美国国立卫生研究院John R. Mascola、Peter D. Kwong等研究人员合作发现，新疫苗可在小鼠模型中诱导广谱HIV中和抗体。这一研究成果于2021年1月15日在线发表在国际学术期刊《免疫学上。

据研究人员介绍，广谱中和抗体（bnAbs）的疫苗诱导是一项重要的HIV研究目标。VRC01类bnAb靶向HIV包膜三聚体上的CD4结合位点，这需要大量的体细胞超突变（SHM）才能有效地中和。尽管取得了重大进展，但从未突变前体开始的VRC01类抗体显示出有限的中和广度，特别是针对大多数循环毒株中存在于D环残基N276上带有聚糖的病毒（glycan276）。

通过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，研究人员引发了能够中和带有glycan276病毒的血清反应，并分离了多个VRC01类bnAb谱系，包括两个谱系，其涵盖超过208个毒株中的50％。代表性bnAb的晶体结构显示出与已知VRC01级bnAb相同的识别模式。结构功能研究进一步查明了关键突变，并且其诱导与特异性免疫相关。因此，VRC01类bnAb可以通过从未突变前体到大于50％广度的顺序免疫而成熟，并且研究人员描述了诱导关键SHM的免疫原和方案。

附：英文原文

Title: Vaccination induces maturation in a mouse model of diverse unmutated VRC01-class precursors to HIV-neutralizing antibodies with >50% breadth

Author: Xuejun Chen, Tongqing Zhou, Stephen D. Schmidt, Hongying Duan, Cheng Cheng, Gwo-Yu Chuang, Ying Gu, Mark K. Louder, Bob C. Lin, Chen-Hsiang Shen, Zizhang Sheng, Michelle X. Zheng, Nicole A. Doria-Rose, M. Gordon Joyce, Lawrence Shapiro, Ming Tian, Frederick W. Alt, Peter D. Kwong, John R. Mascola

Issue&Volume: 2021-01-15

Abstract: Vaccine elicitation of broadly neutralizing antibodies (bnAbs) is a key HIV-researchgoal. The VRC01 class of bnAbs targets the CD4-binding site on the HIV-envelope trimerand requires extensive somatic hypermutation (SHM) to neutralize effectively. Despitesubstantial progress, vaccine-induced VRC01-class antibodies starting from unmutatedprecursors have exhibited limited neutralization breadth, particularly against virusesbearing glycan on loop D residue N276 (glycan276), present on most circulating strains.Here, using sequential immunization of immunoglobulin (Ig)-humanized mice expressingdiverse unmutated VRC01-class antibody precursors, we elicited serum responses capableof neutralizing viruses bearing glycan276 and isolated multiple lineages of VRC01-classbnAbs, including two with >50% breadth on a 208-strain panel. Crystal structures ofrepresentative bnAbs revealed the same mode of recognition as known VRC01-class bnAbs.Structure-function studies further pinpointed key mutations and correlated their inductionwith specific immunizations. VRC01-class bnAbs can thus be matured by sequential immunizationfrom unmutated ancestors to >50% breadth, and we delineate immunogens and regimensinducing key SHM.

DOI: 10.1016/j.immuni.2020.12.014

Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30542-2