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

Immunity 2021 Feb 09

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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. Copyright © 2020 Elsevier Inc. All rights reserved.

Citation

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. Vaccination induces maturation in a mouse model of diverse unmutated VRC01-class precursors to HIV-neutralizing antibodies with >50% breadth. Immunity. 2021 Feb 09;54(2):324-339.e8