当前位置: X-MOL 学术Immunity › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Vaccination induces maturation in a mouse model of diverse unmutated VRC01-class precursors to HIV-neutralizing antibodies with >50% breadth
Immunity ( IF 32.4 ) Pub Date : 2021-01-15 , DOI: 10.1016/j.immuni.2020.12.014
Xuejun Chen 1 , Tongqing Zhou 1 , Stephen D Schmidt 1 , Hongying Duan 1 , Cheng Cheng 1 , Gwo-Yu Chuang 1 , Ying Gu 1 , Mark K Louder 1 , Bob C Lin 1 , Chen-Hsiang Shen 1 , Zizhang Sheng 2 , Michelle X Zheng 1 , Nicole A Doria-Rose 1 , M Gordon Joyce 3 , Lawrence Shapiro 4 , Ming Tian 5 , Frederick W Alt 5 , Peter D Kwong 6 , John R Mascola 1
Affiliation  

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.



中文翻译:

疫苗接种诱导小鼠模型成熟,其中多种未突变的 VRC01 类前体可形成具有 > 50% 宽度的 HIV 中和抗体

广泛中和抗体 (bnAbs) 的疫苗诱导是 HIV 研究的一个关键目标。VRC01 类 bnAb 靶向 HIV 包膜三聚体上的 CD4 结合位点,需要大量的体细胞超突变 (SHM) 才能有效中和。尽管取得了实质性进展,但从未突变前体开始的疫苗诱导的 VRC01 类抗体表现出有限的中和广度,特别是针对大多数循环毒株中存在的环 D 残基 N276 (glycan276) 上带有聚糖的病毒。在这里,使用表达多种未突变 VRC01 类抗体前体的免疫球蛋白 (Ig) 人源化小鼠的顺序免疫,我们引发了能够中和带有聚糖 276 的病毒的血清反应,并分离出多个 VRC01 类 bnAb 谱系,包括两个在一个 208 应变面板。代表性 bnAb 的晶体结构显示出与已知的 VRC01 类 bnAb 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。VRC01 类 bnAb 因此可以通过从未突变祖先到 > 50% 广度的顺序免疫来成熟,我们描述了诱导关键 SHM 的免疫原和方案。

更新日期:2021-02-09
down
wechat
bug