非人类灵长类动物的疫苗接种引发了针对HIV-1 Env三聚体上四表位的广泛中和抗体谱系，这一成果由Richard T. Wyatt小组经过不懈努力而取得。2025年5月7日出版的《免疫学》发表了这项成果。

研究小组用一系列接近天然的三聚体免疫先前经过Env免疫的非人灵长类动物，这些三聚体在保守的CD4结合位点（CD4bs）附近具有N-聚糖缺失，从而将B细胞聚焦到该区域。在用完全糖基化的三聚体增强异源蛋白后，课题组研究人员在几种动物的血清中检测到二级交叉中和活性。从早期应答者的Env结合记忆B细胞中分离出185个匹配的重链和轻链序列，确定了一个广泛中和的抗体谱系LJF-0034，它中和了84个HIV-1全球小组中近70%的成员。高分辨率冷冻电镜（cryo-EM）结构显示了一种分叉的结合模式，该模式通过两个相邻原蛋白的gp120:120界面将CD4bs桥接到V3，避免了近端N276聚糖对CD4bs的阻碍，从而允许中和宽度。这种四元表位确定了未来HIV-1疫苗开发的潜在靶标。

据介绍，通过疫苗接种引发HIV-1包膜糖蛋白（Env）交叉中和抗体仍然是一个主要挑战。

附：英文原文

Title: Vaccination of nonhuman primates elicits a broadly neutralizing antibody lineage targeting a quaternary epitope on the HIV-1 Env trimer

Author: Fabian-Alexander Schleich, Shridhar Bale, Javier Guenaga, Gabriel Ozorowski, Monika àdori, Xiaohe Lin, Xaquin Castro Dopico, Richard Wilson, Mark Chernyshev, Alma Teresia Cotgreave, Marco Mandolesi, Jocelyn Cluff, Esmeralda D. Doyle, Leigh M. Sewall, Wen-Hsin Lee, Shiyu Zhang, Sijy O’Dell, Brandon S. Healy, Deuk Lim, Vanessa R. Lewis, Elana Ben-Akiva, Darrell J. Irvine, Nicole A. Doria-Rose, Martin Corcoran, Diane Carnathan, Guido Silvestri, Ian A. Wilson, Andrew B. Ward, Gunilla B. Karlsson Hedestam, Richard T. Wyatt

Issue&Volume: 2025-05-07

Abstract: The elicitation of cross-neutralizing antibodies to the HIV-1 envelope glycoprotein (Env) by vaccination remains a major challenge. Here, we immunized previously Env-immunized nonhuman primates with a series of near-native trimers that possessed N-glycan deletions proximal to the conserved CD4 binding site (CD4bs) to focus B cells to this region. Following heterologous boosting with fully glycosylated trimers, we detected tier 2 cross-neutralizing activity in the serum of several animals. Isolation of 185 matched heavy- and light-chain sequences from Env-binding memory B cells from an early responder identified a broadly neutralizing antibody lineage, LJF-0034, which neutralized nearly 70% of an 84-member HIV-1 global panel. High-resolution cryoelectron microscopy (cryo-EM) structures revealed a bifurcated binding mode that bridged the CD4bs to V3 across the gp120:120 interface on two adjacent protomers, evading the proximal N276 glycan impediment to the CD4bs, allowing neutralization breadth. This quaternary epitope defines a potential target for future HIV-1 vaccine development.

DOI: 10.1016/j.immuni.2025.04.010

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00173-6