Instituto Biofisika (CSIC, UPV/EHU) and Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), PO Box 644, 48080 Bilbao, Spain.
Department of Physiology, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad, 7, 01006 Vitoria-Gasteiz, Spain; Bioaraba, Microbiology, Infectious Disease, Antimicrobial Agents, and Gene Therapy, 01006 Vitoria-Gasteiz, Spain.
Biochim Biophys Acta Biomembr. 2024 Jan;1866(1):184235. doi: 10.1016/j.bbamem.2023.184235. Epub 2023 Oct 2.
The fusion peptide (FP) and the Trp-rich membrane proximal external region (MPER) display membrane activity during HIV-1 fusion. These domains are highly conserved in the envelope glycoprotein (Env) and, consequently, antibodies targeting these regions block entry of divergent HIV strains and isolates into target cells. With the aim of recovering concurrent responses against the membrane-active Env domains, we have produced hybrid peptides that connect FP and MPER sequences via flexible aminohexanoic acid tethers, and tested their potential as immunogens. We demonstrate that liposome-based formulations containing FP-MPER hybrid peptides could elicit in rabbits, antibodies with the binding sequence specificity of neutralizing antibodies that engage with the N-terminal MPER sub-region. Determination of the thermodynamic parameters of binding using the Fab 2F5 as an N-terminal MPER antibody model, revealed that the hydrophobic interaction surface for epitope engagement appears to be optimal in the FP-MPER hybrid. In general, our data support: i) the use of liposomes as carriers for membrane active peptides; ii) the capacity of these liposome-based vaccines to focus humoral responses to N-terminal MPER epitopes; and iii) the need to include lipid membranes in immunogens to elicit such specific responses.
融合肽（FP）和富含色氨酸的膜近端外部区域（MPER）在 HIV-1 融合过程中显示出膜活性。这些结构域在包膜糖蛋白（Env）中高度保守，因此，针对这些区域的抗体可以阻止不同的 HIV 株和分离株进入靶细胞。为了恢复对膜活性 Env 结构域的同时反应，我们已经产生了通过柔性氨基己酸连接物连接 FP 和 MPER 序列的杂合肽，并测试了它们作为免疫原的潜力。我们证明，含有 FP-MPER 杂合肽的脂质体制剂可以在兔子中引发具有与结合 N 末端 MPER 亚区的中和抗体相同的结合序列特异性的抗体。使用 Fab 2F5 作为 N 末端 MPER 抗体模型来确定结合的热力学参数，结果表明，用于表位结合的疏水性相互作用表面在 FP-MPER 杂合中似乎是最佳的。总的来说，我们的数据支持：i）脂质体作为膜活性肽载体的使用；ii）这些基于脂质体的疫苗将体液反应聚焦于 N 末端 MPER 表位的能力；iii）需要在免疫原中包含脂质膜来引发这种特异性反应。
