Barnes Christopher O, Schoofs Till, Gnanapragasam Priyanthi N P, Golijanin Jovana, Huey-Tubman Kathryn E, Gruell Henning, Schommers Philipp, Suh-Toma Nina, Lee Yu Erica, Cetrulo Lorenzi Julio C, Piechocka-Trocha Alicja, Scheid Johannes F, West Anthony P, Walker Bruce D, Seaman Michael S, Klein Florian, Nussenzweig Michel C, Bjorkman Pamela J
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
Sci Adv. 2022 Aug 12;8(32):eabp8155. doi: 10.1126/sciadv.abp8155.
The induction of broadly neutralizing antibodies (bNAbs) is a potential strategy for a vaccine against HIV-1. However, most bNAbs exhibit features such as unusually high somatic hypermutation, including insertions and deletions, which make their induction challenging. VRC01-class bNAbs not only exhibit extraordinary breadth and potency but also rank among the most highly somatically mutated bNAbs. Here, we describe a VRC01-class antibody isolated from a viremic controller, BG24, that is much less mutated than most relatives of its class while achieving comparable breadth and potency. A 3.8-Å x-ray crystal structure of a BG24-BG505 Env trimer complex revealed conserved contacts at the gp120 interface characteristic of the VRC01-class Abs, despite lacking common CDR3 sequence motifs. The existence of moderately mutated CD4-binding site (CD4bs) bNAbs such as BG24 provides a simpler blueprint for CD4bs antibody induction by a vaccine, raising the prospect that such an induction might be feasible with a germline-targeting approach.
诱导广泛中和抗体（bNAbs）是开发抗HIV-1疫苗的一种潜在策略。然而，大多数bNAbs表现出如异常高的体细胞超突变等特征，包括插入和缺失，这使得它们的诱导具有挑战性。VRC01类bNAbs不仅具有非凡的广度和效力，而且是体细胞突变程度最高的bNAbs之一。在此，我们描述了一种从病毒血症控制者BG24中分离出的VRC01类抗体，其突变程度远低于该类别的大多数亲属，同时具有相当的广度和效力。BG24-BG505 Env三聚体复合物的3.8埃X射线晶体结构显示，尽管缺乏常见的互补决定区3（CDR3）序列基序，但在gp120界面处存在VRC01类抗体特有的保守接触。像BG24这样的中度突变的CD4结合位点（CD4bs）bNAbs的存在为通过疫苗诱导CD4bs抗体提供了一个更简单的蓝图，增加了通过靶向种系方法实现这种诱导的可能性。
