重组HIV包膜三聚体筛选出靶向三聚体顶端的四级依赖性抗体。

Recombinant HIV envelope trimer selects for quaternary-dependent antibodies targeting the trimer apex.

作者信息

Sok Devin, van Gils Marit J, Pauthner Matthias, Julien Jean-Philippe, Saye-Francisco Karen L, Hsueh Jessica, Briney Bryan, Lee Jeong Hyun, Le Khoa M, Lee Peter S, Hua Yuanzi, Seaman Michael S, Moore John P, Ward Andrew B, Wilson Ian A, Sanders Rogier W, Burton Dennis R

机构信息

Department of Immunology and Microbial Science, International AIDS Vaccine Initiative Neutralizing Antibody Center, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, International AIDS Vaccine Initiative, New York, NY 10038;

Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;

出版信息

Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):17624-9. doi: 10.1073/pnas.1415789111. Epub 2014 Nov 24.

DOI:10.1073/pnas.1415789111

PMID:25422458

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4267403/

Abstract

Broadly neutralizing antibodies (bnAbs) targeting the trimer apex of HIV envelope are favored candidates for vaccine design and immunotherapy because of their great neutralization breadth and potency. However, methods of isolating bnAbs against this site have been limited by the quaternary nature of the epitope region. Here we report the use of a recombinant HIV envelope trimer, BG505 SOSIP.664 gp140, as an affinity reagent to isolate quaternary-dependent bnAbs from the peripheral blood mononuclear cells of a chronically infected donor. The newly isolated bnAbs, named "PGDM1400-1412," show a wide range of neutralization breadth and potency. One of these variants, PGDM1400, is exceptionally broad and potent with cross-clade neutralization coverage of 83% at a median IC50 of 0.003 µg/mL. Overall, our results highlight the utility of BG505 SOSIP.664 gp140 as a tool for the isolation of quaternary-dependent antibodies and reveal a mosaic of antibody responses against the trimer apex within a clonal family.

摘要

由于具有广泛的中和广度和效力，靶向HIV包膜三聚体顶端的广泛中和抗体（bnAbs）是疫苗设计和免疫治疗的理想候选者。然而，针对该位点分离bnAbs的方法一直受到表位区域四级结构性质的限制。在此，我们报告使用重组HIV包膜三聚体BG505 SOSIP.664 gp140作为亲和试剂，从一名慢性感染供体的外周血单核细胞中分离四级依赖性bnAbs。新分离的bnAbs名为“PGDM1400 - 1412”，表现出广泛的中和广度和效力。其中一个变体PGDM1400异常广泛且有效，跨亚型中和覆盖率为83%，中位IC50为0.003 µg/mL。总体而言，我们的结果突出了BG505 SOSIP.664 gp140作为分离四级依赖性抗体工具的实用性，并揭示了一个克隆家族中针对三聚体顶端的抗体反应图谱。