Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):6049-54. doi: 10.1073/pnas.1303682110. Epub 2013 Mar 22.
Efforts to design an effective antibody-based vaccine against HIV-1 would benefit from understanding how germ-line B-cell receptors (BCRs) recognize the HIV-1 gp120/gp41 envelope spike. Potent VRC01-like (PVL) HIV-1 antibodies derived from the VH1-202 germ-line allele target the conserved CD4 binding site on gp120. A bottleneck for design of immunogens capable of eliciting PVL antibodies is that VH1-202 germ-line BCR interactions with gp120 are uncharacterized. Here, we report the structure of a VH1-202 germ-line antibody alone and a germ-line heavy-chain/mature light-chain chimeric antibody complexed with HIV-1 gp120. VH1-202 residues make extensive contacts with the gp120 outer domain, including all PVL signature and CD4 mimicry interactions, but not critical CDRH3 contacts with the gp120 inner domain and bridging sheet that are responsible for the improved potency of NIH45-46 over closely related clonal variants, such as VRC01. Our results provide insight into initial recognition of HIV-1 by VH1-2*02 germ-line BCRs and may facilitate the design of immunogens tailored to engage and stimulate broad and potent CD4 binding site antibodies.
为了设计出针对 HIV-1 的有效抗体疫苗，我们需要了解原始 B 细胞受体（BCR）如何识别 HIV-1 的 gp120/gp41 包膜刺突。源自 VH1-202 原始 BCR 等位基因的强效 VRC01 样（PVL）HIV-1 抗体靶向 gp120 上的保守 CD4 结合位点。设计能够引发 PVL 抗体的免疫原的一个瓶颈是，VH1-202 原始 BCR 与 gp120 的相互作用尚未得到充分研究。在这里，我们报告了一个 VH1-202 原始抗体和一个原始重链/成熟轻链嵌合抗体与 HIV-1 gp120 复合物的结构。VH1-202 残基与 gp120 外域广泛接触，包括所有 PVL 特征和 CD4 模拟相互作用，但不包括与 gp120 内域和桥接片的关键 CDRH3 接触，这些接触负责 NIH45-46 比密切相关的克隆变体（如 VRC01）具有更高的效力。我们的结果提供了对 VH1-2*02 原始 BCR 最初识别 HIV-1 的深入了解，并可能有助于设计针对 CD4 结合位点的广泛而有效的抗体的免疫原。
