可以杀灭更多的HIV；原始的分离的抗体就可以通过单一克隆的免疫细胞进行大量生产，随后就可以源源不断产生单克隆抗体，目前这种重新设计的抗体已经进入了临床试验阶段。
  早在2013年，来自斯克利普斯研究所的研究人员就在Science上刊文，他们利用晶体学和低温电子显微检查技术解析了HIV的包膜蛋白的结构，而如今研究者们可以更加深入地理解这种包膜蛋白的结构，并以其作为靶点开发新型的疗法。Crowe指出，如果计算机设计可以在未来预测病毒的外膜结构，那么我们就将可以在病毒爆发之前设计出新型的抗体及疫苗。（转化医学网360zhyx.com）
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Redesigned HIV antibodies exhibit enhanced neutralizing potency and breadth
JCI doi:10.1172/JCI80693
Jordan R. Willis1,2,3, Gopal Sapparapu3, Sasha Murrell4, Jean-Philippe Julien4, Vidisha Singh3, Hannah G. King3, Yan Xia5,6, Jennifer A. Pickens3, Celia C. LaBranche7, James C. Slaughter6, David C. Montefiori7, Ian A. Wilson4, Jens Meiler2,5,8, and James E. Crowe Jr.3,9,10
Several HIV envelope-targeting (Env-targeting) antibodies with broad and potent neutralizing activity have been identified and shown to have unusual features. Of these, the PG9 antibody has a long heavy chain complementarity determining region 3 (HCDR3) and possesses unique structural elements that interact with protein and glycan features of the HIV Env glycoprotein. Here, we used the Rosetta software suite to design variants of the PG9 antibody HCDR3 loop with the goal of identifying variants with increased potency and breadth of neutralization for diverse HIV strains. One variant, designated PG9_N100FY, possessed increased potency and was able to neutralize a diverse set of PG9-resistant HIV strains, including those lacking the Env N160 glycan, which is critical for PG9 binding. An atomic resolution structure of the PG9_N100FY fragment antigen binding (Fab) confirmed that the mutated residue retains the paratope surface when compared with WT PG9. Differential scanning calorimetry experiments revealed that the mutation caused a modest increase in thermodynamic stability of the Fab, a feature predicted by the computational model. Our findings suggest that thermodynamic stabilization of the long HCDR3 in its active conformation is responsible for the increased potency of PG9_N100FY, and strategies aimed at stabilizing this region in other HIV antibodies could become an important approach to in silico optimization of antibodies.