Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA.
Immunity. 2021 Feb 9;54(2):324-339.e8. doi: 10.1016/j.immuni.2020.12.014. Epub 2021 Jan 15.
Vaccine elicitation of broadly neutralizing antibodies (bnAbs) is a key HIV-research goal. The VRC01 class of bnAbs targets the CD4-binding site on the HIV-envelope trimer and requires extensive somatic hypermutation (SHM) to neutralize effectively. Despite substantial progress, vaccine-induced VRC01-class antibodies starting from unmutated precursors have exhibited limited neutralization breadth, particularly against viruses bearing glycan on loop D residue N276 (glycan276), present on most circulating strains. Here, using sequential immunization of immunoglobulin (Ig)-humanized mice expressing diverse unmutated VRC01-class antibody precursors, we elicited serum responses capable of neutralizing viruses bearing glycan276 and isolated multiple lineages of VRC01-class bnAbs, including two with >50% breadth on a 208-strain panel. Crystal structures of representative bnAbs revealed the same mode of recognition as known VRC01-class bnAbs. Structure-function studies further pinpointed key mutations and correlated their induction with specific immunizations. VRC01-class bnAbs can thus be matured by sequential immunization from unmutated ancestors to >50% breadth, and we delineate immunogens and regimens inducing key SHM.
疫苗引发广泛中和抗体（bnAbs）是 HIV 研究的一个关键目标。VRC01 类 bnAbs 靶向 HIV 包膜三聚体上的 CD4 结合位点，需要广泛的体细胞超突变（SHM）才能有效中和。尽管取得了很大进展，但从未突变的前体开始诱导的疫苗产生的 VRC01 类抗体表现出有限的中和广度，特别是针对具有 loop D 残基 N276 上糖基（glycan276）的病毒，该糖基存在于大多数循环株中。在这里，我们使用表达不同未突变 VRC01 类抗体前体的人源化免疫球蛋白（Ig）小鼠的序贯免疫，引发了能够中和具有 glycan276 的病毒的血清反应，并分离出多种 VRC01 类 bnAbs 谱系，其中包括两种在 208 株面板上具有 >50%广度的 bnAbs。代表性 bnAbs 的晶体结构揭示了与已知 VRC01 类 bnAbs 相同的识别模式。结构功能研究进一步确定了关键突变，并将其诱导与特定免疫相关联。因此，VRC01 类 bnAbs 可以通过从未突变的祖先进行序贯免疫来成熟到 >50%的广度，我们描绘了诱导关键 SHM 的免疫原和方案。
