2019年11月12日，美国斯克里普斯研究所Richard T. Wyatt研究小组在《免疫》发表论文。他们发现用聚糖修饰的HIV NFL衣壳三聚体-脂质体能够引起多个位点的广泛中和抗体。

研究人员表示，引起针对HIV-1包膜糖蛋白（Env）三聚体的广泛中和抗体（bNAb）仍然是重大的疫苗挑战。大多数交叉保守的蛋白质决定簇被自身N-聚糖掩盖所封闭，从而限制了B细胞对潜在多肽表面的识别。聚糖掩盖的例外包括保守的受体CD4结合位点（CD4bs）和靠近弗林蛋白酶切割位点的糖蛋白（gp）41元件。

研究人员在兔中进行了异源三聚体脂质体活化：增强以驱动对交叉保守位点特异的B细胞。为了优先将CD4bs暴露于B细胞，研究人员去除了近端N-聚糖，同时保持了不依赖于切除的NFL三聚体的天然状态，然后逐步进行N-聚糖还原和异源增强。这种方法成功地诱导了CD4bs定向、交叉中和的Abs，包括一个靶向独特聚糖蛋白抗原决定簇的抗体和一个指向gp120与gp41界面的bNAb（广度为87％），这些结构均通过高分辨率冷冻电镜得以解析。这项研究提供了通过疫苗接种引发bNAb免疫原性的理论证明。

附：英文原文

Title: Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability

Author: Viktoriya Dubrovskaya, Karen Tran, Gabriel Ozorowski, Javier Guenaga, Richard Wilson, Shridhar Bale, Christopher A. Cottrell, Hannah L. Turner, Gemma Seabright, Sijy O’Dell, Jonathan L. Torres, Lifei Yang, Yu Feng, Daniel P. Leaman, Néstor Vázquez Bernat, Tyler Liban, Mark Louder, Krisha McKee, Robert T. Bailer, Arlette Movsesyan, Nicole A. Doria-Rose, Marie Pancera, Gunilla B. Karlsson Hedestam, Michael B. Zwick, Max Crispin, John R. Mascola, Andrew B. Ward, Richard T. Wyatt

Issue&Volume: November 12, 2019

Abstract: The elicitation of broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer remains a major vaccine challenge. Most cross-conserved protein determinants are occluded by self-N-glycan shielding, limiting B cell recognition of the underlying polypeptide surface. The exceptions to the contiguous glycan shield include the conserved receptor CD4 binding site (CD4bs) and glycoprotein (gp)41 elements proximal to the furin cleavage site. Accordingly, we performed heterologous trimer-liposome prime:boosting in rabbits to drive B cells specific for cross-conserved sites. To preferentially expose the CD4bs to B cells, we eliminated proximal N-glycans while maintaining the native-like state of the cleavage-independent NFL trimers, followed by gradual N-glycan restoration coupled with heterologous boosting. This approach successfully elicited CD4bs-directed, cross-neutralizing Abs, including one targeting a unique glycan-protein epitope and a bNAb (87% breadth) directed to the gp120:gp41 interface, both resolved by high-resolution cryoelectron microscopy. This study provides proof-of-principle immunogenicity toward eliciting bNAbs by vaccination.

DOI: 10.1016/j.immuni.2019.10.008

Source: https://www.cell.com/immunity/fulltext/S1074-7613(19)30452-2