美国国立卫生研究院Peter D. Kwong团队近期取得重要工作进展，他们研究发现，在以融合肽为前体的SHIV感染猕猴体内存在强效、广泛的HIV-1中和作用。相关研究成果2024年10月28日在线发表于《细胞》杂志上。
据介绍，基于抗体的HIV-1疫苗需要诱导强效的交叉反应性HIV-1中和反应。
为了证明实现这一目标的可行性，研究人员将针对脆弱融合肽位点的疫苗接种，与猿猴人类免疫缺陷病毒（SHIV）感染相结合。在四只具有疫苗诱导的中和反应的猕猴中，SHIV感染在208菌株组上将血浆中和率提高到45%-77%（几何平均50%抑制稀释[ID50]≈100）。
通过抗体分离和冷冻电镜（cryo-EM）结构测定对这些反应进行分子解剖，研究人员发现16个抗体谱系中有15个具有交叉分支中和，指向融合肽易损位点。
在每只猕猴中，来自记忆B细胞的分离抗体再现了血浆中和反应，融合肽结合抗体的宽度达到40%-60%（50%抑制浓度[IC50]<50μg/mL），总谱系浓度估计为50-200μg/mL。纵向图谱表明，这些反应发生在SHIV感染之前。
总之，这一研究为一到几个B细胞谱系，提供了强有力的、广泛中和的血浆反应的体内分子例子。
附：英文原文
Title: Potent and broad HIV-1 neutralization in fusion peptide-primed SHIV-infected macaques
Author: Hua Wang, Cheng Cheng, James L. Dal Santo, Chen-Hsiang Shen, Tatsiana Bylund, Amy R. Henry, Colin A. Howe, Juyun Hwang, Nicholas C. Morano, Daniel J. Morris, Sergei Pletnev, Ryan S. Roark, Tongqing Zhou, Bryan T. Hansen, Forrest H. Hoyt, Timothy S. Johnston, Shuyi Wang, Baoshan Zhang, David R. Ambrozak, Jordan E. Becker, Michael F. Bender, Anita Changela, Ridhi Chaudhary, Martin Corcoran, Angela R. Corrigan, Kathryn E. Foulds, Yicheng Guo, Myungjin Lee, Yingying Li, Bob C. Lin, Tracy Liu, Mark K. Louder, Marco Mandolesi, Rosemarie D. Mason, Krisha McKee, Vinod Nair, Sijy O’Dell, Adam S. Olia, Li Ou, Amarendra Pegu, Nagarajan Raju, Reda Rawi, Jesmine Roberts-Torres, Edward K. Sarfo, Mallika Sastry, Andrew J. Schaub, Stephen D. Schmidt, Chaim A. Schramm, Cindi L. Schwartz, Sarah C. Smith, Tyler Stephens, Jonathan Stuckey, I-Ting Teng, John-Paul Todd, Yaroslav Tsybovsky, David J. Van Wazer, Shuishu Wang, Nicole A. Doria-Rose, Elizabeth R. Fischer, Ivelin S. Georgiev, Gunilla B. Karlsson Hedestam, Zizhang Sheng, Ruth A. Woodward, Daniel C. Douek, Richard A. Koup, Theodore C. Pierson, Lawrence Shapiro, George M. Shaw, John R. Mascola, Peter D. Kwong
Issue&Volume: 2024-10-28
Abstract: An antibody-based HIV-1 vaccine will require the induction of potent cross-reactive HIV-1-neutralizing responses. To demonstrate feasibility toward this goal, we combined vaccination targeting the fusion-peptide site of vulnerability with infection by simian-human immunodeficiency virus (SHIV). In four macaques with vaccine-induced neutralizing responses, SHIV infection boosted plasma neutralization to 45%–77% breadth (geometric mean 50% inhibitory dilution [ID50] ～100) on a 208-strain panel. Molecular dissection of these responses by antibody isolation and cryo-electron microscopy (cryo-EM) structure determination revealed 15 of 16 antibody lineages with cross-clade neutralization to be directed toward the fusion-peptide site of vulnerability. In each macaque, isolated antibodies from memory B cells recapitulated the plasma-neutralizing response, with fusion-peptide-binding antibodies reaching breadths of 40%–60% (50% inhibitory concentration [IC50] < 50 μg/mL) and total lineage-concentrations estimates of 50–200 μg/mL. Longitudinal mapping indicated that these responses arose prior to SHIV infection. Collectively, these results provide in vivo molecular examples for one to a few B cell lineages affording potent, broadly neutralizing plasma responses.
DOI: 10.1016/j.cell.2024.10.003
Source: https://www.cell.com/cell/abstract/S0092-8674(24)01151-6