Schleich Fabian-Alexander, Bale Shridhar, Guenaga Javier, Ozorowski Gabriel, Àdori Monika, Lin Xiaohe, Castro Dopico Xaquin, Wilson Richard, Chernyshev Mark, Cotgreave Alma Teresia, Mandolesi Marco, Cluff Jocelyn, Doyle Esmeralda D, Sewall Leigh M, Lee Wen-Hsin, Zhang Shiyu, O'Dell Sijy, Healy Brandon S, Lim Deuk, Lewis Vanessa R, Ben-Akiva Elana, Irvine Darrell J, Doria-Rose Nicole A, Corcoran Martin, Carnathan Diane, Silvestri Guido, Wilson Ian A, Ward Andrew B, Karlsson Hedestam Gunilla B, Wyatt Richard T
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.
The Scripps Research Institute, Department of Immunology and Microbiology, La Jolla, CA, USA.
Immunity. 2025 Jun 10;58(6):1598-1613.e8. doi: 10.1016/j.immuni.2025.04.010. Epub 2025 May 7.
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.
通过疫苗接种诱导针对HIV-1包膜糖蛋白（Env）的交叉中和抗体仍然是一项重大挑战。在此，我们用一系列接近天然的三聚体对先前已接种Env的非人灵长类动物进行免疫，这些三聚体在保守的CD4结合位点（CD4bs）附近存在N-聚糖缺失，以使B细胞聚焦于该区域。在用完全糖基化的三聚体进行异源加强免疫后，我们在几只动物的血清中检测到2级交叉中和活性。从一名早期应答者的Env结合记忆B细胞中分离出185条匹配的重链和轻链序列，鉴定出一种广泛中和抗体谱系LJF-0034，它能中和84株HIV-1全球毒株组成的病毒库中近70%的毒株。高分辨率冷冻电子显微镜（cryo-EM）结构揭示了一种分叉结合模式，该模式通过两个相邻原聚体上的gp120:120界面将CD4bs与V3连接起来，避开了近端N276聚糖对CD4bs的阻碍，从而实现中和广度。这种四级表位为未来HIV-1疫苗开发定义了一个潜在靶点。
